MXPA99003894A - Substituted arylalkylamines as neurokinin antagonists - Google Patents

Abstract

Compounds represented by structural formula (I) or a pharmaceutically acceptable salt thereof are disclosed, wherein:A1 is -CH2R6, -OR6, -N(R6)(R7), -S(O)eR13, -(C(R6)(R7))1-6-OR6, -(C(R6)(R7))1-6-N(R6)(R7) or -(C(R6)(R7))1-6-S(O)eR13 and A2 is H, or A1 and A2 together are=O,=C(R6)(R7),=NOR6 or=S;Q is phenyl, naphthyl, -SR6, -N(R6)(R7), -OR6 or heteroaryl;T is H, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl;b is 0, 1 or 2;b1 is 1 or 2;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(=NOR6)-, -S(O)2N(R6)-, -N(R6)S(O)2-, -N(R6)C(O)O- or -OC(O)-;R6, R7, R8a, and R13 are H, alkyl, hydroxyalkyl, alkoxy alkyl, phenyl or benzyl;or R6 and R7, together with the nitrogen to which they are attached, form a ring;R9 and R9a independently are R6 or -OR6;Z is optionally substituted (II), wherein g is 0-3 and h is 1-4, provided the sum of h and g is 1-7;wherein the aryl, phenyl, benzyl, naphthyl, heterocycloalkyl and heteroaryl groups are optionally substituted. Methods of treating asthma, cough, bronchospasm, inflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.

Description

ARIL ALQUILAMINES SUBSTITUTED AS NEUROCYNIN ANTAGONISTS I? BACKGROUND OF THE INVENTION 5 The present invention relates to a type of aryl | substituted alkylamines useful as antagonists of tachykinin receptors, in particular as antagonists I I of the neuropeptide receptor neurokinin-1 (NK-.) And / or the | Neurokinin-2 receptor (NK2) and / or the receptor I 10 neurokinin-3 (NK3). Neurokinin receptors are found in the 1 nervous system and in the circulatory system and in tissues I peripheral mammals, and therefore are involved in a variety of biological processes. Accordingly, neurokinin receptor antagonists are expected to be useful in the treatment or prevention of different disease states of mammals, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine. and epilepsy, nociception, and various gastrointestinal disorders, such as Crohn's disease. In particular, NKi receptors have been reported to be involved in microvascular effusion and mucus secretion, and K2 receptors have been associated with the contraction of the smooth muscle, making the antagonists of the NKi and NKi receptor especially useful in the treatment and prevention of asthma. Some receptor antagonists of Ki and NK2 have been > previously described: aryl alkylamines were described in U.S. Patent No. 5,350,852, published September 27, 1994, and spiro-substituted azacycles were described in WO 94/29309, published December 22, 1994.

COMPENDIUM OF THE INVENTION i The compounds of the present invention are represented by the formula I e of them, in A1 is -CH2R6, -OR6, -N (R6) (R7), -S (0) eR13, - (C (R6) (R7))? -6 ~ OR6, - (C (R6) { R7))? _ 6-N (R6) (R7) or - | C (R6) (R7) h -y-S (015R13 and A2 is i H, or A1 and A2 together are = 0, = C (R6) (R7), = N0R6 or = S; Q is R5-f enyl, R5-naphthyl, -SR6, -N (R6) (R7), -OR6 or R5-I 1 heteroaryl, 1 T is H, R -aryl, R4-heterocycloalkyl, R -heteroaryl, I 4 .0 25 R-cycloalkyl or cycloalkyl with bridge R; b is O, 1 or 2; bi is 1 or 2; X is a bond, -C (O) -, -O-, -NR6-, -S (0) e-, -N (R6) C (0) - -C (0) N (R6) -, - OC (0) NR6-, -OC (= S) NR6, -N (R6) C (= S) O-, C (= NOR6) -, -S (0) 2N (R6) -, -N (R6) S (O) 2-, -N (R6) C (0) 0- OR -OC (O) -; 4 R and R are independently 1-3 substituents I independently selected from the group consisting of i H, halogen, -OR6, -0C (0) R6, -OC (O) N (R6) (R7), -N ( R6) (R7), J alkyl of C? -6, -CF3, -C2FS, -COR6, -C02R6, -CON (R6) (R7), -JO S (0) eR13, -CN, -OCF3, - NR6C02R16, -NR6C0R7, -NR8CON (R6) (R7), R1S-phenyl, R15-benzyl, N0, -N (R6) S (0) 2R13 or -S (0) 2N (R6) (R7); i 4 5 or adjacent R substituents or adjacent R substituents 1 can form a group -0-CH2-0-; and R4 may also be R15-I 1 heteroaryl; 15 R, R, R, Ra and R are selected I I independently of the group consisting of H, alkyl of K C1-6, C2-Cg hydroxyalkyl, Ci-Cß alkoxy alkyl of C? I C6 R -phenyl and R1S-benzyl; or R6 and R7, together with the I I nitrogen to which they are attached, they line a ring of 5 to 6 I 20 members, where 0, 1 or 2 ring members are . { select from the group consisting of -O-, -S- and -N (R19) -; , R and R are independently selected from group j consisting of R and -OR6, as long as R9 is OH, X is I a bond, -CÍO) -, -N (R6) C (0) - or -C (= N0R6) - ~~~ 2 I5 R is independently selected from the group that consists of H and Ci-Cß alkyl; R is 1 to 3 substituents independently selected from the group consisting of H, Cj-Ce alkyl, Ci-Cß alkoxy, Ci-Ce alkylthio, halogen, -CF3, -CF5, -COR10, -C02R10, -C ( 0) N (R10) 2, -S (0) eR10, -CN, -N (R10) COR10, -N (R10) CON (R10) 2 and ~ N02; R16 is Ci-β alkyl, R15-phenyl or R15-benzyl; R19 is H, C? -6 alkyl, -C (0) N (R10) 2, -C02R10, - (C (R8) (R9)) f-C02R10 O- (C (R8) (R9)) uC (O) N (R10) 2; f is 1-6; u is 0-6; Z is > f is 1-6; i g and j are independently 0-3; h and k are independently 1-4, as long as the 0 sum of h and g is 1-7; 1 I J is two hydrogen atoms, = 0, = S, or L and L1 are independently selected from the group [consisting of H, Ci-Cß alkyl, Ci-Cβ alkenyl, ! cycloalkyl-CH2-, benzyl-R1S, heteroaryl-R15, -C (0) R6, -25 (CH2) m-OR6, - (CH2) mN (R6) (R7), - (CH) m "C (0) -OR6 and - (CH2) m- C (0) N (R6) (R7); m is 0 to 4, provided that j is O, m is 1-4; R2S is H, C? -C6 alkyl, -CN, R15-phenyl or benzyl-R15; R and R are independently selected from the group consisting of H, Ci-C-aryl-R alkyl and heteroaryl-R4; or R is H, Ci-Cß alkyl, aryl-R 4 or hetero-R 4, and R 27 is -C (0) R 6, -C (0) -N (R 6) (R 7), -C. { 0) (aryl-R4), C (O) (heteroaryl-R4), -S02R13 or -S02- (aryl-R4); R28 is H, -C (R6) (R19)) t-G or - (C (R6) (R7)) v-G2; t and v are 0, 1, 2 or 3, provided that j is 0, t ~ is 1, 2 or 3; R29 is H, C] .- C6 alkyl, -C (R10) 2S (O) eR6 / phenyl-R4 or heteroaryl-R; G is H, aryl-R, heterocycloalkyl-R, heteroaryl-R, cycloalkyl-R4, -OR6, -N (R6) (R7), -COR6, -C02R6, -CON (R7) (R9), S (0) eR13, -NR6C02R16, -NR6C0R7, -NR8CON (R6) (R7), -N (R6) S (0) 2 13, -S (0) 2N (R6) (R7), -OCfOJR6, -OC (0) N (R6) (R7), -C (= NOR8) N (R6) (R7), -C (= NR25) N (R6) (R7), -N (R8) C. { = NR25) N (R6) (R7), -CN, -C (O) N (R6) OR7 or -C (0) N (R9) - (heteroaryl-R4), provided n is 1 and v is 0 or when R9 is -OR6, G is not -OH or -N (R6) (R7); Y G is aryl-R, heterocycloalkyl-R, heteroaryl-R, cycloalkyl-R4, -COR6, -C02R16, -S (O) 2N (R6) (R7) or C0N (R6) (R7). Preferred are compounds of formula I wherein X is -0-, -NR6-, -N (R6) C (0) -, -OC (0) NR6 or -N (R6) C (0) 0. They are more preferred are the compounds of the formula I wherein X is -NR | or -N (R) C (0) -. Also preferred are compounds wherein I b is 0 or 1, when X is -NR6- or -N (R6) C (0) -. Also preferred are compounds where bi is 1. T is I p preferably aryl-R or heteroaryl-R, especially with 1 I aryl-R4, phenyl-R4 being more preferred. ! Also preferred are compounds wherein R a and R j are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are compounds wherein R and R • are each hydrogen, X is -NR- or -N (R) C. { 0) -, T is aryl- R4 and R4 is two substituents that are selected from Ci-Cß alkyl, halogen, -CF3 and Ci-Cs alkoxy. When T_ is heteroaryl-R, a preferred definition includes pyridinyl- I Also preferred are compounds wherein Q is i W1 phenyl-R5, naphthyl-R5 or heteroaryl-R; the definitions I especially preferred for Q are phenyl-R, wherein R is 'preferably two halogen substituents, and benzothienyl. 2O The compounds of the formula I are preferred where I A1 is -OR6, -N (R6) (R7), -S (0) eR13 or - (C (R6) (R7))? -6-N (R6) (R7) and A 2 is H; Also preferred are compounds where A 1 and A2 I together are = 0, = C (R6) (R7) or = N0R6. The preferred definitions of Z are the following Z groups are more preferred This invention also relates to the use of a compound 20 of formula I in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as arthritis, conditions in the central nervous system such as migraine and epilepsy, nociception and various disorders Gastrointestinal I such as Crohn's disease. In another aspect, the invention relates to a I pharmaceutical composition containing a compound of the I formula I in a pharmaceutically acceptable carrier. I The invention also relates to the use of said W pharmaceutical composition in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as 'arthritis, migraine, nociception and various gastrointestinal disorders such as Crohn's disease.

