MXPA99004128A - Substituted oximes derivatives useful as neurokinin antagonists - Google Patents

Abstract

The compounds (a, b, c, d, e, f, g, h, i, j, k or l) are disclosed for use as neurokinin antagonists.

Description

DERIVATIVES OF SUBSTITUTE QXIMAS USEFUL AS NEURQCININ ANTAGONISTS FIELD OF THE INVENTION The present invention relates to a genus of substituted oximes, hydrazones and oiefins, useful as antagonists of tachykinin receptors, in particular, as neuropeptide antagonists of neurocipin 1 receptor (NK-i) and / or neurokinin 2 receptor (NK2). ) and / or neurokinin 3 receptor (NK3).

BACKGROUND OF THE INVENTION Neurokinin receptors are found in the nervous system and in the circulatory system and peripheral tissues of 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 various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, non-perception, and several gastrointestinal disorders such as Crohn's disease. In particular, it has been reported that NK1 receptors are involved in microvascular effusion and mucus secretion, and has been associated with NK2 receptors with smooth muscle contraction, making the receptor antagonists Ki and NK2 especially useful in the treatment and prevention of asthma. Some NKi and NK2 receptor antagonists have been described above: aplaxkylamines are described in U.S. Patent No. 5,350,852, issued September 27, 1994, and spiro-substituted azacycles are described in WO 94/29309, published on 22 of December of 1994.

BRIEF DESCRIPTION OF THE INVENTION The compounds of the present invention are represented by the formula I: or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or 3; b and d are independently 0, 1 or 2; R is H, C 6 alkyl, OR 6 or C 2 -C 6 hydroxyalkyl; A is = N-OR1, = N-N (R2) (R3), = C (R11) (R12) or = NR25; X is a bond, -C (O) -, -O-, -NR6-, S (?) ß-, -N (R6) C (0) -, -C (0) N (R6) -, - 0C (O) NR6-, -OC (= S) NR6-, -N (R6) C (= S) 0-, -C (= NOR1) -, -S (0) 2N (R6) -, -N (R6) S (0) 2, N (R6) C (0) 0- or -OC (O) -, with the proviso that when d is 0, X is a bond, -C (O) -, - NR6-, -C (0) N (Rs) -, -N (R6) C (0) -, -OC (0) NR-, -C (= NOR1) -, - N (R6) C (= S ) 0-, -OC (= S) NR6-, - N (R6) S (0) 2- or - N (Rβ) C (0) 0-; with the proviso that when A is = C (R11) (R12), and d is 0, X is not -NRS- nor -N (R6) C (0) -; and with the proviso that when it is = NR25, d is 0 and X is - NR6- or - N (R6) C (0) -; T is H, R4-aryl, R4-heterocycloalkyl, R4-hetero-pyl, phthalimidyl, R4-cycloalkyl or R10-c? Doalkyl bridged; Q is R5-heteroaryl; R1 is H, C? -β alkyl, - (C (R6) (R7)) nG, -G2, - (C (R6) (R7)) PM- (C (R13) (R14)) n- ( C (R8) (R9)) uG, -C (0) N (R6) - (C (R13) (R1)) n- (C (R8) (R9)) lJ-G or - (C (R6)) (R7)) pM- (R4-heteroaryl); R2 and R3 are independently selected from the group consisting of H, C?. Beta alkyl, -CN, - (C (Rβ) (R7)) nG, -G2, -C (?) - (C (R8) ( R9)) "- G and - S (0) TR13, or R2 and R3, 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 selected from the group consisting of -O-, -S- and -N (R19) -; R4 and R5 are independently 1-3 substituents, independently selected from the group consisting of H, halogen, -OR6, -OC (0) R6, -? C (0) N (R6) (R7), -N (R6) (R7), Ci-β alkyl, -CF3, -C2F6, -COR6, -C ?2R8, -C0N (R6) (R7), -S (0) eR13, -CN, -OCF3, -NR8C02R1ß, - NRßCOR7, - NR8CON (R6) (R7), R15-phenyl, R5-benzyl, N02, -N (R6) S (0) 2R13 or -S (0) 2N (R6) (R7); 0 adjacent R4 substituents or adjacent R5 substituents can form a -0-CH2-0- group; and R4 may also be R15-heteroaryl; R6, R7, R8, R6a, R7a, R83, R13 and R14 are independently selected from the group consisting of H, Ci ^ alkyl, C2-C6 hydroalkyl, aicox d-CβJ-C, -C6 alkyl, R15- phenyl and R15-benzyl; or R6 and R7, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, where 0, 1 or 2 ring members are selected from the group consisting of -O-, -S- and -N (R19) -; R9 and R9a are independently selected from the group consisting of R6 and -OR6; R10 and R, 0a are independently selected from the group consisting of H and Ci.β alkyl; R11 and R12 are independently selected from the group consisting of H, C? -C6 alkyl, -C02R6, -OR6, -C (0) N (R6) (R7), C6 hydroxyhalky, - (CH2) r0C ( 0) R6, - (CH2) r0C (0) CH = CH2, - (CH2) rO (CH2) s-C02R6, - (CH2) r-0- (CH2) sC (0) N (R6) (R7) and - (CH2) rN (R6) (Rr); R15 is 1 to 3 substituents independently selected from the group consisting of H, C? -C? Alkoxy alkyl, Ci-Ce alkylthio, halogen, -CF3, -C2F5, -COR10, -C02R10, -C (O) N (R10) 2, S (O) eR10a, -CN, -N (R1 °) COR1 °, -N (R, 0) COR10, -N (R10) CON (R10) 2 and -NOz; R16 is alkyl of d-β, R15-phenyl or R15-benzyl; R19 is H, C -Cβ alkyl, -C (O) N (R10) 2, -C02R10, - (C (R8) (R9)) r C? 2R10 or - (C (R8) (R9)) uC ( O) N (R10) 2; f, n, p, r and s are independently 1-6; u is 0-6; G is selected from the group consisting of H, R4-aryl, R4-heterocycloalkyl, R -heteroaryl, R4-cycloalkyl, -OR8, -N (R6) (R7), -COR6, -C02R6, C (0) N ( R7) (R9), -S (0) eR13, -NR6C02R16, -NR6C02R16, -NR8COR7, -NR8CON (R6) (R7), -N (R6) S (0) 2R13, -S (0) 2N (R6) ) (R7), -OC (0) R6, -OC (0) N (R6) (R7), -C (= NOR8) N (R6) (R7), -C (= NR25) N (R6) ( Rr), -N (R8) C (= NR25) N (R6) (R7), -CN, -C (0) N (R6) 0R7, and -C (0) N (R9) - (R -heteroaryl ), with the proviso that when n is 1 and u is 0, or when R9 is -OR8, G is not -OH or -N (R6) (R7); is selected from the group consisting of a double bond, -O-, N (R6) -, -C (O) -, -C (R6) (OR7) -, -C (R8) (N (R6) (R7)) -, -C (= NOR6) N (R7) - , -C (N (R8) (R7)) = NO-, -C (= NR25) N (R6) -, -C (0) N (R9) -, -N (R9) C (0) -, -C (= S) N (R9) -, -N (R9) C (= S) - and -N (R6) C (0) N (R7) -, with the proviso that when n is 1, G it is not OH or -NH (R6); and when p is 2-6, M can also be -N (R6) C (= NR2) N (R7) - or -OC (0) N (R6) -; G2 is R4-aryl, R -heterocycloalkyl, R -heteroaryl, R -cycloalkyl, -COR6, -C02R'6, -S (0) 2N (R6) (R7) or -CON (R6) (R7); e is 0-2, with the proviso that when e is 1 or 2, R13 and R10a are not H; R 25 is H, C 1 -C 6 alkyl, -CN, R 15 -phenyl or R 6 -benzyl; Z is or morpholinyl; g and j are independently 0-3; h and k are independently 1-4, with the proviso that the sum of h and g is 1 -7; J is two hydrogen atoms, = 0, = S, = NR9 or = NOR1; L and L1 are independently selected from the group consisting of H, d-C6 alkyl, CrC6 alkenyl, -CH2-cycloalkyl, R1d-benzio, R16-heteroaryl, -C (0) R6, - (CH2 ) m-OR6, - (CH2) mN (R6) (R7), - (CH2) mC (0) -0R8 and - (CH2) mC (0) N (R6) (R7); m is from 0 to 4, with the proviso that when j is 0, m is 1 -4; R26 and R27 are independently selected from the group consisting of H, C? -C6 alkyl, R4-aplo and R -heteroaryl; or R28 is H, alkyl of d-Ce, R4-aryl or R -heteroappe and R27 is -C (0) R6, -C (0) -N (R6) (R7), -C (?) (R4- aryl), -C (0) R4-heteroaryl), -S02R13 or -S02- (R4-aryl); R28 is H, - (C (R6 (R19)) rG, - (C (R6) (R7)) v-G2 or -N02; t and v are 0, 1, 2 6 3, with the proviso that when j is 0, t is 1, 2 or 3; R29 is H, C? -C? Alkyl, -C (R10) 2S (0) eR6, R -phenyl or R4-heteroaryl; R 30 is H, C 1 -C 6 alkyl, R 4 -cycloalkyl, - (C (R 1c) 2) w- (R -phenyl), - (C (R 10) 2) W (R -heteroaryl), -C (0 ) R6, C (0) OR6, -C (0) N (R6) (R7), RIO V R10 V 1"- * r. - (C) -C-N (R6) (R7) - (C) w-C-N 3 RIO R? O ^ -L w is 0, 1, 2 0 3; V is = 0, = S or = NR6; and q is 0-4.

Preferred are compounds of formula I wherein X is -O-, -C (O) -, a bond, -NR6- -S (0) e-, -N (R6) C (0) -, -OC ( 0) NR6 or C (= NOR1) -. More preferred are compounds of formula I wherein X is -O-, -NR6-, -N (R6) C (0) - or -OC (0) NR6. Additional preferred definitions are: b is 1 or 2 when X is -O- or -N (R8) -; b is 0 when X is -N (R6) C (0) -; and d is 1 or 2. Preferably, T is R ^ -aryl, R ^ heteroaryl, R-cycloalkyl or bridged R10-cycloalkyl, with R "aryl, especially R ^ -phenyl being preferred. they prefer the compounds wherein R6a, R7a, R a and R9a are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are the compounds in which R8a and R9a are each hydrogen, d and d are each 1, X is -O-, NR6-, -N (R6) C (0) - or -OC (0) NR6 T is Rianyl and R4 is two substituents selected from Ci-Cß alkyl, halogen, -CF3 and Ci-Cβ alkoxy- Preferred definitions for T which is R -heteroaryl, include R4"-quinolinyl and oxadiazolyl. Preference is given to compounds of formula I in which R is hydrogen Preferably, Q is R5"heteropole, wherein R5 is hydrogen. An especially preferred definition for Q is benzothienyl. Preferred are compounds of formula I wherein A is = N-OR 1 or = N-N (R 2) (R 3) Most preferred are compounds wherein A is = N-OR 1. R1 is preferably H, alkyl - (CH2) "- G, - (CH2) pM- (CH2) nG or -C (0) N (R6) (R7), wherein M is -O- or -C (0 ) N (R9) - and G is C02R6, -OR6, -C (0) N (R6) (R9), -C (= N0R8) N (R6) (R7), -C (0) N (R9) (R4-heteroaryl) or R ^ heteroaryl. R2 and R3 are independently preferably H, d-C6 alkyl, - (C (R6) (R7)) n-G or G2. The preferred definitions of Z are: and R30-N N- the following groups being very preferred: This invention also relates to the use of a compound of formula I in the treatment of 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 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, bronchospasm, inflammatory diseases such as arthritis, migraine, nociception, and various gastrointestinal disorders such as Crohn's disease.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "alkyl" means straight or branched alkyl chains. "Lower alkyl" refers to alkyl chains of 1 to 6 carbon atoms and, similarly, lower alkoxy refers to alkoxy chains of 1 to 6 carbon atoms. "Cycloalkyl" means cyclic alkyl groups having from 3 to 6 carbon atoms. "Bridged cycloalkium" refers to saturated C7-C10 rings comprised of a cycloalkyl ring or fused bicycloalkyl ring and an alkylene chain attached at each end to non-adjacent carbon atoms of the ring or rings. Examples of such bridged bicycloalkyl rings are adamantyl, mirtanil, noradamantyl, norbornyl, bicyclo [2.2.1] heptyl, 6,6-dimethebicyclo [3.1.1.] Heptyl, bicyclo [3.2.1] octyl, and bicyclo [2.2.2] octyl. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. "Halogen" refers to fluorine, chlorine, bromine or iodine atoms. "Heterocycloalkyl" refers to saturated rings of 4 to 6 members comprising 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S- and -N (R19) -, the remaining ring members being carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

R -heterocyc-cloalkyl refers to those groups in which the substitutable carbon atoms of the ring have a R4 substituent. "Heteroaplo" refers to benzofused or simple aromatic rings of 5 to 10 members comprising 1 to 4 heteroatoms independently selected from the group consisting of -O-, -S- and N =, provided that the rings do not include adjacent oxygen atoms and / or sulfur.