DETAILED DESCRIPTION Ó As used herein, the term "alkyl" I means linear or branched alkyl chains, "lower alkyl" refers to alkyl chains of 1-6 carbon atoms I carbon and, likewise, lower alkoxy refers to chains | alkoxy of 1-6 carbon atoms. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. m "Halogen" refers to fluorine, chlorine, bromine or iodine atoms. "Heterocycloalkyl" refers to tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and 'piperazinyl. Hetero-cycloalkyl-R refers to such Groups where the substitutable carbon atoms in the 'ring have a substituent R. I 1"Heteroaryl" refers to aromatic anilXos benzofused or simple from 5 to 10 members containing 1 ! to 4 heteroatoms independently selected from the group consisting of -0-, -S- and -N =, provided that the I rings do not include oxygen atoms and / or sulfur atoms? adjacent. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, and the like. tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and thiazolyl. The examples of benzofused heteroaryl groups are indolyl, Quinolyl, benzothienyl (i.e., tianaphtenyl), > benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. Group N-dxides are also included I heteroaryl containing nitrogen. All the i! isomers of position, for example, 1-pyridyl, 2-pyridyl, : 3-pyridyl and 4-pyridyl. "Heteroaryl-R" refers to such groups wherein the substitutable carbon atoms of the ring have a substituent R4. When the substituents R and R form a ring and additional hetero-atoms are present, the rings do not include adjacent oxygen atoms and / or sulfur atoms or 3 adjacent heteroatoms. Commonly, the rings thus formed are morpholinyl, piperazinyl and piperidinyl. In the above definitions, wherein variables such as R6, R7, R8, R9, R13 and R15 are said to be selected independently from a group of substituents, we mean that R, R, R, R, R and R 15 are independently selected, but also that when a variable R, R, R, R, R, R or R appears more > once in a molecule, those events are independently selected (for example, if R is -OR where R is methyl, X can be -N (R) - where R is ethyl). Fit I similar, R4 and R5 can be independently selected Of a group of "substituents and, where more than one R 4 and R 5 are Present, the substituents are independently selected; those skilled in the art can recognize "that the size and nature of the 'Substituent (s) affects the number of substituents that I 1 can present. The compounds of the invention can have at least one asymmetric carbon atom and, therefore, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as part of this invention. The ! invention includes isomers d and 1, both in pure form and in I! mixture, including racemic mixtures. The isomers can be prepared using conventional techniques, by reacting any optically pure starting material or optically enriched f or by separating the isomers from I | a compound of formula I. Those skilled in the art will appreciate that for some 2J5 compounds of formula I, an isomer will show greater activity pharmacological than other isomers. The compounds of the invention have at least one amino group that can form pharmaceutically salts »Acceptable with organic and inorganic acids. Examples 5 of the acids suitable for the formation of salts are: hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral acids II and carboxylic acids. known to experts in the technique. Salt is prepared by putting the shape in contact Free base with a sufficient amount of the desired acid to produce the salt. The free base form can be regenerated by treating the salt with a suitable diluted aqueous base solution such as aqueous sodium bicarbonate. The The free base form is somewhat different from its respective salt form in certain physical properties, such as the ? Solubility in polar solvents, but on the other hand the salt is equivalent to their respective free base forms for purposes of the invention. Certain compounds of the invention are acids (for example, those compounds which possess a carboxyl group).

These compounds form pharmaceutically acceptable salts with organic and inorganic bases. Examples of such salts are sodium, potassium, calcium, aluminum, gold salts and silver. Also included are the salts that are formed with pharmaceutically acceptable amines, such as ammonia, hydroxy alkylamines, N-methylglucamine and the like. The compounds of formula I can be prepared using methods well known to those skilled in the art. The following are common procedures for preparing different compounds; the skilled artisan will recognize that other procedures may be applied, and that the procedures may be suitably modified to prepare other compounds within the scope of the formula • I.

Process A: I Compounds of formula I, wherein X is -C (0) -, - ik 0-, -S (0) e-, -C (0) N (R6) -, -0C (0 ) NR6-, -OC (= S) NR6) -, S (0) 2N (R6) - or -0C (0) -, Q is phenyl R5, bi is 1 or 2, and the rest of the variables are as defined above, I can be prepared as shown in the following Reaction scheme: 20 In step 1, compound 1, wherein R is as defined above, is treated with a halogenating agent such as I2 or N-bromosuccinimide in an organic solvent such as CH3CN, THF or DMF at a temperature in the range of 0 to "25 ° C to give halolactone 2.

Dissolve in a methyl alcohol. The stirred mixture is added at a ratio of the epoxide 3. Lower than 1 may be suitable such as a compound of the In step 3, a solution of the epoxide 3 in an alcohol such as CH 3 OH, CH 3 CH 2 OH or, more preferably, CF 3 CH 20 H is • treated with a nucleophile Z of secondary amine where R is? as defined above, at 0-90 ° C to give the lactone 4. Step 4 : For compounds where X is -C (0) N (R) - and bi is 1, lactone 4 is treated with the corresponding dialkyl amine-ib N (R6) C (Ra) (R6a) -T in an alcohol such as CH3OH, CH3CH20H, or 1 more preferably CF3CH2OH, from 0 to 90 ° C to give the amide fe 5. The compounds of the formula 5 can be converted to I the corresponding keto compounds (where A1 and A2 together Are = 0) by oxidation with an appropriate reagent such as 2P pyridinium dichromate, Dess Martin reagent, reagent I Jones, TPAP or Swern oxidation; the keto compounds are converted into the corresponding oximes (compounds wherein A and A together are = N0R) by treatment of the keto compound with hydraxyl amine or an appropriate alkoxy amine pyridine at 23 ° C to 80 ° C. Consequently, "the corresponding olefmas (compounds where A1 and A2 together I are = C (R) (R)) can be prepared from the respective keto compounds using standard chemistry itting known to those skilled in the art.