Examples of heteroaryl groups of a single ring are piphodyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazoium, thiadiazolyl, pyrazinyl, pyrimidium, pyridazinyl and triazolyl. Examples of benzofused heterolalk groups are indolyl, quinolyl, benzothienyl (ie, thionaphtenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. Also included are N-oxides of hetero-halo groups containing nitrogen. All positional isomers are contemplated, for example, 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. R "heteroaryl" refers to those groups wherein the substitutable carbon atoms of the ring have a substituent R4. Where substituents R2 and R3 or R6 and R7 on a nitrogen atom form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and / or sulfur atoms or 3 adjacent heteroatoms. Typical rings thus formed are morpholinyl, piperazinyl and piperidinyl. In the structures in the definition of Z, the substituents L and L1 may be present on any substitutable carbon atom, including in the second structure the carbon to which the group -N (R26) (R27) is attached. In the above definitions, where the variables R6, R7, R8, R9, R10, R13, R14, R15 and R30, for example, it is said that they are selected independently from a group of substituents, it is understood that R8, R7, R8, R9, R10, R13, R14, R15 and RC are independently selected, but also that where a vapable R6, R7, R8 occurs , R9, R10, R13, R14, R15 and R30 more than once in a molecule, these occurrences are independently selected (for example, if R is -OR6- where R6 is hydrogen, X can be -N (R6) - wherein R6 is ethyl). Similarly, R4 and R5 can be independently selected from a group of substituents, and wherein more than one R4 and R5 are present, the substituents are independently selected; those skilled in the art will recognize that the size and nature of the substituent or substituents will affect the number of substituents that may be present. The compounds of formula I can have at least one asymmetric carbon atom, and all isomers including diastereomers, enantiomers and rotational isomers, as well as E and Z isomers of the oxime, hydrazone and olefin groups are contemplated as part of this invention. . The invention includes d and I isomers in both pure form and in mixture, including racemic mixtures. The isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials, or by separating the isomers of a compound of formula I.

The person skilled in the art will appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than 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, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to the skilled artisan. The matter. 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 suitable diluted aqueous base solution, such as dilute aqueous sodium bicarbonate. The free base form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but the salt otherwise is equivalent to its respective free base forms for the 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 inorganic and organic bases. Examples of said salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Pharmaceutical salts formed with amines are also included acceptable such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like. The compounds of formula I can be prepared using methods well known to the person skilled in the art. Next, typical procedures are given for preparing composite compounds; the person skilled in the art will recognize that other methods may be applicable, and that the methods may be suitably modified to prepare other compounds within the scope of the compounds of formula I.

Method A - Compounds of formula I as defined above can be prepared as shown in the following reaction scheme: Step 1: (A: R21 = alkoxy B: R21 = Cl C: R21 = -N (CH3) OCH3) In step 1, a compound of formula 2A, in which Q is as defined above, is reacted with a kiss such as lithium diisopropylamide (LDA) or KH in an inert organic solvent such as THF or DE, to generate a dianion. An acid, ester or amide chloride of formula 1A, B, or 1 C is added to give a ketone of formula 3. Preferred reaction temperatures vary from -78 ° C to 30 ° C. Alternatively, the compounds of formula 3 are can generate by reacting a compound of formula 1, preferably J_C, with a metallized species of formula QCH2Mt wherein Mt is a metal such as MgHal, where "Hal" is halogen or lithium. Metallized species QCH2Mt can be generated by conventional methods such as treatment of compounds of formula QCH Hal with Mg, or by treating QCH3 with an organolithium base. Step 2: 3 In step 2, for compounds of formula I wherein R is not hydrogen, the ketone 3 is reacted with a suitable base such as LDA or KH in an inert organic solvent such as THF. For compounds in which R is alkyl or hydroxyalkyl, a compound R-R17"is added, wherein R17"is a leaving group such as Br, I or triflate. where R is OH, an appropriate oxidizing agent such as dimethyldioxirane or Davis reagent is added. Preferred reaction temperatures range from -78 ° to 50 ° C.

Step 3: In step 3, the ketone 4 is reacted with a base such as LDA in a solvent such as THF, then an olefin of formula 5 is added, wherein R17"is as defined above, to give the adduct 6. The Preferred reaction temperatures vary from -78 ° C to 60 ° C Step 4: In step 4, the ketone 6 is reacted with HA ', where A' is NH-OR1, NH-N (R2) (R3) or NHR25, in an organic solvent such as pyridine at a temperature of 25 ° C. at 150 ° C to give a compound of formula 7.

Step 5: In step 5, a compound of formula 7 is oxidized by means of ozonolysis to give an aldehyde of formula 8. Suitable organic solvents include ethyl acetate, ethanol or the like. Preferred reaction temperatures are -78 to 0 ° C Step 6: In step 6, an aldehyde of formula 8 is reacted with a compound of formula Z-H, wherein Z is as defined above. Step 6 is preferably carried out with a suitably substituted amine (such as its acid salt, for example CHI or maleate or as its free base) and a hydride source such as NaBH3CN or sodium triacetoxyborohydride in a protic solvent (vgr. CH3OH, CH3CH2OH, or CF3CH2OH) with 3A sieves to obtain the compound of formula I. Any suitable temperature can be used with preferable temperatures between 0 ° C and 25 ° C Alternatively, a compound of formula I can be prepared from 6 by means of the following reaction scheme: Compound 6 is oxidized to form a compound of formula 9 under conditions similar to those described for step 5 above. The aldehyde of formula 9 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 the formula HA 'as described above in Step 4 to obtain the compound of formula I.

Method B: The compounds of formula I wherein X is -O- or a bond, and d is 1 or 2, can be prepared by means of the following reaction scheme, starting with the ketone 4 of procedure A. Alternatively, the compounds of Formula 4 can be prepared from compounds of formula ID, wherein X is -O-, R63 and R7 are each of them H, and d is 1, which in turn is prepared according to any of the following two schemes of reaction: Scheme to: wherein a compound of formula 10, wherein R21 is alkoxy or -N (CH3) OCH3, and R17 is as defined above, is reacted with an alcohol of the formula HO- (C (R8a) (Rβa)) - T in the presence of a suitable base such as Cs2C03 or KHMDS.

Scheme b: wherein a compound of formula 10a, wherein R21 is alkoxy, is reacted with a compound of R20-R17 in which R17 is a leaving group such as Cl or Br, and R2C is any of the formula: wherein R4, R8a, R9a and b are as defined above, or R20 is trialkyl or diaplalkysilyl in the presence of a suitable base such as Cs2C03, Hunigs base or KHMDS.

Step 1 : In step 1, the compounds of formula 4 are treated with an appropriate base such as NaHDMS, reacted with alkylating agents of the formula R33C (0) CH2R17 or R33C (0) CH = CH2 wherein R33 is alkoxy or -N ( CH3) OCH3, and R17 is as defined above.

Step 2: OR 'R9a RN R' 11 »- R v ***. A (C -) d, - - d- xX- (< QO b. - - T o i i Q R7 a B 12 In step 2, the compounds of formula V can be converted to the corresponding oxime of formula 12 in a manner similar to that described in process A, step 4.

Step 3: In step 3, a compound of formula 12 (or H, that is, where A 'is O) is converted to the corresponding aldehyde 13 (or keto-ester lactol) 11) by treatment with a suitable reducing agent such as a DIBAL, in a suitable inert organic solvent such as THF, at a temperature of about -100 to -20 ° C.

Step 4: In step 4, compound 13. is reacted with an amine ZH in a manner similar to that described in process A, step 6, to obtain the compound of formula I. Alternatively, as shown in the following scheme of reaction, the compounds of formula 14 wherein R is H, A 'is = 0, X is -O- and R33 is alkoxy, can be converted into the corresponding lactol of formula 15 by means of treatment with a suitable reducing agent such as DIBAL, in a suitable inert organic solvent such as THF, at a temperature of -100 to -20 ° C, approximately: The lactol is then reacted with an amine ZH as deciphered in the process A, step 4, to give the aminoalcohol 6. When R20 is diarylalkysilyl, the compound 4 (derivative of JjE) taken by the same steps (steps 1 to 4), is converted to compound 15 16, which is desilylated by treatment with fluorophore ion, preferably TBAF, to give the alcohol oxime 17. twenty Step 5: The alcohol oxime 17 can be alkylated, acylated or reacted with socianates to obtain ether or carbamate compounds of formula 1. The alkylations are carried out using a base such as NaH, K2C0 or Cs2C03, in a solvent such as DMF, THF or CH2Cl2, with an alkylating agent such as an alkyl or benzyl halide or sulfonate. The acylations are carried out using an appropriate carboxylic acid in the presence of a dehydrating agent, for example DEC in the presence of HOBT.

Process C The compounds of formula I, wherein A is an oxime wash and X is an amide or urea, are prepared by the oxidation of an alcohol oxime and the reaction of the resulting aldehyde with an amine, followed by alkylation, acylation, sulfonation or reaction with an isocyanate as shown below: Step 1: R10 ^ 11! I aíV ¡H n In step 1, the alcohol oxime 17 is oxidized with o-iodoxybenzoic acid at room temperature in a solvent such as DMSO or DMF in the presence of an acid such as trifluoroacetic acid.

Step 2: In step 2, compound 18 is reacted with an amine R6NH, wherein R6 is as defined above, in an alcohol such as CH3OH, CH3CH20H, preferably CF3CH2OH, in the presence of a dehydrating agent such as molecular sieves and a reducing agent such as NaCNBH3 to obtain 19.

Step 3: In step 3, the amine 19 can be alkylated, acylated, sulfonylated or reacted with isocyanates to obtain compounds of formula 1. The alkylations are carried out using a base such as TEA, K2C03 or Cs2C03, in a solvent such as DMF, THF or CH2Cl2, with an alkylating agent such as an alkyl or benzyl halide or sulfonate. The acylations are carried out using an appropriate carboxylic acid in the presence of a dehydrating agent, for example DEC in the presence of HOBT. The sulfonating is carried out by treatment with appropriate sulfonyl chlorides in the presence of a base such as diisopropylethylamine or Et ^ in solvent such as CH2Cl2 or THF. In the above procedures, the corresponding olefins (compounds in which A is = C (R11) (R12)) can be prepared from the respective keto compounds using the standard Wittig chemistry, known to the person skilled in the art. Reactive groups not involved in the above processes can be protected during reactions with conventional protecting groups that can be removed by standard procedure after the reaction. The following table 1 shows some typical protective groups: TABLE 1 G It has been found that the compounds of formula I are antagonists of the Nr ^ and / or NK2 and / or NK3 receptors, and are therefore useful in the treatment of conditions caused or aggravated by the activity 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 forms such as capsules, tablets, powders, wafers, 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.

Pharmaceutically acceptable excipients and additives include fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricantsflavors, thickeners, coloring agents, emulsifiers and the like, non-toxic and chemically compatible. The daily dose of a compound of formula I for treating 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 to about 5 mg / kg. For an average body weight of 70 kg, the dosage scale is therefore about 1 to about 1500 mg of drug per day, preferably about 50 to about 200 mg, preferably about 50 to about 500 mg / kg per day , administered in a single dose or in 2 to 4 divided doses. However, the exact dose is determined by the clinician in charge and depends on the power of the administered compound, age, weight, condition and patient's response. The following are examples of preparation of 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 J? • ^ o r CF.