(O) -, -0-, -S (0) e-, -) 2N (R6) - or -OC (O) - and an appropriate agent H4 or NaBH4 with a temperature in the range of ~ 78 ° C to 80 ° C to give the corresponding diol 4b. With appropriate protection of the reactive groups, the compounds of the formula 4b can be converted to the compounds wherein X is -C (0) -, -0-, - S (0) e-, -0C (0) NR6- , -0C (= S) NR6-, -C (= N0R6) -, -S (0) 2N (R6) - or - 20 OC (0) - by appropriate exchange of functional groups or functionalization of the terminal alcohol group. The corresponding keto compounds (compounds where A 1 and A2 together are = 0) can be prepared by oxidation with a suitable reagent such as pyridinium dichromate, reagent by Dess Martin, Jones Reagent, TPAP or Swern Oxidation; the synthesis of the corresponding oximes (compounds where A1 and A2 together are = N0R) is made by treatment of the keto compounds with hydroxylamine or an appropriate alkoxyamine in pyridine at 23 ° C to 80 ° C. Accordingly, the corresponding olefins (compounds wherein A and A together are = C (R) (R)) can be prepared from the respective keto compounds using standard Witting chemistry known to those skilled in the art.

Method B: The compounds of the formula I, wherein X is -NR-, -NR6C (0) -, -N (R6) C (= S) 0-, -N (R6) S (0) 2-, -N (R6) C (0) 0- or -N (R6) C (0) N (R7) - Q is phenyl RS, i is 1 and the rest of the variables are as defined above, they can be "prepared as shown in the following reaction scheme: Step 1: 1 & In step 1, the acid 1_ is subjected to the common conditions of a Curtius rearrangement, for example; treatment with diphenylphosphoryl azide and a suitable base such as triethylamine (Et3N) in a suitable solvent such as t-butanol. After heating to reflux, cooling and appropriate purification such as crystallization or chromatography on silica gel, the corresponding N-Boc protected amine of compound 6 is separated. The deprotection of the Boc group by standard conditions known to those skilled in the art, such as treatment with an acid such as hydrochloric acid or trifluoroacetic acid, provides compound 6.

Step 2: In step 2, the amine 6 is acylated by standard procedures, for example, by treatment with a chloride clade of the formula TC (R9a) (R8a) COCÍ, wherein T, R8a and R 9a are as defined above, in presence of an amine base in an inert organic solvent such as CH2C12 or toluene, preferably CH2Cl2 at a temperature from -10 to 50 ° C, suitable bases include (CH3) 3N, Et3"N and pyridine, preferably Et3N. acylation, such as anhydrides, are also suitable Other coupling methods known to those skilled in the art, such as As copulation with EDC, they can also be used. In correspondence, for the preparation of compounds where X is -N (R6) S (0) 2-, -N (R6) C (0) 0- or -N (R6) C (0) N (R7) -, the amine? it is treated with the appropriate sulphonyl halide, chloroformate 5 or isocyanate, respectively.

Step 3: In step 2, compound 7 is treated with a base such as NaH or LDA in an inert organic solvent such as THF, ether, DMSO or DMF, preferably THF. The resulting anion is treated with an alkylating agent R L, where R is as defined above and L is a suitable leaving group such as Cl, Br, I, triflate or esylate, to give the product of formula 8. The reactions are usually carried out at 0-50 ° C. 2.0 Step I In step 3, compound 8 is oxidized to epoxide 9 by treatment with an oxidizing agent, such as dimethyl dioxirane in an inert organic solvent such as an acetone, at a temperature of 0 to 30 ° C. Other suitable oxidants may be used, for example m-CPBA in a solvent such as CH2Cl2. Suitable protective groups may be necessary, in R a, R a and in T over fractions susceptible to oxidation under these conditions.

Step 5: In step 5, the epoxide of formula 9 is converted to the amine of formula 11 by treatment with an epoxide solution 9 in an alcohol such as CH3OH, CH3CH2OH or more preferably CF3CH2OH, with a secondary amine nucleophile Z, 1_0 as was defined earlier, at 0-90 ^ C to give the aminoalcohol of the formula 1_1. The compounds of formula 11 can be converted into the corresponding keto I (compounds where A and A together are = 0), in I 2 corresponding oximes (compounds where A and A together are = N0R) as described above in the procedure A. Accordingly, olefins corresponding (compounds wherein A1 and A2 together are = C (R) (R)) can be prepared from the keto compounds using standard Witting chemistry known to those skilled in the art.

Procedure C: 12 12. For compounds where X is a bond, -C (O) -, -0-, - NR ° -, S (0) e-, -N (R °) C (0) - -C (0 ) N (R °) - -OC (O) NR -N (R) C (= S) 0- C (= N0R) - -S (0) 2N (R6) - N (R6) S (0) 2 -, -N (R6) C (0) 0 6 -0C (0) - and bi is 1, the nitroolefin 12 is added to a mixture of a copper salt, preferably CuCN and a vinyl magnesium bromide in a suitable solvent , preferably THF, at a temperature in the range of -78 ° C to 0 ° C, to give, after work and proper purification, the nitro product 1_3. This product can be reduced to give the primary amine 6, or the nitro group can be transformed into the corresponding carboxylic acid by a standard Nef reaction, then to the primary alcohol with the transformations of the functional group known to those skilled in the art. Such compounds can be converted into compounds where X is -C (0) -, -O-, -S (0) ß- / -OC (0) NR6-, -OC (= S) NR6-, -C (= NOR_6) -, -S (0) 2N (R) - or -OC (O) - by exchange of suitable functional groups or functionalization of the alcohol group »Terminal. The corresponding keto compounds (ie, compounds where A 1 and A2 together are = 0) can be ! prepared by oxidation with suitable reagents such as Pyridinium dichromate, Dess Martin reagent, reagent I Jones, TPAP, or Swern oxidation; the synthesis of oximes I I corresponding (ie, compounds where Ai and A2 1 0 together are = N0R) is done by treatment of the keto compound \ with hydroxylamine or an appropriate alkoxylamine in pyridine a I 23 ° C-80 ° C. Consequently, the corresponding olefins (compounds where A and A together are = C (R) (R)) can be prepared from the respective keto components 1/5 using the standard Witting chemistry known to those skilled in the art. Reactive groups not involved in the above processes can be protected during reactions with conventional protective groups, which can be removed by standard procedures after the reaction. The following table shows some common protective groups: tablets, powders, capsules, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions or powders for reconstitution. The pharmaceutical compositions can be prepared with conventional excipients and additives, using well-known pharmaceutical formulation techniques. The pharmaceutically acceptable excipients and additives include chemically compatible, non-toxic fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavorants, thickeners, coloring agents, emulsifiers "and the like.

The daily dose of a compound of formula I for the inflammatory, migraine, nociceptive and gastrointestinal disorders is about O.lmg to about 20 mg / kg of body weight per day, preferably from about 0.5 to about 15 mg / kg. For an average body weight of 70 kg the dose range is, therefore, from about 1 to about 1500 mg of drug per day, preferably approximately 50 to about 200 mg, more preferably about 50 to about 500 mg / kg per day, given in a single dose or divided into 2-4 doses. The exact dose, however, is determined by the clinical assistant and this depends on the potency of the compound administered, the age, weight, condition and response of the patient.

The following are examples of preparation of the ! starting materials and the compounds of formula I.