Treat methyl glycolate (1.4 g, 0.015 mol) in 50 ml of anhydrous THF at 0 ° C with sodium hydride (0.65 g, 0.0165 mol). Stir the mixture for 0.5 hour and add 3,5-bis trifluoromethylbenzyl bromide (5 g, 0.0165 moles). Allow the mixture to reach room temperature and stir for 10 more hours. Quench the reaction with CH3OH (5 mL). Wash with water (3 x 100 ml) and brine (2 x 100 ml), separate the organic layers, dry over MgSO, filter and concentrate under vacuum to obtain a crude oil. Purify by silica gel chromatography (10% EtOAc / hexane) to obtain pure product (4.2 g).

PREPARATION 2 Me0 ^ d ^ OS1Bu '(P) 2 O 2 Treat methyl glycolate (14 g, 0.15 mol) in 200 ml of CH2Cl2 with Et ^ N, (23 ml, 0.165 mol), dimethylaminopyridine (3 g, 0.03 mol) and t-butyldiphenium silylchloride (46 g, 0.165 mol) . Stir the mixture for 24 hours and then dilute with 200 ml of CH2Cl2. Wash with water (3X100 ml), and brine (2 x 100 ml), separate the organic phases, dry over gS? , filter and concentrate under vacuum to obtain a crude oil. Pupficar by means of chromatography of silica gel (hexane as eluent) to obtain pure product (46 g).

PREPARATION 3 Treat a solution of 2-thiophenacetic acid (1.6 g, 11.2 mmol) in anhydrous THF (100 mL, -78 ° C) with lithium hexadimethylsilazide (24.5 mmol, 1 M THF sol). Heat the solution at 0 ° C for a period of 2 hours, then cool to -78 ° C and add dropwise [[3,5-bis (trifluoromethyl) phenol] -methoxy-ethyl acetate (3.55 g, 11.2 mmol) as a solution in THF. (10 ml). Stir the resulting mixture for 4 hours and allow the temperature to reach 0 ° C. Quench the reaction with 1 ml of HOAc and stir for 4 hours. Dilute the reaction with EtOAc (100 ml), wash the organic phases with water (2 × 50 ml) and brine (1 × 50 ml), dry (Na 2 SO 4) and concentrate to obtain 3.4 g of pure product. Purify by silica gel chromatography (Et20: hexane, 3: 7) to give the title compound, 2.8 g (7.3 mmol, 65.4%) as a colorless foam. MS: (CI + / CH4) (M + H +) 383.

PREPARATION 4 Treat a solution of 4-picoline (1.42, 15 mmol) in anhydrous THF (50 ml, -10 ° C) with phenyllithium (15 mmol, 8.3 ml of cyclohexane: Et20) and stir for 1 hour at 0 ° C. solution at -78 ° C and add the product of example 47, step 1 (5.27 g, 15 mmol), dropwise as a solution in THF (10 ml), and stir the resulting mixture for 4 hours (-78 ° C to 0 ° C) and quench with saturated aqueous NH4CI (10 ml), extract with EtOAc (100 ml), wash with water (2X50 ml), brine (50 ml), dry (Na2SO), and concentrate. silica gel column chromatography (EtOAc: hexane, 8: 2) to obtain the title compound. MS: (CI + / CH4) (M + H +) 378. Using a similar procedure with the appropriate heteroaryl acid or the heteroaryl methyl compound and a corresponding methyl ester, the following compounds were prepared, wherein Q and T are as defined in the table: PREPARATION 5 Step 1 The ketone of preparation 4H is taken by steps 1 to 4 of Example 1 Step 2: Treat the product of step 1 (6.3 g, 0.009 mol) in 50 ml of anhydrous THF with tetrabutylammonium fluoride (0.01 mol). Stir the mixture at room temperature for 24 hours and then dilute with 100 ml of EtOAc. Wash with water (2 × 50 ml) and brine (2 × 50 ml), separate the organic phases and dry over MgSO 4, filter and concentrate under vacuum to obtain a crude oil. Purify by silica gel chromatography (CH3OH saturated with 1.5% ammonia / hexane: EtOAc, 3: 1) to obtain the title compound (4.1 g). MS: (FAB + M + H +) = 439.2.

PREPARATION 6 Piperidines substituted-Method A Step 1 : Dissolve 4-aminomethylpiperidine (30.00 g, 0.263 mol) in CH3OH (500 mL), cool to -30 ° C under N2, add di-t-butyl bicarbonate (38.23 g, 0.175 mol) in CH3OH (100 mL) in the form of drops, let slowly reach 23 ° C and shake for 16 hours. Concentrate, add CH2Cl2 (700 mL), wash with saturated aqueous NaCI (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 1.1-dimethyl. ethyl 4 - [(1, 1-d-methyl) -lethyloxycarbonyl) methyl] -1-p-peridinecarboxylate.

Step 2: Dissolve the product (19.65 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.

Add pyridine (10.87 g, 11.1 ml, 0.137 mol) then chlorovaleryl chloride (15.63 g, 13.0 ml, 0.101 mol), allow to slowly reach 23 ° C and stir for 16 hours. Add saturated aqueous NH4CI (300 mL), separate the layers and extract with CH2Cl2 (2X250 mL). Dry the combined organic extracts (MgSO4), filter and concentrate. Purify by chromatography (1000 ml of flash silica gel, eluent: EtOAc: hexane, 1 '1, then EtOAc). Combine the appropriate fractions and concentrate to give 25.36 g (0.0762 mol, 84%) as a colorless oil. MS (CI / CH4): m / e 333 (M + 1) t t - BBuuOO 'N ^ Step 2B: Treat the product from step 1 in a procedure similar to that described for step 2A, using chlorobutyryl chloride. MS (FAB): m / e 319 (M + 1) Step 3: t-BuO C Preparation 6A: 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 O-C under N2. Add the product (25.35 g, 0.0762 moles) from step 2A in dry THF (150 ml) in the form of drops, shake at 23 ° C for 30 minutes, reflux for 6 hours, and stir at 23 ° for 16 hours. Cool to 0 ° C and add water (150 ml) and 1 N HCl (150 ml), concentrate and extract with EtOAc (3x200 ml) Wash the combined organic extracts with saturated aqueous NaCl, dry (MgSO 4), filter and concentrate. Purify by chromatography (600 ml of flash silica, eluent: CH3OH 5% -CH2Cl2) Combine the appropriate fractions and concentrate to give 21.62 g (0.0729 moles, 96%) of the title compound as a yellow oil. ): m / e 297 (M + 1).

M3uO ^ X Preparation 6B: Treat the product from step 2B in a procedure similar to that described for preparation 6A. MS (FAB): m / e 283 (M + 1). or \ t-BuO0 ~ Preparation 6C. Combine the product (1.50 g, 5.06 mmol) of preparation 6A and Lawesson's reagent (1.13 g, 2.78 mmol) in dry THF (20 mL) under N2. Stir at 23 ° C for 20 hours. Concentrate and purify by chromatography (200 ml of flash silica gel, eluent: EtOAc: hexane, 1: 3, EtOAc: hexane, 1: 2, then EtOAc: hexane, 1: 1). Combine the appropriate fractions and concentrate to give 1.30 g (4.16 mmol, 82%), as a green oil. MS (FAB): m / e 313 (M + 1).

Preparation 6D: Dissolve the product (2.50 g, 8.43 mmol) of preparation 6A 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 K2C03 (4.66 g, 33.74 mmol). Reflux for 4 hours and cool to 23 ° C. Add water (100 ml), concentrate and extract with CH 2 Cl 2 (4 × 50 ml) Dry the combined organic extracts (MgSO 4), filter and concentrate Purify by chromatography (200 ml instant silica gel, eluent: CH3OH 7% -CH2CI2).

Appropriate fractions and concentrate to give 1.72 g (6.09 mmol, 72%) of the title compound as a colorless oil. MS (FAB): m / e 283 (M + 1). d Preparation 6E: Dissolve the product (1.50 g, 5.06 mmol) of preparation 6A in dry THF (20 ml) and cool to -78 ° C under N2. Add [(CH3) 3Si] 2NLi (5.5 mL in 0.1 M THF, 5.5 mmol) and stir at -78 ° C for one hour. Add bromomethylcyclopropane (0.820 g, 0.59 mL, 6.07 mmol), warm slowly to 23 ° C and stir for 16 hours Add saturated aqueous NH4CI (40 mL), extract with EtOAc (3x30 mL), wash the combined organic extracts with aqueous NaCl Saturated, dried (MgSO 4), filtered and concentrated Purify by chromatography (175 ml of flash silica gel); eluent: CH3OH 2% -CH2Cl2, then CH3OH 4% -CH2Cl2). Combine the appropriate fractions and concentrate to give 0.93 g (2.65 mmol, 53%) of the title compound as a colorless oil MS (FAB): m / e 351 (M + 1).

Preparation 6F: Treat the product of preparation 6A in a procedure similar to that described for preparation 6G, using allyl bromide. MS (CI / CH): m / e 337 (M + 1).

Step 3: Dissolve separately the products of preparation 6A to 6H in CH2Cl2, add trifluoroacetic acid and stir at 23 ° C for 4 hours.

Concentrate, add 1N NaOH, extract with CH2Cl2, dry the combined organic extracts (MgSO4), filter and concentrate to obtain the corresponding substituted piperidines: PREPARATION 7 Piperidines substituted Method B Step 1 : Preparation 7A: Combine 1-benzyl-4-piperidone (2.00 g, 10.6 mmol) and 3-pyrrolinol (0.92 g, 10.6 mmol) in titanium isopropoxide (3.75 g, 3.9 ml, 13.2 mmol) and dry CH2CL2 (4 ml), stir at 23 ° C under N2 for 5 hours, add EtOH (30 ml) and NaCNBH3 (0.66). g, 10.6 mmol) and stir for 16 hours, add water (50 ml) and CH 2 Cl 2 (50 ml), filter through celite, separate the filtrate layers and extract with CH 2 Cl 2 (2x50 ml). NaHCO3, saturated aqueous, dried (MgSO4), filtered and concentrated, purified by means of chromatography (150 ml of flash silica gel, eluent: 10% CH3OH with NH3-CH2Cl2, 15% CH3OH with NH3-CH2CI2 then 20% CH3OH with NH3-CH2Cl2) Combine the appropriate fractions and concentrate to give 1.88 g (7.22 mmol, 68%) as a colorless oil MS (CI / CH4): m / e 261 (M + 1) .Using the preparation procedure 7A and the appropriate amine, prepare preparations 7B and 7C: Preparation 7B: o "'" Jb * O-- © EM (FAB): m / e 302 (M + 1) Preparation 7C: X-MS (CI / CH4): m / e 271 (M + 1) Step 2: Treat each of the preparations 7A, 7B and 7C separately with Pd / C catalyst in CH3OH and formic acid at 23 ° C under N2 for 16 hours. Filter each mixture through celite, wash with CH 3 OH, concentrate the filtrates, add 1.0 N NaOH and extract with EtOH: CH 2 Cl 2, 1: 4, dry, filter and concentrate to obtain preparations 7-1, 7-2, and 7 -3: PREPARATION 8 Piperidines substituted Method C Step 1: Using 1,1-dimethylethyl 4-foppil-piperidinecarboxylate and the appropriate amine in a reductive amination procedure similar to that described in example 42, step 9, preparations 8A, 8B and 8C are carried out: Preparation 8A: MS (Cl / isobutane): m / e313 (M + 1) Preparation 8B: , -BUCI - '- H EM (CI / CH4): m / e313 (M + 1) Preparation 8C: t-BuO V - '^ "^ OH OH (FAB): m / e299 (M + 1) Step 2: Using the procedure described in Preparation 6, Step 3, prepare the following compounds: PREPARATION 9 Dissolve the product of preparation 5 (0.146 g, 0.33 mmol) and o-iodoxybenzoic acid (0.186 g) in 10 ml of anhydrous DMSO and add dropwise trifluoroacetic acid as 1 ml of THF solution. Shake the mixture for 4 hours. Neutralize the reaction with aqueous Na 2 CO 3 solution (5ml).

Dilute the reaction with 30 ml of EtOAc. Separate the organic phases and wash with 2X 10 ml of water and 2X10 ml of brine. Dry over MgSO4 and concentrate under vacuum. Treat the crude aldehyde product in 10 ml of anhydrous toluene with methylamine (0.66 mmole). Stir for 2 hours and then remove the solvent under vacuum. Redissolve in 10 ml of tpfluoroethanol and treat with sodium cyanoborohydride (0.041 g, 0.66 mmol). Stir the resulting mixture for 10 hours and then quench the reaction with 2 ml in water. Dilute the reaction with EtOAc (50ml) and wash the organic phases with water (2X 25ml) and brine (1 X 25ml). Dry (Na2SO4) and concentrate to obtain the crude product. Purify by preparative plate chromatography on silica gel (CH3OH saturated 20% ammonia / hexane: EtOAc, 3: 1) to give the title compound, 0.09 g. MS (M + H +) = 452.1.