? Example 1: 5 N- [2- (3,4-dichlorophenyl) -3-hydroxy-4- (4-hydroxy-4-phenyl-1-j-piperidinyl) butyl] -N-methyl benzamide Step 2: Treat a solution of the product from Step 1 (15 g,; 65 mmol) in dry THF (250 ml), keep cool in a large water bath at room temperature, with Dibal-H (140 ml, 140 mmol, 2.15 eq) for 30 minutes. Shake the resulting solution for 30 min at 23 ° C, pour into Et20 (500 ml), treat with water | (5 ml), 15% NaOH (5 ml) and water (15 ml). Stir for 5 min, I dilute the mixture with Et20 (200 ml) and treat with 15% NaOH (15 ml). Add MgS? 4 to originate a colorless precipitate.

Remove the aluminum salts by filtration through a I 10 thick glass frit. Wash the solids with Et20 (11) and concentrate the filtrate in vacuo to give 13.2 g (65 mmol, i 99%) of 3-13, 4-dichlorophenyl) -2-propen-l-ol as an off-white solid. I l's Step 3: Treat a solution of the product from Step 2 (13.2 ig, 65 mmol) in CH2C12 (250 ml) at 0 ° C with pyridine (7.89 ml, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 325 [ sic] 0. 05eq), followed by CH3C0C1 (6.48 ml, 74.75 mmol, 1.15 eq).

! Allow the mixture to warm to 23 ° C, empty in 1M HCl 2p (100 ml) and washing the resulting organic layer again with 1M HCl (100 ml), followed by water (5 x 100 ml); pH = 6.5-7. 1 Dry the organic layer (Na 2 SO 3) and concentrate to obtain 15.4 g, (62.9 mmol, 97%) of 3- (3,4-dichlorophenyl) -i 1 2-propen-1-ol acetate as a colorless oil. . 2b Step 4: Treat a solution of the product from Step 3 (15 g, 61 mmol, dried by azeotropic distillation with toluene, 1 x 50 ml) in dry THF (250 ml) at -78 ° C with chlorotriethylsilane ^ (20.2 ml, 120 mmol, 2.0 eq) followed quickly by the Addition of potassium bis (trimethylsilyl) amide (183 ml, 91.5 mmol, 1.5 eq 0.5 M in toluene) by addition sample I for 50 min. Heat the mixture to 23 ° C and heat to reflux for 3 h. Gradually cool the solution overnight, then quench with saturated NH4CI (150 mL).

^ W Shake the resulting mixture vigorously for 3 hours, treat with ! HCl 1M (150 ml) and then extract with Et20 (500 ml). Extract the I aqueous layer with Et20 (400 ml), wash the organic layers 1 combined with 5% NaOH (300 ml) and extract with 5% NaOH (8 x 50 ml). Cool the combined aqueous layers to 5 ° C and, keeping the temperature at 5-10 ° C, carefully acidify with concentrated HCl (ca 175 ml) to pH 1. Extract the aqueous layer with CH2C12 (2 x 800 ml), Dry (Na 2 SO) and concentrate to give 13.4 g (54.5 mmol, 89%) of 3- (3,4-dichlorophenyl) -4-pentendic acid as an oil weakly. yellow.

Step 5: Treat a solution of the product from Step 4 (13.75 g, 56 mmol, dried by azeotropic distillation with toluene, 100 ml) in dry, freshly distilled t-butanol (250 ml) with Et3N freshly distilled (9.34 ml, 70 mmol, 125 eq) followed by Diphenylphosphoryl azide (15.1 ml, 70 mmol, 1.25 eq).

I Heat the resulting solution to reflux for 24 h, cool ! and concentrate to the vacuum. Treat the resulting product with? toluene (100 ml), concentrate (2 x), dissolve in hexane: EtOAc 81: 1) and filter through a pad of silica gel , (4 x 10 cm), eluting with hexane: EtOAc (1: 1) (1L). Concentrate the filtrate to obtain 20.7 g of crude carbamate 1,1-dimethylethyl- [2- (3, 4-dichlorophenyl) -3-butenyl]. l'p Step 6: Treat a solution of the product from Step 5 (5.32 g of ca 88% pure, 14.8 mmol) in CH2C12 (100 ml) with trifluoroacetic acid (100 ml) and stir for 2 h at 23 ° C. Treat the Mix with heptane (50 ml) and concentrate in vacuo. Work the resulting crude product into hexane: EtOAc (1: 1) and f apply to a pad of silica gel (4 x lOcm) | packed with hexane: EtOAc (1: 1). Wash the cap with the P same solvent (1 L) and then elute the desired product j with CH2C12: CH3OH (saturated with ammonia) (9: 1) (1.5 L).

I Combine the washings of the product and concentrate to give_3.9 g of raw amine used in the next step without further Purification Step 7: Cool a solution of the product from Step 6 (14.8 mmol) in CH2C12 (100 mL) at 0 ° C and treat with Et3N (3.5 mL, 25.2 mmol, 1.5 eq) and benzoyl chloride (2.1 mL, 17.6 mmol). , 1. 05 eq). After 10 minutes, dilute the mixture to 150 ml with CH2C12 and wash with 10% aqueous citric acid (50 ml), water 850 ml) and saturated aqueous NaHCO3 (50 ml), then dry I (Na 2 SO 4) and concentrate, Whiten the whitish solid, resulting completely white with hexane (40 ml) to give 3.29 g (10 mmol, 68%, by three steps) of N- [2- (3,4 -, dichlorophenyl) -3-butenyl] benzamide as a colorless solid.

| Step 8: Wash a suspension of NaH (312 mg of 60% in mineral oil, 7.81 mmol, 1.25 eq) in hexane with dry pentane (2 x 100 ml), suspended in dry THF (30 ml) and treat | with the product of Step 7 (2.0 g, 6.25 mmol), at 23 ° C. i Shake the resulting yellow suspension for 20 min at 23 ° C, Then add CH3I (777 μL, 12.5 mmol, 2.0 eq). After of 1 h, empty the mixture on a gel pad of I silica packed with hexane: EtOAc (1: 1) (500 ml) and concentrate the filtrate to give 2.1 g (6.25 mmol,> 99%) of I N- [2- (3,4-dichlorophenyl) -3-butenyl] -N-methyl benzamide as a light yellow liquid. 20 j Step 9: Treat a solution of the product from Step 8 (2.1 g, j 6.25 piiaol) in dry CH2Cl2 (50 ml) with a fresh solution j prepared from dimethyldioxirane in acetone (100 ml ca 0.08 ; M in acetone). Stir the solution for 20 h, concentrate at I 25 vacuum, perform azeotropic distillation with toluene (2 x 75 ml) and then purify chromatography on silica gel (column: 4 x 16 cm; eluent: hexane: EtOAc (1: 1) to obtain the A-syn: 854 mg (2.44 mmol 39%) of (trans -N- [2 - (3,4-dichlorophenyl) -2-oxiranyl ethyl] -N-methyl benzamide 15 as a colorless oil, and isomer B: 1.04 g (2.98 mmol, i 48%) of (cis) -N- [2- (3,4-dichlorophenyl) -2-oxiranyl ethyl] -N-methyl benzamide as a colorless solid (total yield i 87%).

Step 10: Treat a solution of isomer A from Step 9 (201 mg, 0.574 mmol) in 2,2,2-trifluoroethanol (3 ml) with 4-α-hydroxy-4-phenylpiperidine (508 mg, 2.87 mmol, 5 eq), and stir the resulting light yellow solution for 24 hrs. ° C Concentrate in vacuo, distill azeotropically with toluene : 5 (2 x 5 ml) and concentrate. Purify the resulting crude solid by chromatography on silica gel (column: 2.5 x 18 cm, eluent: gradient CH2C12: CH30H (saturated with ammonia) (97: 3) to (95: 5)) to obtain 302.8 mg (0.574 mmol, > 99% of the title compound as a colorless foam. HRMS (FAB, M + H +): m / e calculated for [C 29 H 33 Cl 2 N 2? 3] +: 527.1868, 527.1853 was found. The compounds of Examples 2-4 are prepared by methods similar to those described in Example 1. For the Examples 3-4, the starting material is 3- (4-methoxyphenyl) -4-pentenolco acid, prepared from octyl-3- (4-methoxy) - 2-propenopathy [sic] in a similar way to the procedure ^ 0 HRMS (FAB, M + H +): m / e calculated for [C29H33CI2N2O3] +: "527.1868, found 527.1863. (the stereochemistry shown is relative).

Example 3 P HRMS (FAB, M + H +): m / e calculated for [C3oH36N2? ] 489.2753, 489.2754 was found.

Example 4 HRMS (FAB, M + H +); m / e calculated for [C30H36N2O4] +: 489.2753, 489.2735 was found. 10 Example 5 .6 mmol, THF bromide, 78 Heat the solution to -20 ° C, stir for 10 min, then add to a solution of trans-β-nitrostyrene (5 g, 33.5 mmol) in dry THF (15 mL). Shake the suspension for 1 h, then empty in a 1: 2 mixture of 0.1 M HCl / acetic acid (600 j ml). Extract the resulting aqueous phase with CH2C12 (400 mL), I wash the organic layers with water (2 x 300 ml), dry I i (Na 2 S 4) and concentrate to give 7 g of crude product. ? Purify by silica gel chromatography (7 x 16 cm, eluent: hexane / CH2Cl2 (3: 1) (ΔI) gradient a (2.1)) to obtain 2.5 g (14.1 mmol, 42%) of the desired product as a clear yellowish liquid.

Step 2: Shake aluminum strips (5g) with a solution of 1JD 2% aqueous HgCl2 (60 ml) for 1.5 min. Decant the aqueous layer, wash the metal sheet with ethanol (2 x 50 ml) followed Ether (2 x 50 ml) and suspend in ether 850 ml) / THF (30 ml).

I Add the product from Step 1 (2.5 g) as a solution in THF (20 ml). Add water (5 ml) and CH3OH (5 ml) and shake the suspension for 48 h at 23 ° C. Filter the resulting suspension j through a celite layer (10 x 3.5 cm), rinsing with CH3OH. Concentrate the filtrate to obtain 2.1 g (14.1 mol, >; 95%) of 2- (3,4-dichlorophenyl) -3-butenyl amine as a light yellow oil. 20 Step 3: Use the product of Step 2 in a procedure as described in example 1, steps 7-10, to obtain the title compound (cis isomer): HRMS (FAB, M + H +): m / e calculated for [C29H35N2O3] +: 25 493.2648, 459.2643 was found.

Example 6 Isolate the trans isomer prepared by the process described in Example 5: HRMS (FAB, M + H +): m / e calculated for [C29H35N203] +: 459.2648 was found 459.2644 Examples 7 and 8 (diastereomers) are prepared in a manner similar to that described in Example 5 using 4-chloro-trans-β-nitroestirane as the starting material.

Example 7 HRMS (FAB, M + H +): m / e calculated for [C29H3sCl2N2? 3] 493.2258, 493.2261 was found.

Example 8 HRMS (FAB, M + H +): m / e calculated for [C29H33C1N203] +: 493.2258, 493.2270 was found. Examples 9 and 10 were prepared by a procedure similar to that of Example 5 using 4-met l-trans-β-nitrostyrene. Example 9 HRMS (FAB, M + H +): m / e calculated for [C3oH36N2? 3] +: 473.2804, 473.2803 was found.

Example 10 HRMS (FAB, M + H +): m / e calculated for [C3oH36N203] +: 473.2804, 473.2798 was found.

Example 11 lb Using as starting material 1, 1-dimethylethyl- [2- (3, 4-dichlorophenyl) -3-butenyl] carbamate, the process described in Example 1, steps 9-10, is carried out to obtain i the title of the compound.

[C26H34Cl2N2? 4]: a similar way '8 to get the composed of the title. HRMS (FAB, M + H +): m / e calculated for [C2 H3eCl2N2? 4] +: 523.2130, 523.2136 was found. Examples 13, 14 and 15 are prepared from Examples 1, 2 and 2 [sic] respectively, using a procedure similar to that of Example 1, step 8.

Example 13 [C3oH34Cl2N203] +: [C30H34Cl2N2? 3] " Example 15 HRMS (FAB, M + H): m / e calculated for [C3? H36Cl2N203]: 555.2181, 555.2181 was found.

Example 16 Treat the product of Example 1 in acetone with Jones's reagent and stir at 0 ° C for 1 h. Extract the product with CH2C12 and purify by chromatography on silica gel to obtain the title compound MS: m / e 525 (FAB, M + H +). Examples 17 and 18, regioisomers of the oxime ether, are prepared by heating the product of Example 16 in pyridine with o-methoxylamine HCl at 60 ° C for 30 min. After removing the pyridine by vacuum, the crude product is purified in one. column silica gel. 5 Example 17 HRMS (FAB, M + H +): m / e calculated for [C30H33CI2N3O3] 554.1977, 554.1985 was found.

I 15 I I HRMS (FAB, M + H): m / e calculated for [C30H33CI2N3O3]: i 554.1977, 554.1979 was found. Examples 19, 20, 21 and 22 are prepared from Examples 1, 2, 5 and 6, respectively, using a Procedure similar to that described in Example 1, step 8, I but using 3, 5- (bistrifluoromethyl) benzyl bromide as I the alkyl halide.

Example 19 HRMS (FAB, M + H +): m / e calculated for [C38H37Cl2F6N2? 3] 753.2085, 753.2058 was found. 10 Example 20 [C38H37Cl2F6N2? 3] +: Example 21 HRMS (FAB, M + H +): m / e calculated for [C38H39F6N203] ^ 685.2865, 685.2851 was found.

Example 22 HRMS (FAB, M + H +): m / e calculated for [C38H39F6N20] +: 685.2865, 685.2864 was found. Examples 23 and 24 are prepared from Examples 1 and 2, respectively, by stirring the amide in dry THF with LIAIH4 for 30 min, at 23 ° C, separating between Et20, water and NaOH, removing the aluminum salts by filtration. , and filtering through a plug of silica gel.

HRMS (FAB, M + H +): m / e calculated for [C29H35Cl2N2a2] 513.2076, 513.2069 was found.

HRMS (FAB, M + H +): m / e calculated for [C29H3sCl2N202] +: fe 513.2076, 513.2058 was found. ? Examples 25 and 26 were prepared from the Examples 19 and 20, respectively, using a procedure similar to used in Examples 23 and 24, using dimethyl borane sulfide as the reductant.

Example 25 HRMS (FAB, M + H +): m / e calculated for [C38H39Cl2F6N202] +: 739.2293, 739 was found. 2289 Example 26 I HRMS (FAB, M + H): m / e calculated for [C38H39Cl2F6N2? 2]: 739.2293, 739.2280 was found. The following formulations exemplify some of the 'dosage forms of this invention. In each, the term "active compound" refers to a component of the < formula I. 25 EXAMPLE A Tablets No. Ingredient mg / tablet mg / tablet 1 Active compound 100 500 2 Lactose USP 122 113 3 Food-grade corn starch, camo 30 40 a 10% paste in purified water 4 Corn starch, food grade 45 40 Magnesium stearate 3 7 Total 300 700 > Method of preparation _ 5 Mix ingredients Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Grind wet granules through a coarse screen (eg, W, 0.63 cm) if necessary. i) Dry the wet granules. Sieve the dry granules if necessary [...] and mix with item number 4 and mix with 10-15 minutes. Add item number 5, and mix by] 1-3 minutes. Compress the mixture to an appropriate size and weight in a suitable tableting machine. fifteen 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 NF 4 7 Total 250 700 Method of elaboration Mix the elements numbers 1, 2 and 3 in a suitable mixer for 10-15 minutes. Add item number 4 and mix for 1-3 minutes. Fill the mixture in hard gelatin capsules, two pieces, suitable or in a suitable encapsulating machine.

EXAMPLE C Sterile powder for injection Ingredient mg / vial g / vial Sterile active powder 100 500 For reconstitution add sterile water for injection or bacteriostatic water for injection. The in vitro and in vivo activity of the compounds of the Formula I can be determined by the following procedures.

W In vitro procedure to identify the activity of NKi The test compounds are evaluated for their ability to inhibit the activity of substance P agonist NKi in the isolated vas deferens of guinea pig. Freshly cut deferent vessels were removed from Hartley male guinea pigs (230-350 g) and suspended in 25 ml of fabric baths with JO Kreb's Henseleit solution heated to 37 ° C and constantly gassed with 95% O2 and 5% C02. The tissues are adjusted up to 0.5 g and brought to equilibrium by a ! period of 3TJ minutes. The vas deferens were exposed to an electric field stimulation (Grass stimulator) 1'5 S48) every 30 seconds at an intensity that causes tissue i a shrinkage of 80% of its maximum capacity. All faith responses are recorded isometrically by means of a 1 force displacement transducer (FT03) and recorder I, Harvard Electronics. 20 Suenciancia P potentiates contractions stimulates I induced by the electric field of the vas deferens 1 guinea pig. In unpaired studies, all tissues (control ! or treated with medication) are exposed to cumulative concentrations of substance P (1 x 10 ~ 10 M-7 x 10"7 M). individual log-concentrations of the test compounds ; they are given to separate tissues and equilibrium is allowed for 30 minutes before a concentration-response curve of substance P is generated. When lesser tissues are separated, they are used for each control and concentration of individual drug for each drug trial. . The inhibition of substance P is demonstrated by a 'shift to the right of your concentration curve-? answer. These trips are used to ; determine the value of pA2 that is defined as the negative log 1/0 of the molar concentration of the inhibitor that may require ^ the use of the double agonist to elicit a chosen response. This value is used to determine the relative potency of the antagonist.

Test of NK2 in tra < The methodology and general characterization of the response of the hamster trachea to the neurokinin agonists providing an assay of the NK2 monoreceptor is found in C.A. Maggi, et al., Eur. J. Pharmacol. 166 (1989) 435 and J.L. Ellis, et al., J. Pharm. Exp. Ther. 267 (1993) 95. Continuous monitoring of the isometric tension is achieved with Grass FT-03 force displacement transducers connected to electronic Buxco preamplifiers built in a Graphtec Linearcorder Model WR 3310.

Charles River LAK male hamsters: LVG (SYR), 100-200 g food weight are stunned by a blow to the head, The loss of the corneal reflex is assured, the hamsters P sacrifices by thoracotomy and cutting the heart. Segments of cervical trachea are removed to Krebs buffer at room temperature, pH 7.4, aerated with gas 95% of Q * > -5% C02, and cleaned of adherent tissue. The segments are cut into two ring segments of 3-4 mm in length.

The trachea rings are suependidos of the transducers and anchored in organ baths, 15.0 ml, enchaquetados de ^ water, by means of hooks of stainless steel and silk 6-0.-! The baths are filled with Krebs buffer, pH 7.4, maintained at 37 ° C and continuously aerated with 95% 02 95% C02 gas.

The trachea rings are placed under tension ÍS initial of 1.0 g and allowing to reach an equilibrium period of 90 min with 4 test cycles of 1 μM NKA, washing and recovery at intervals of 20 min. A pretreatment of 30 min with vehicle is followed by cumulative addition of ascending doses of NKA (3 nM-1 μM final concentration, intervals of 5 min between additions).

| The final NKA response is followed by a 15 min wash and recovery period. A pretreatment of 30 min I with a test compound or its vehicle is followed by i cumulative additions of ascending dosies of NKA (3 nM - 25 10 uM final concentration if necessary, 5 min interval between additions). The final NKA response is followed by a lmM carbachol test to obtain a maximum stress response in each tissue. Tissue responses to NKA are recorded as positive displacements on the baseline converted to voltage in grams by comparison with standard weights. The responses are normalized as a percent of the maximum tissue tension. The ED50 are calculated for NKA from the doses NKA responses of the control and treated, and compared. The test compounds result in an agonist dose ratio = 2 at a scanning concentration of 1 μM (ie, pA2 -> 6.0) are considered active. Other dose response data are obtained for assets so that an apparent estimate of pA2 can be calculated. The pA2 is calculated by estimating K¡_ as described in Furchgott (where pA2 = -Log Ka, RF Furchgott, Pharm. Rev. 7 [1995] 183) or by Shild Plot Analysis (O. Arunlakshana S HO Shild, Br , J. Pharmacol. 14 [1959] 48) if the data are sufficient.

Effect of NK antagonists! in guinea pigs on via microvascular filtration in the respiratory tract induced by substance P Studies are performed on male Hartley guinea pigs weighing in the range of 400-650 g. The animals are provides water and food ad libitum. The animals are anesthetized by intraperitoneal injection of dialurethane (containing 0.1 g / ml diallyl barbituric acid, 0.4 g / ml ethylurea and 0.4 g / ml urethane). The trachea is channeled just below the larynx and the animals are ventilated (Vt = 4 ml, f = 45 breaths / in) with a Harvard rodent respirator. The jugular vein is channeled for the injection of medications. The Evans blue dye technique (Danko, G- et al., Pharmacol, Commun., 1, 203-209, 1992) is used to measure microvascular filtration through the respiratory tract (AML). Evans blue (30 mg / kg) is injected intravenously, followed one minute later by i.v. injection. of substance P (10 μg / kg). Five minutes later, the thorax is open and a 13-gauge blunt-tipped needle passes through the aorta. It does an incision in the right atrium and the blood is expelled by washing with 100 ml of saline through the aortic catheter. The lungs and trachea are removed in block and the trachea and bronchi are then dried with filter paper and heavy. Evans blue is extracted by incubating the tissue at 37 ° C for 18 hr in 2 ml formamide in capped tubes. The absorbance of the formamide extracts of the dye is measured at 620 nm. The amount of dye is calculated by interpolation of a standard curve of Evans blue in the range of 0.5-10 μg / ml in formamide. The dye concentration is expressed as ng of dye per mg of heavy wet tissue. -The test compounds are suspended in vehicles of cyclodextran and dosed i.v. 5 minutes before the '5 substance P.

Measurement of in vivo activity of NK2 in vivo I Cobayoe Hartley males (400-500 mg). With free access to food and water are anesthetized with an injection Intraperitoneal Jp 0.9 ml / kg dialurethane (containing 0.1 g / m of diallyl barbituric acid, 0.4 g / ml of ethylurea and 0.4 g / ml of urethane). After induction in a surgical plane of anesthesia, vein cannulae are implanted I jugular, trachea and esophagus to facilitate breathing mechanics. The measurement of the "esophageal" pressure and Administration of medication, respectively. ft The guinea pigs are placed inside a plethysmograph of 'full body and the catheters are connected the cuerpoe ; of ealida on the wall of the plethismgraph. The air flow is measured using a differential pressure transducer i (Validyne, Northridge CA, model MP45-1 range ± 2 cm H20) that measures pressure through a protective wire net I covering a one-inch hole in the wall of the I plethysmograph. The air flow signal is integrated electrically to a signal proportional to the volume. The Transpulmonary pressure is measured as the pressure difference , between the trachea and the esophagus using a transducer , differential pressure (Validyne Northridge, CA, model MP45-1, f range ± 20 cm H20). The signals of the volume, air flow and transpulmonary pressure are monitored by means of a pulmonary analysis computer (Buxco Electronics, Sharon, CT, model 6) and used for the derivation of pulmonary resistance (Rj,) and dynamic pulmonary elasticity (CDyn) • I 10 Bronchoconstriction due to NKA \ Increasing IV doses of NKA are administered to ; semilogarithmic intervals (0.01-3 μg / kg) allowing i recovery of the baseline of pulmonary mechanics between 1 each dose. The peak of bronchoconstriction occurs within 1.5 of the 30 seconds after each dose of agonist. The , dose response is interrupted when Cpyn is reduced 80-90% of its baseline. A dose response is performed for NKA in 1 each animal. The test compounds are suspended in the cyclodextran vehicle and i.v. 5 min before the initiation of the dose response of NKA. , For each animal, the curves doeis answer for NKA 1 are constructed by graphing the percentage increases in j R O decrement in Cuyn against the log dose of the agonist. The ! doses of NKA that increase the RL by 100% (RL 100) or decrements CD? N by 40% (CD? N 40) of the values of the line base are obtained by linear-log interpolation of the dose response curves. > Neurokinin receptor binding assay (s) 5 Chinese hamster ovary (CHO) cells transfected with the coding regions for human neurokinin 1 (NK1) of the 2 receptors (NK :) of human neurokinin are 1 grown in a minimum essential medium of Dulbecco 'supplemented with 10% fetal bovine serum, 0.1 mM JO non-essential amino acids, 2 mM of glutamine, 100 units / ml of penicillin and streptomycin, and 0.8 mg of G418 I g / ml at 37 ° C in a humidified atmosphere containing 5% of C02 1 The cells are separated from the T-175 bottles with a sterile solution containing 5 mM EDTA in ealine.

I j buffered with phosphates. The cells are harvested by h centrifugation and washed in RMPI medium at 40 ° C for 5 minutes. j The package is resuspended in trie-HCl (pH 7.4) containing 1 μM foforamidon and 4 μg / ml of chymoetatin at a density cell of 30 x 106 cells / ml. The euspension is then j homogenized in a Brinkman Polytron (position 5) by 30-45 ' seconds. The homogenate is centrifuged at 800 x g for 5 min at 4 ° C until collecting unbroken cells and nuclei. He Supernatant is centrifuged in a Sorvall RC5C at 19,000 rpm (44.00 x g) for 30 min at 4 ° C. The package is resuspended, An aliquot is removed for a protein determination (BCA) and washed again. The resulting package ee : stored at -80 ° C. ^ To bind the receptor binding, 50 μl of [H] substance P (9-Sar, 11-Met [02]) (specific activity 41 Ci / mmol) (Dupont.NEN) (0.8 hM for the NK-1 assay). { or [H] -neurocinin A (specific activity 114 Ci / mmol) (Zenca) (1.0 nM for the NK-2 assay) is added to tubes containing buffer (50 mM Tris-HCl (pH 7.4) with 1 mM MnCl2 and 10 0.2% bovine serum albumin) and DMSO or the compound of «9 test. The binding is initiated by the addition of 100 μl of membrane (10-20 μg) containing the human NK-1 receptor or NK-2 in a final volume of 200 μl. After 40 minutes at room temperature, the reaction is interrupted by rapid filtration on Whatman GF / C filters that have been pre-soaked in 0.3% polyethyleneimine. The filters are washed twice with 3 ml of 50 mM tris-CHI (pH 7.4), and the filters are added to 6 ml of a Liquid cocktail of Ready-Safe scintillation and quantified by spectrometry. liquid scintillation in an LKB 1219 RackBeta counter. The non-specific binding is determined by the addition of 1 μM of CP-99994 (NK-1) or 1 μM SR-48968 (NK-2) (both synthesized, by the department of chemistry of the Inetituto de Research by Schering-Plow). The IC50 values are determine from the union curves by competition and Ki values are determined according to Cheng and 1 Prusoff using the experimentally determined value of 0.8 ! nM for the receiver NK-1 and 2.4 nM for the receiver JíK-2.

P Percent inhibition is the difference between i «5 percent maximum specific binding (MSB) and 100%. The by ; MSB cent is defined by the following equation, where "dpm" is disintegrations per minute: (fn of the unknown) - (non-specific binding dpm) 'MSB% = > x 100 i (total binding day) - (non-specific binding dpm) , it can be recognized that the compuets of the formula I exhibit antagonist activity of NKi, NK2 and / or NK3 at 1 different grades, for example, certain compounds have ! strong NK antagonist activity, but weaker activity 'antagonist for NK2 and NK3, while others spn strongly 1 antagonists of NK2, but weak antagonists for NKi, and H'S NK2. Although compounds with approximate equipotence are preferred, it is also within the scope of this invention to use the compounds of different NK1 / NK2 / NK3 antagonist activity when clinically appropriate. Through the use of test procedures described above, the compounds of the present Invention exhibit a range of activity: the percent "of inhibition at a dose of 1 μM, is in the range from ; about 1 up to about 81% inhibition of NKi and / or about 1 to about 96% inhibition of NK2. Preferred are compounds that exhibit more than about 50% NK inhibition and about 1 to about 96% »Of inhibition of NK2; Compounds are also preferred exhibit about 1 to about 81% inhibition ! of NKi and more than about 50% inhibition of NK2.

Compounds that exhibit more than i about 50% inhibition of NKi and greater than I 1 approximately 50% inhibition of NK2; of these In the case of compounds, compounds which exhibit greater than about 75% inhibition of N i and greater than about 75% inhibition of NK 2 are more preferred.

Claims (3)

1. CLAIMS 1. A compound represented by the structural formula: or a pharmaceutically acceptable salt thereof, wherein: A1 is -CH2R6, -OR6, -N (R6) (R7), -S (0) eR13, - (C (R6) (R7))? -6- OR6, - (C (R6) (R7)) 1-6-N (R6) (R7) OR - (C (R6) (R7))? -6-S (0) e 13 Y ñ2 is H, or A1 and A2 together are = 0, = C (R6) (R7), = N0R6 or = S; Q is R5-phenyl, R5-naphthyl, -SR6, -N (R6) (R7), -OR6 or R5-heteroaryl; i 4 4 15 T is H, R -aryl, R -heterocycloalkyl, R -heteroaryl, R-cycloalkyl or cycloalkyl with R-bridge; b is 0, 1 6 2; bi is 1 or 2; X is a bond, -C (0) -, -0-, -NR6-, -S (0) e-, -N (R6) C (0) - 20, -CC ((00)) NN (( RR ° 6)) - ,, --00CC ((00)) NNRR ° 6-- ,, --00CC ((== SS)) NNRR ° 6 ,, -N (R6) C (= S) 0 -, - _, - _Nvr ('Rr »° 6) S (0) 2-, -N (R6) C (0) 0- d -OC (0) -; 4 5 1 R and R are independently 1-3 substituents i j independently selected from the group consisting of J H, halogen, -OR6, -0C (0) R6, -OC (O) N (R6) (R7), -N (R6) (R7), C6 -6 alkyl, -CF3, -C2F5, -COR6, -C02R6, -CON (R6) (R7), - S (0) eR13, -CN, -OCF3, -NR6C02R16, -NR6COR7, -NR8C0N (R6) (R7), R15-f enyl, R15-benzyl, N02, -N (R6) S (O) 2 13 or -S (O) 2N (R6) (R7); or adjacent R substituents or adjacent R substituents »They can form a group -0-CH2 ~ 0-; and R 4 can also be R 15 - 5 heteroaryl; I R6, R7, R8, R8a and R13 are selected 1 independently of the group consisting of H, alkyl of C1-6, C2-C6 hydroxyalkyl, Ci-C3 alkyl, C? -Cf alkoxy, R15-phenyl and R1-benzyl; or R6 and R7, together with the nitrogen to which they are attached, form a "ring of 5 to 6 members, wherein 0, 1 or 2 ring members are I select from the group consisting of -O-, -S- and -N (R) -; i R and R are independently selected from the group [consisting of R and -OR, as long as R is OH, X is 1J5 a bond, -C (O) -, -N (R6) C (0) - or -C (= NOR6) - j R is independently selected from the group consisting of H and Ci-Ce alkyl; 1 1 R15 is 1 to 3 substituents independently I I selected from the group that you connected in H, Ci-Cß alkyl, Alkoxy of Ci-Cg, alkylthio of Ci-Ce, halogen, -CF3, -C2FS, -COR10, -C02R10, -C (O) N (R10) 2, -S (O) e 10, -CN, -N (R10) COR10, -N (R10) CON (R10) 2 and -N02; I R16 is C? -6 alkyl, R1S-phenyl or Rls-benzyl; I R19 is H, C? -6 alkyl, -C (O) N (R10) 2, -C02R10, -25 (C (R8) (R9)) f-C02R10 or - (C (R8) (R9) ) U "C (O) N (R10) z, f is 1-6; Z is f is 1-6; g and j are independently 0-3; h and k are independently 1-4, as long as the sum of h and g is 1-7; J is two hydrogen atoms, = 0, = S, = NR or = N0R; L and L are independently selected from the group consisting of H, C? -C? Alkyl, Ci-C? Alkenyl, cycloalkyl-CH2-, benzyl-R15, heteroaryl-Rls, -C (0) R6, - (CH2 ) m-OR6, - (CH2) mN (R6) (R7), - (CH2) mC (0) -OR6 and - (CH2) m- C (0) N (R6) (R7); p I m is 0 to 4, provided that j is 0, m is 1-4; ! R 25 is H, C 1 -C 6 alkyl, -CN, R 15 -phenyl or benzyl-R 15; R 26 and R 27 are independently selected from the group consisting of H, Ci-Cß alkyl, aryl-R and heteroaryl-R; or ! , R26 is H, Ci-Cß alkyl, aryl-R4 or heteroari lo-R4, and R27 [is -C (0) R6, -C (0) -N (R6) (R7), -C (0) (aryl-R4), I C (0) (heteroaryl-R4), -S02R13 or -S02- (aryl-R4); R28 is H, -C (R6) (R19)) t-G or - (C (R6) (R7)) v-G2; t and v are 0, 1, 2 or 3, provided that j is 0, t is 1, 2 or 3; R29 is H, C? -Ce alkyl, -C (R10) 2S (O) eR6, phenyl-R4 or P heteroaryl-R4; 5 G is H, aryl-R, heterocycloalkyl-R, heteroaryl-R, ! Cycloalkyl-R4, -OR6, -N (R6) (R7), -COR6, -C02R6, -CON (R7) (R9), iS (0) eR13, -NR6C02R16, -NR6COR7, -NR8CON (R6) ( R7), -N (R6) S (O) 2R13, | -S (0) 2N (R6) (R7), -OC (0) R6, -OC (0) N (R6) (R7), -C (= NOR8) N (R6) (R7), -C (= NR2S) N (R6) (R7), -N (R8) C (= NR2S) N (R6) (R7), -CN, -C (O) N (R6) OR7 10 or -C (0) N (R) - (heteroaryl-R), as long as n is 1 and v ^ is 0 or when R9 is -OR6, G is not -OH or -N (R6) (R7); Y G is aryl-R4, heterocycloalkyl-R, heteroaryl-R, ! cycloalkyl-R4, -COR6, -C02R16, -S (O) 2N (R6) (R7) or j -CON (R6) (R7). 1. The compound of claim 1 wherein X ee -O-, I -NR6, -N (R6) C. { 0) -, -OC (0) NR6-, or -N (R6) C (O) O-. 3. The composition of any of claims 1 or | 2, wherein A1 is -CHR6, -OR6, -N (R6) (R7), -S (O) eR13 or, -, (C (R6) (R7))? -6-N (R6) (R7) ) and A2 is H; or A1 and A2 together are = 0, was of claims 1, 2 or R-heteroaryl; Q is R5-phenyl, and Z is selected from the group 5. The compound of any of claims 1, 2, 3 or 4, wherein b is 0 or 1; b, is 1; X is -NR6- or -N (R6) C (0) -I; Rßa and R9a are independently selected from the group ] consists of: hydrogen, hydroxyalkyl and alkoxyalkyl; T is Phenyl substituted by two substituents selected from I group consisting of C6-C6 alkeyl, halogen, -CF3 and ! Ci-Cß alkoxy; and Q is phenyl disubstituted by halogen, H naphthyl or benzothienyl. I 6. The compound of claim 1, which is: N- [2- (3,4-dichlorophenyl) -3-hydroxy-4- (4-hydroxy-4-phenyl-l-piperidinyl) butyl] -N-methyl benzamide; ! N- [3-hydroxy-4- (4-hydroxy-4-phenyl-1-piperidinyl) -2- (4-methoxyphenyl) butyl] -N-methyl benzamide; N- [3-hydroxy-4- (4-hydroxy-4-phenyl-1-piperidinyl) -2- phenylbutyl] -methylbenzamide; N- [2- (4-chlorophenyl) -3-hydroxy-4- (4-hydroxy-4-phenyl-1-piperidinyl) util] -N-methyl benzamide; N- [3-H? Drox? -4- (4-hydroxy-4-phenyl-1-piperidinyl) -2- (4-P-methylphenyl) -butyl] -N-methyl-benzamide; 5 1, 1-dimethylethyl- [2- (3,4-dichlorophenyl-3-hydroxy-4- (4-hydroxy-4-phenyl-1-piperidinyl) butyl] carbamate; 1,1-dimethylethyl- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-phenyl-1-? Piperidinyl) -3-methoxybutyl] carbamate; j N- [2- (4-chlorophenyl) -4- (4-hydroxy-4-) phenyl-1-piperidinyl) -3-10 methoxybutyl] -N-methyl benzamide; H N- [2- (3, -dichlorophenyl) -4- (4-methoxy-4-phenyl-1-piperidinyl) -3-methoxybutyl ] -N-methyl benzamide;! N- [2- (3, 4-dichlorophenyl) -4- (4-hydroxy-4-phenyl-1-piperidinyl) -i! 3-oxobutyl] -N-methyl benzamide; 5 N- [2- (3, -dichlorophenyl) -4- (4-hydroxy-4-phenyl-1-piperidinyl) - I j 3- (methoxy-II) butyl] -N-methylbenzamide; or N-faith [3- [[3,5-bis (trifluoromethyl) phenyl] methoxy] -2- (3, 4- | dichlorophenyl) -4- (4-hydroxy-4-phenyl-1-piperidinyl) butyl-N-1 methyl benzamide; 2p N- [3- [[3,5-bis (trifluoromethyl) phenyl] methoxy] -4- (4-h? droxl-4- | phenyl-1-piperidyl) -2-phenylbutyl] -N-methylbenzamide;; a- [l- (3,4-dichlorophenyl) -2- [meth] (phenylmethyl) amino] ethyl] -4- hydr oxy-4-phenol-1-piperidinetanol; or 1- [2- [[3,5-bis (trifluoromethyl) phenyl] methoxy] -3- (3,4-dichlorophenyl) -4- [methyl (phenylmethyl) amino] butyl] -4-phenyl-4- (piperidinol) . 7. A pharmaceutical composition containing an effective amount of a compound of any one of claims 1, 2, 3, 4, 5 or 6 in a pharmaceutically acceptable carrier. 8. A method of preparing a composition as recited in claim 7 comprising mixing a The compound of any one of claims 1 to 6 with a pharmaceutically acceptable carrier. I 9. The use of a compound of any of claims 1 to 6 for the preparation of a medicament I for the treatment of asthma, cough, bronchoeepaemo, ! diseases of the central nervous system, inflammatory diseases and gastrointestinal disorders. 10. A method of treatment - asthma, cough, bronchospasm, central nervous system diseases, inflammatory diseases and gastrolntestinalee disorders comprising 20 administering an effective amount of a compound of any of claims 1 to 6, to a mammal in need of such treatment.