EXAMPLE 1 Step 1: Dissolve the product of preparation 3 (2.6 g, 0.0068 mol) in 30 ml of anhydrous THF, cool to -78 ° C and add dropwise sodium hexadimethylsilazide (0.0075 mol) as a 1M THF solution. Stir the mixture for 0.5 hours at -78 ° C. Treat the resulting yellow solution with N, N-met? L-methoxy-iodoacetamide (0.0068 mol) as 5 ml of a THF solution. Raise the reaction temperature to 0 ° C for 4 hours and then quench with an aqueous solution of NH 4 Cl (5 ml). Dilute the reaction with 100 ml EtOAc. Separate the organic phases and wash with 2X50 ml of water and 2X50 ml of brine. Dry over MgSO 4 and concentrate under vacuum. Purify the crude product by means of flash silica gel chromatography by diluting with 10% EtOAc / hexane to obtain 1.6 g of pure product. EM: The M + = 422.

Step 2: Shake a mixture of the product of step 1 (0.5 g, 0.00105 mole), methoxylamine hydrochloride (0.52 g, 0.0045 mole) and NaOAc (0.42 g) in 15 ml of a mixture EtOH: water (5: 1) during 20 hours. Remove the solvent under vacuum, redissolve the crude product in 50 ml of EtOAc and wash with 2X50 ml of water. Dry the organic phases and remove the solvent under vacuum. Purify the crude product by flash chromatography on silica gel by diluting with 20% EtOAc / hexane to obtain 2 isomeric oximes. Yield of isomer A: 0.33 g; yield of isomer B: 0.05 g. MS: isomer A, FAB (M + H) +513.2; MS: isomer B, FAB (M + H) +513.2.

Step 3: Dissolve the main isomer from step 2 (0.65 g, 0.00127 moles) in 20 ml of anhydrous THF and cool to -78 ° C. Add dropwise diisobutylaluminium hydride (0.0045 mol) as a 1M hexane solution. Monitor the reaction by withdrawing samples at intervals to detect the presence of starting material (approximately 1 hour). Quench the reaction at -78 ° C by adding a saturated Na 2 SO 4 solution. Heat the reaction with vigorous stirring (2 hours) and remove precipitated aluminum salts by filtration. Wash the collected solids with 2X50 ml of Et20. Combine the filtrates and concentrate under vacuum.

Step 4: Redissolve the crude aldehyde from step 3 in trifluoroethanol (10 ml) and add phenylhydroxypipepdine (0.15 g, 0.0008 mol), and pulverized 3 A molecular sieves (1 g). After stirring for 0.5 hour, add sodium cyanoborohydride (0.002 mole) and continue stirring for 20 hours.

Dilute the reaction with Et20 (100 mL), filter out the molecular sieves and remove the solvent under vacuum. Purify by flash chromatography on silica gel eluting with CH3OH saturated with 1% ammonia / hexane: EtOAc, 3: 1. Yield: 0.04 g of the isomer A. EM: (FAB + M + H +) = 615. 4 EXAMPLE 2 Starting with the appropriate ketone of preparation 4 and using the corresponding product from step 3 of example 1, and the appropriate amines of the above (preparations 6-8) in the procedure of example 1, the following compounds were prepared: EXAMPLE 3 Prepare the aliloxime ether of the product of Example 2K, using a procedure similar to that used in Example 1, using O-allyl hydroxylamine hydrochloride as the alkoxlamine. MS: FAB (M + H +): 690.9.

EXAMPLE 4 Compounds of the following structural formula were prepared using the procedures described below, wherein the definitions of R1 are shown in the following table: Example 4A: Treat a solution of the product of example 3 (367 mg, 0.53 mmol) in 80% aqueous ethanol with Pd (PPh3) 4 (60 mg, 0.053 mmol, 0.05 eq) and triethylammonium formate (3 ml of solution 1 M in THF, 5 equivalents) and stir at reflux for 4 hours. Cool, concentrate and purify by silica gel chromatography (2.5 x 16.5 cm; CH2CL2 / Hex 8: 2 p / 6% NH; j / MeOH) to give 150 mg of the product as a film.

Example 4B: Treat a solution of Example 4A (93 mg, 0.143 mmole) in DMF (10 ml) at 0 ° C with 60% NaH in mineral oil (7 mg), stir for 40 minutes and treat with bromoacetonitrile, 0.034g. Stir for 30 minutes, drain in half-saturated EtOAc (250 ml) / NaHCO 3 (200 ml), and extract. Wash the organic layer with water (2x100 ml), then brine (10 ml) and dry over Na2SO4.

Purify the crude mixture by means of silica gel chromatography (4 15 cm; hex EtOAc: 1 p / 2% Ey to give 30 mg of the crude product as an oil.

Example 4C: Treat a H2NOH "HCl (0.14 mmol, 5 eq) suspension in ethanol with KOH in MeOH (680 μL, 0.68 mmol, 5 eq), treat with sound for 5 minutes and then add to a solution of Example 4B ( 24 mg, 0.035 mmol) in ethanol (5 ml). Heat for 2.5 hours at 60 ° C, filter, concentrate under vacuum and purify by chromatography on silica gel (2.5 x 14 cm; CH 2 Cl 2 / MeOH (NH 3) 95: 5) to give 9 mg of the product.

Example 4D: Treat the product of Example 4A (23 mg) in a manner similar to Example 4B, using 2-bromo-1- (but? Ldimet? Lsyloxy) etapol (10 mg) as the alkyl halide, followed by desilylation (3 h, 23 ° C) with 1 M TBAF in THF.

Example 4E: Treat the product of Example 4A in a manner similar to Example 4B, using CH 3 1 as the alkyl halide to obtain the desired product.

EXAMPLE 5 Treat a solution of Preparation 5 (0.1 g, 0.23 mmol) in anhydrous THF (5 mL) with dichlorophenyl isocyanate (0.065 g, 0.35 mmol). Stir the resulting mixture for 1 hour and then quench the reaction with 2 ml of water. Dilute the reaction with EtOAc (50 ml) and wash the organic phases with water (2x25 ml), brine (1 x 25 ml) Dry (Na 2 S 4) and concentrate to obtain a crude product. Purify by preparative silica gel chromatography (CH OH saturated with 5% ammonia / hexane: EtOAc, 3.1) to give the title compound, 0.105 g. MS: (FAB + M + H +) = 626.3. Using a similar procedure, prepare the compounds of the following formula, where the variables are as defined in the table: EXAMPLE 6 Treat a solution of preparation 9 (0.1 g, 0.23 mmoies) in Anhydrous THF (54 ml) with 3,5-bis-trifluoromethylphenisocyanate (0.065g, 0.35 mmol). Stir the resulting mixture for 1 hour and then quench the reaction with 2 ml of water. Dilute the reaction with EtOAc (50 ml) and wash the bases Organics with water (2x25 ml) and brine (1 x 25 ml). Dry (Na2SO4) and concentrate to obtain the crude product. Purify by preparative silica gel chromatography (CH OH saturated with 5% ammonia / hexane: EtOAc, 3: 1) to give the title compound, 105 g MS: (FAB + M + H +) = 706.

EXAMPLE 7 To a solution of CH2Cl2 (2 ml) containing the product of preparation 9 (0.05 g, 0.11 mmol), 3,5-dichlorobenzoic acid (0.023 g, 0.13 mmol), and hydroxybenzotriazole (0.0171 g, 0.13 mmol), add hydrochloride of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide (0.025 g, 0.13 mmol). Stir the mixture for 4 hours and then dilute with 25 ml of CH2Cl2. Wash the organic phases with water (2x25 ml) and brine (1x25 ml). Dry (Na 2 S 4) and concentrate to obtain the crude product. Purify by preparative silica gel chromatography (CH3OH saturated with 10% ammonia / hexane: EtOAc 3: 1) to give the title compound, 0.09 g MS: (M + H +) = 624.2.

Using a similar procedure, prepare the compounds of the following formula, where the variables are as defined in the table: EXAMPLE 8 Treat a solution of CH2Cl2 (5 ml) of amine 12 (0.069 g, 0.152 mmol) and diisopropylethylamine (0.04 ml) with 3,5-bis-trifluoromethylphenylsulfonyl chloride (0.057 g, 0.18 mmol). Stir the mixture for 1 hour and then dilute with 25 ml of CH2Cl2. Wash the organic phases with water (2x25 ml) and brine (1x25 ml). Dry (Na2SO4) and concentrate to obtain the crude product. Purify by preparative silica gel chromatography (methanol saturated with 10% ammonia / hexane: EtlOAc, 3: 1) to give the title compound, 0.03 g (FAB + M + H +) = 728.7. Using a similar procedure, prepare the compounds of the following formula, where the variables are as defined in the table: The following formulations exemplify some of the dosage forms of this invention. In each of them, the term "active compound" refers to a compound of formula i.

EXAMPLE A Tablets or. Inheritent ma / tablet ma / tablet Active compound 100 500 Lactose USP 122 113 Corn starch, grade 30 40 food, as a 10% paste in purified water Corn starch, grade 45 food 40 Magnesium stearate 3 7 Total 300 700 Method of manufacture Mix ingredients Nos. 1 and 2 in a suitable mixer for 10 to 15 minutes. Granulate the mixture with the ingredient No. 3. Grind the wet granules through a coarse screen (eg, 0.63 cm), if necessary. Dry the wet granules. Sift dry granules if necessary and add ingredient number 4 and mix for 10 to 15 minutes. Add ingredient number 5 and mix for 1 to 3 minutes. Compress the mixture to an appropriate size and weight in a suitable tabletting machine.

EXAMPLE B Cameras No. Inherdent ma / tablet ma / tablet 1 Active compound 100 500 2 Lactose USP 106 123 3 Corn starch, grade 40 70 Food. Magnesium stearate NF 4 7 Total 250 700 Manufacturing method Combine ingredients 1, 2, and 3 in a suitable mixer for 10 to 15 minutes. Add ingredient number 4 and mix for 1 to 3 minutes. Empty the mixture into suitable 2-piece hard gelatin capsules by means of a suitable encapsulating machine.

EXAMPLE C Sterile powder for injection Ingredient ma / bottle mq / bottle Sterile active powder 100 500 For reconstitution, add sterile water for injection or bacterial water for injection. The in vitro and in vivo activity of the compounds of formula I can be determined by means of various methods known in the art, such as a test of their ability to inhibit the activity of substance P agonist of NK-i, a test of NK2 of isolated hamster trachea, a test of the effect of NKi antagonists on microvascular airway effusion, induced by substance P, measuring live NK2 ip activity in guinea pigs, measurement of bronchoconstriction due to NKA, and tests of neurokinin receptor binding. Typical procedures are published in WO06 / 34864. The activity of 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 binding (MSB) and 100%. The percentage of MSB is defined by means of the following equation, where "dpm" means disintegrations per minute: (dpm of unknown) - (non-specific binding dpm)% MSB = X 100 (total binding dpm) - (specific binding dpm) It will be recognized that the compounds of formula (I) exhibit NK-i, NK2 and / or NK3 antagonist activity in various degrees, for example certain compounds have strong NK-i antagonist activity, but weaker antagonist activity of NK2 and NK3, while others are strong antagonists of NK2, but weaker antagonists of Ki and Nk3. Although compounds with approximately equivalent potency are preferred, it is also within the scope of this invention to use compounds with unequal antagonist activity of NK? / NK2 / NK3, when clinically appropriate. Using the test procedures described above, the following data (Ki) were obtained for the preferred and / or representative compounds of formula (I): The compounds of the present invention exhibit a scale of activity: the percentage inhibition at a dosage of 1μM, ranges from about 0 to about 100% inhibition of NKi, and / or about 0 to about 100% inhibition of NK2. Compounds having a Ki = 100nM for the NK receptor are preferred. Compounds having a Ki = 100nM for the NK2 receptor are also preferred. Another group of preferred compounds are those having a Ki = 100nM for each of the NKi and Nk2 receptors.

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1.- A compound represented by means of the formula: