MXPA99001751A - Piperazino derivatives as neurokinin antagonists - Google Patents

Abstract

The invention relates to compounds of formula (I). These compounds are neurokinin antagonists. These compounds are useful in the treatment of chronic airway diseases such as asthma.

Description

"PIPERAZINE DERIVATIVES AS NEUROQNE ANTAGONISTS" BACKGROUND OF THE INVENTION The present invention relates to a subtle composite genus as neurokinin receptor antagonists. In particular, these may be antagonists of the neurokinin-1 (NKi) receptor. Some may also be antagonists of the neurokinin-1 (NKi) receptor and neurokinin-2 (NK2) receptor antagonists, ie, double-receptor antagonists of NK1 / NK2. Some may also be antagonists of the neurokinin-2 receptor (NK2). Some may also be antagonists of the neurokinin-3 (NK3) receptor. Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals and, therefore, are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various malarial disease states, for example, lung disorders such as asthma, cough, bronchiospasm, chronic obstructive pulmonary diseases and airway hyperreactivity; pruritus skin disorders, for example, atopic dermatitis, and hives and skin temperature rise; inflammatory diseases of neurogenic inflammation such as arthritis, migraine, nociception; CNS (central nervous system) diseases such as anxiety, Parkinson's disease, movement disorders and psychosis; seizure disorders, kidney disorders, urinary incontinence, eye inflammation, inflammatory pain and eating disorders such as inhibition of food intake, allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression, vomiting and various gastrointestinal disorders such as Crohn's disease . In particular, it has been reported that NKi receptors are involved in microvascular leakage and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, making the antagonists of the NKi and NK2 receptors especially useful in the treatment and prevention of asthma. In addition, NK3 receptor antagonists are especially useful in the treatment and prevention of asthma, diseases and inflammatory conditions, such as eye inflammation, allergic rhinitis, hives and skin temperature rise, psoriasis, atopic dermatitis, - - CXS diseases such as anxiety and Parkinson's disease.

: M ??:; : OF THE INVENTION The inver. m: "- is related to the compounds of the formula where X is independently O, (H, H), NRd or S; n is from l; is from 0 to 2; And it's from 0 to 2; is 1, and Y is from 1 to 3; or m is 2 and Y is 0; each R is independently H, alkyl of 1 to 6 carbon atoms, - (CH): -? .- is where ni is from 1 to 6; R is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, CN, ORa, phenyl, substituted phenyl, ber.mlo, substituted benzyl or allyl, and with the additional proviso that not more than R. - is another that is not -n e-- resiauo; / • N O Ra O 11 I R 2S -ORa, SRa, -CN, Rr -C- -Rb -OR • aa ORa R- 'is H, alkyl of 1 to ß carbon atoms or (CH OR., With the proviso that no more than one Rc 'is other than n: is H; each R and R i is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms; , phenyl, substituted phenyl, benzyl, substituted benzyl, when the Ra and Rb are attached to the same nitrogen, then R- and R? together with the nitrogen atom to which they are fixed, form a ring of 4 to 7. members, wherein each R, and R2 is independently H, rents from 1 to 6 carbon atoms, CFJ, - - 0 O II II C2F5, Cl, Br, I, F, N02l 0Ra, CN, NRaRbl C-Ra -0- C-Ra O Ra Rb O a OO II I Ra I II I II 11 II I _ - O - CN -Rb -NC-ORa - NC-Rb -C-ORa - C-N-Rb O O. II -S - R "~ • SRE -S - NHR = -n where R, is not H or when Ri and R are on the adjacent carbon atoms in a ring, they can form where n 'is 1 c 2; and each R3 is independently H, alkyl of 1 to 6 carbon O atoms, CF-., CiF ^, II • C-Ra OO Ra II II IO-C-Ra -C- NR, b • Cl, Br, I , F, OP, OCF ^ or phenyl; Ap is a heteroaryl or substituted heteroaryl, - Q is N or CH; Ar. is heteroaryl, substituted heteroaryl, where p: and p. each one is independent of 1 to 4 with the proviso that p: y p. added together are from 2 to 6; p = is from 1 to 2; each R- is independently selected from the group consisting of H, OH, c-Ra alkyl of 1 to 6 carbon atoms, - (CH) -. - RA where n: is from 1 to 6 with the proviso that when neither is 1, R. is not OH nor; also with the proviso that when n? is 2, R < > it is alkyl of 1 to 6 carbon atoms and two R1 can be fixed. to the nitrogen atom to form a quaternary salt; each Rd and Ri is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, aillo; n- from 0 to 4; R- and Rt-side is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, halo; or R < - and R-: n together with the carbon atom to which they are fixed, they can also form a carbonyl group with the proviso that no more than one carboyl group is in the residue of carbon.

R i is H, - -ORa,-> - R.

O '- Rb,' 'C- O- Ra, -? - CN, -? - N- C- O R where Rb is not H, R '. is H, alkyl of 1 to 6 carbon atoms, allyl, cycloalkyl of 3 to 6 carbon atoms, R. can also be, where X < is 0, (H, H), NRJ, OR S; Or R. is heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl when n < is from 0 to 4; or when R < -, Rf are n together with the carbon atom to which they are fixed, form a carbonyl group and n < is 1, R. may also be OR, where R is not H, and R. may also be - (NR., R?), O-heteroaryl, O-substituted heteroaryl, O-heterocycloalkyl, O-substituted heterocycloalkyl, -NR.-heteroaryl, -NR [alpha] -substituted heteroaryl, -NR.-heterocycloalkyl, -NR [alpha] -substituted heterocycloalkyl, a pharmaceutically acceptable salt thereof thereof. All the variables in the abovementioned formulas, for example, Z, R-, R. and R-., Have the same meanings through the specification unless specified: cont. The comp. These preferred compounds of the invention are compounds of the Z-null, wherein each X is O, or (H, H) and at least one is preferred: in ra-r-biher compounds of The formula I wherein both X and J are also preferred are the compounds of the formula I wherein I is O,: T. is the H of the 3. The compounds of the formula I are also preferred. where : ". is i and u is 0. Also preferred are compounds of the formula I wherein:: - - in ae of Q is K each X is appropriately O, S or NR ..; each X is substantially CH or N; and n is c 1 The compounds of the formula are prepared I where Ar e Also preferred are the compounds of the formula I wherein 1 is - > - - Also preferred are the compounds of the formula I wherein Z is Also preferred are the compounds of the formula I wherein Z is In the aforementioned rings, an R. and a P may be present at any position in the anille that will allow a substitution. The compounds of the formula II are also preferred ü where R is H; and is from 1 to 3; pi and p are 2; Re and R: are H, alkyl of 1 to 6 carbon atoms, cycloalkyl or allyl of 3 to 6 carbon atoms; n-. is from 0 to 4; and Ap and Ar both are Also preferred are compounds of formula II, wherein R is or R-, Rt n together with the carbon atom to which they are fixed, form a carbonyl group, nor is 1 and Rc- is The compounds of the formula II er are also preferred. where R. is The compounds of the formula III are also preferred ip where R- is H; and is from 1 to 3; pi and p2 are 2; Re and Rf are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or allyl; n is from 0 to 4; and Ap and Ar2 are both The compounds of the formula III wherein Rβ is or Re, Rf taken together with the carbon atom to which they are attached, form a carbonyl group, is 1 and Re is He preached; also the compounds of the formula III, in den: es The compounds of the formula IV are also preferred where R.- is H; and is i to 3; pi and p? they are 1-2; R ^ and Rf are H, alkyl of 1 to 6 and omes of carbon, cycloalkyl of 3 to 6 - carcinoal atoms: aillo; n- is from 0 to 4; and Ap and Ar¿ are both R3 The compounds of the formula IV in aon are also prepared; or R, Rf tomacos 711.10 with the carbon atom to which they are fixed, form a carbonyl muco, n. is 1 and R- is - We prefer the compounds of formula IV where R is The examples of the invention are compounds of the formulas where Z is -or a compound that is selected from the group consisting of where Z or a compound that is selected from the group consisting of where or a compound that is selected from the group consisting of - - where Z is or a compound that belongs to the group consisting of or a compound that is selected from the group consisting of - in gift or a compound selected from the group consisting of in do - compound that is selected from the group consisting of Cl or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I, in combination with a pharmaceutically acceptable carrier. The invention also relates to a method for inducing neurokinin antagonism, comprising administering an antagonist effective amount of neurokinin of a compound of the formula I to a mammal in need thereof. The invention also relates to a method for treating chronic respiratory diseases such as asthma and allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrosites, osteoarthritis and rheumatoid arthritis; migraine; disorders of the central nervous system such as depression, psychosis, dementia and Alzheimer's disease; Down's Syndrome; neuropathy; multiple sclerosis; ophthalmic disorders; conjunctivitis, autoimmune disorders; graft rejection; systematic lupus erythematosus; Gl disorders such as Crohn's disease and ulcerative colitis, disorders of bladder function; circulatory disorders such as angina; Raynaud's disease; vomit, cough and pain. In particular, the invention also relates to a method for treating asthma comprising administering to a mammal in need of this treatment, an effective amount of anti-asthma of a compound of formula I, for that purpose. The invention also relates to the use of a compound of the formula I for the preparation of a medicament useful for inducing neurokinin antagonism in the treatment of the diseases mentioned above.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "alkyl" means a straight or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms. The number of carbon atoms can be designated. For example, "alkyl of 1 to 6 carbon atoms" represents a straight or branched saturated hydrocarbon having from 1 to 6 carbon atoms. The term cycloalkyl of 3 to 6 carbon atoms means a cycloalkyl having from 3 to 6 carbon atoms, which is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkenyl" means a straight or branched saturated alkenyl having from 2 to 6 carbon atoms. The number of carbon atoms can be designated. For example"C2-C6 alkenyl" represents a straight or branched alkenyl having from 1 to 6 carbon atoms. The term "alkynyl" means a straight or branched alkynyl having from 2 to 6 carbon atoms. The number of carbon atoms can be designated. For example, "C 2 -C 6 alkynyl" represents a straight or branched chain alkynyl having from 2 to 6 carbon atoms.

As used herein, a thick dark line (- * ») represents a chemical bond that comes from above the plane of the page. A line of scripts (Ü * [«'« ME) represents a chemical bond that comes below the plane of the page.

As used herein, ', for example, means that Ri, R and R3 may be in any of the rings of the aforementioned naphthyl residue. In the rings that will be shown below, a Ra and an Rb may be present in any position in the ring, which will allow a substitution: Similarly, in the rings shown below, an Rc may be present at any position in the ring that will allow a substitution: There are asymmetric centers in the compounds of the formula I of the invention. Accordingly, the compounds of the formula I include stereoisomers. All isomeric forms and mixtures thereof remain dentn < of the scope of the present invention. Unless stated otherwise, the methods of preparation disclosed herein may result in distribution. products that include all the structural isomers, the possible ones, even though it will be understood that the physiological response can vary according to the stereochemical structure. The isomers can be separated by conventional means such as fractional crystallization, plate or column preparation chromatography on silica, alumina or reverse phase supports or HPLC (high performance liquid chromatography). The enantiomers can be separated where appropriate, by derivatization or salt formation with an optically pure reagent, followed by separation by one of the aforementioned methods. Alternatively, the enantiomers can be separated by chromatography on a chiral support. The compounds of the formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g. the hemihydrate. In general, solvated forms, with pharmaceutically acceptable solvents for example, water, ethanol and the like, are equivalent to unsolvated forms for the purposes of the invention. Those compounds of the formula I which contain a basic group such as -CH 2 NH 2, form the pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts are non-toxic acid addition salts formed by adding to a suitable compound of the invention at about a stoichiometric amount of a mineral acid such as HCl, HBr, H2SO4 or H3PO4 of an organic acid such a propylene, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, para-toluenesulfonic, methanesulfonic, citric, maleic, fumaric, succinic and the like, respectively.

General Methods of Preparation The compounds of this invention can be prepared by one of the following general methods. As used herein, RT means room temperature. Unless indicated otherwise, the variables in the structural formulas presented below are as defined above. The starting materials and reagents used in the methods and examples that st; will show below, are already known and can be prepared according to known methods. As used herein the term "substituted phenyl" means wherein Ri, R¿ and R3 are as described herein. "Substituted" means substituted by Ri, R¿ and / or R3, as defined herein. "Arilo". it denotes phenyl, naphthyl, ± ndenyl, tetrahydronaphthyl, iidanyl, anthracenyl or fluorenyl.

"Halogen" refers to the fluoro, chloro, bromo or iodo atoms. "Heterocycloalkyl" refers to rings of 4 to 6 members comprising from 1 to 3 heteroatoms which are independently selected from the group consisting of -O-, -S- and -N (R ^) -, with the remaining ring members being carbon. Examples of the heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. "Heteroaryl" refers to aromatic rings of to 10 simple or benzofundid members comprising from 1 to 3 heteroatoms which are independently selected from the group consisting of -O-, -S- and -N =. Examples of heteroaryl groups of a single ring are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are quinolinyl, tianaphtenyl and benzofurazanyl. The N-oxides of the nitrogen-containing heteroaryl groups are also included. All positional isomers are proposed, e.g., 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. When the substituents R ^ and R3 form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and / or sulfur atoms and three adjacent heteroatoms. Typical rings formed in this manner are morpholinyl, piperazinyl and piperidinyl. As used herein, the term "BOC" means t-butoxycarbonyl. As used herein the term "Ph" means phenyl. As used herein the term "RT" means room temperature. As used herein the term "parallel synthesis" means the preparation of individual chemical compounds as one of a batch of, for example, 20, 30 or even 100 identical reactions in usually a single substrate but using a different reagent in each container . These reagents are always of the same kind in this case, either carboxylic acids or organic amines in any set of parallel reactions. The conditions used for each reaction are identical to those described in the examples, with the exception that a single treatment is generally employed, a simple wash either with acid or a base if appropriate, and then with water. The presence of the product is detected by thin layer chromatography (TLC) using the products known as representative standards. The additional characterization by HPLC / MS combination is usually carried out. No further purification is carried out on these materials before they are subjected to biological tests. As used herein, each Rc and Rc "is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, phenyl unsubstituted or substituted and unsubstituted or substituted benzyl. The starting materials in the methods presented below are either known or can be prepared according to known methods. In particular, the following compounds are either known or can be prepared according to known methods. Diamine A, the compounds of formulas A, VI, VIII, X, XI, XIV, XVIII, XIX, XXa, A ', XXV, and Z-H, as well as the esters of formula XI and the compounds of the formula ali Jo Method 1. If the group Ar2 is an aromatic group without substituents I or Br, then the following method can be used to prepare the useful intermediates (IV): - The transition metal catalyzed coupling of 2-chloropyrazine with an aromatic Grignard reagent in a dry ether solvent, such as THF, yields the aryl-substituted pyrazine of the formula II '. The catalyst shown, nickel chloride 11 [1,2-bis- (diphenylphosphino) ethane], is a preferred reagent for this transformation. When Ar2 has no halo substituents, the reduction of a compound of the formula II 'by catalytic hydrogenation, using, for example, palladium aceteate, preferably in an acetic acid solvent, results in the preferential reduction of the pyrazin ring , leaving the aromatic ring unreduced, ie, results in a compound of the formula II. Similarly, 10 percent Pd on vegetable carbon (Pd-C) can be used in an alcohol solvent, preferably methanol, with or without the addition of a small amount (1 to 5 equivalents) of acetic acid. The time Reaction time of approximately 1 to 24 hours will usually be sufficient for this reaction, which preferably. It is carried out at a high temperature or - - slightly above it (up to approximately 50 ° C) and using hydrogen pressure from 1 to approximately 6 atmospheres.

The intermediate of formula II can also be prepared from a compound of formula II ', even if the group R 2 contains halogen atoms, by reduction using a donor do ion strong hydride, hydride preferably lithium aluminum (LAH) or diisobutyl aluminum hydride (DIBAL-H), in an ether solvent, for example ether, THF or dimethoxane ethane (DME). Selective alkylation of a compound of formula II is possible using low temperature conditions. Therefore, reacting a compound of the formula II with an aryl-substituted alkyl halide of the formula III wherein 1 is from 0 to 2, results in the formation of the 4-substituted derivative of the formula IV. Appropriate conditions include the use of a halogenated solvent, such as CH2Cl2, at low temperature. The appropriate temperatures are initially -78 ° C allowing the reaction mixture to gradually warm to room temperature, if the reaction does not - - It is completed after several hours. The reaction is catalyzed by the addition of an equivalent amount of an organic base, such as triethylamine and diisopropylenetylamine (Hünig's base) Method 2. If the group r2 contains one or more halogen atoms in an aromatic ring and the other groups are in Method 1, then an alternative route for a compound of the formula IV is preferred. In addition, this method can be used to prepare compounds in which 1 is from 0 to 2. The mono-protection of the diamine of the formula (A), preferably with BOC anhydride, or other known agents that introduce the protecting group of t-butyloxycarbonyl, in an alcohol solvent, such as methanol, preferably at a temperature of about -10 ° C, produces a compound of the formula V.

These compounds are used to carry out a reductive amination reaction with the aldehyde of the formula VI in order to produce an amine of the formula VII. (In the structures (A), (V), (VII) and (IX) of the present, Rc can be linked to any position between the two nitrogens In the cyclic structures such as (IVA) presented below, rc may be linked to any cyclic available location is occupied by a carbon atom and which is between the two nitrogens. suitable for this type of reaction conditions include the use of an alcohol solvent, preferably methanol, or 2, 2, 2-trifluoroethanol, it made slightly acidic which a weak organic acid, such as acetic acid, and a reducing agent known to favor reductive amination reactions, preferably sodium cyanoborohydride, aBH3CN.

The reaction of a compound of formula VII with an alpha-haloketone of formula VIII, wherein Ar2 preferably represents a halogenated aromatic ring, but may be any of the aromatic rings claimed in presence of an organic base, such as di -isopropylethylamine, also known as the Hünig Base, in an ether solvent, such as THF, results in the formation of the intermediates of the formula IX.

Removal of the BOC protecting group using an appropriate acidic catalyst, such as trifluoroacetic acid, followed by intramolecular reductive amination, under conditions such as those described above for the preparation of a compound of the formula VII. leads to the formation of the compounds of the formula IVA.

Ar (IVA) Method 3. An alternative route for the compounds of the invention wherein I is from 0 to 2 is as follows. The normal coupling of an N-protected amino acid of formula X, wherein Ar2 is as described above, with an amino acid ester derivative (R 'is alkyl of 2 to 4 carbon atoms, preferably, the ethyl ester of the formula XI; Et in the present formulas means ethyl), produces a dipeptide of the formula XII. A suitable protecting group is BOC, although many others can also be used. Other amino acid esters can also be used.

Normal coupling techniques can be applied, one example being the use of N-hydroxybenzotriazole (HOBT) and a carbodiimide solulle in water, such as l- (3-dimethylaminopropyl) -ethylcarbodiimide (DEC), in a non-hydroxy solvent. ico such as CH2Cl2, DMF or a mixture of the two aforementioned solvents. The reaction is preferably carried out at or below room temperature and it takes from 1 to 40 hours to complete depending on the substrates.

Removal of the protecting group under normal conditions followed by treatment of the product with a base results in cyclization to diketopiperazine of formula XIII. Appropriate conditions for the removal of the exemplified BOC group are well known in the art and include catalysis by trifluoroacetic acid (TFA). A suitable cyclization base is an alkali metal salt of an alcohol in the same alcohol used as the solvent. For example, a solution of sodium ethoxide in ethanol can be used. The temperature of preference is around room temperature, but may be slightly above or below within the range of 0 ° C to about 40 ° C. The reaction is usually completed within a few hours. Appropriate reaction times are from 1 to 24 hours.

The reduction of the diketopiperazine of the formula XIII in a compound of the formula II can be achieved preferably with a strong hydride reducing agent such as LAH or a solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene (which it is also known as Red-Al®), or the complex of BH3.S (CH3) 2. Suitable solvents for this reaction are DME and other ethers of higher boiling temperature since the reaction is carried out at elevated temperatures of about 50 ° C to about 110 ° C, preferably about 90 ° C.

Alternatively, a compound of formula IE can be prepared by the graph shown below (J. Me. Chem., 9, 181 (1966)). As used herein, L is any easily obtainable ester residue such as alkyl of 1 to 7 carbon atoms, most preferably methyl or ethyl.

A compound of formula II can be converted into a compound of formula IV by the processes described in Method 1 above or Method 6 which will be provided below.

Method 4. Intermediates of formula IV or IVA, formed through any of the above methods, can also be processed in the following manner. A compound of the formula IVA will be used in the Graphs. The reaction of a compound of the formula IVA with an activated halo-acid generally the acid halide of the formula XIV, wherein Hai represents Cl, Br, or 1, renders the acylated derivative of the formula XV, ie, m is 1 for formula I. An organic base is used to absorb the hydrogen halide formed in the reaction, with the appropriate bases being triethylamine (TEA) and Hünig Base. Suitable reaction media include halogenated solvents, such as methylene chloride and chloroform. The reaction of preference is carried out at low temperature, at least initially. The appropriate temperatures are in the region of -50 ° C to -80 ° C. Subsequently in the reaction it may be desirable to allow the mixture to warm up to more or less room temperature to ensure that the reaction is complete.

The reaction of the halogenated amides of the formula XV with an amine of the formula ZH results in the formation of the products of the formula XVI, which are compounds of the invention wherein X is O and m is 1. The compounds of the formula XVI have been modified to show the fact that these products could have been prepared from the compounds of the formula IVA as well as from the formula IV. Suitable solvents for this reaction are halogenated hydrocarbons, such as methylene chloride and an organic base which is present to absorb the H-Hal formed. The appropriate bases include the Hünig Base. The reaction is carried out more or less or around room temperature, a temperature within the range of 0 ° C to 40 ° C. The reaction is completed within 1 to 48 hours.

Method 5. The compounds of formula XVI wherein and? 0 can be converted into other compounds of the invention of the formula XVII by reduction under controlled conditions.

Suitable reducing agents for carrying out this transformation include the borane-dimethylsulfide complex, as well as other less selective reagents such as LAH, (assuming that no other reactive group is present, -for LAH), Red-Al®, and diborane in ether. The e ective temperatures for the borane-dimethylsulfide complex to reduce the compounds of formula XVI vary from room temperature to the reflux temperature of the reagent solution in THF (about 80 ° C).

Method 6. Intermediates of formula XVIII can be acylated selectively by coupling with an acid of formula XIX. Normal coupling techniques may be applied with one example being the use of HOBT, a water-soluble carbodiimide, such as DEC, and an organic base such as triethylamine, in a non-hydroxylic solvent, such as CH2Cl2. at a temperature of about -20 ° C initially. The mixture can be allowed to warm to room temperature to complete the reaction. The reaction product is the amide of formula XX.

The compounds of the formula XX can also be acylated using an acid halide of the formula XIV. The reaction is carried out, preferably at a temperature of about -78 ° C, through a period d -.l. 1 to 12 hours, in a halogenated solvent, such as methylene chloride or a similar solvent. An organic tertiary amine is used to absorb the H-Hal produced in the reaction. Suitable amines include triethylamine and Hünig Base. As used in the present Hai means Cl, Br or I.

The compounds of the formula XXI, ie, m is 1 in the formula I, y = 1-3, I = 0-2 can be used for further reaction without isolation. The additional organic base, for example, the Hünig Base, is added to the mixture followed by Z-H, at a temperature of or around -78 ° C. The reaction is completed by allowing the mixture to warm to room temperature overnight yielding the compounds of formula XXII, after treatment and purification by normal methods.

- The compounds of the formula XXII, wherein y = 1-3, can be converted into other products of the formula XXIII by reduction under controlled conditions.

Suitable reducing agents for effecting this transformation include the borane and methyl sulfide complex, as well as other less selective reagents, such as LAH, Red-Al®, and diborane in ether or other non-reactive solvents such as THF. Using the complex of botan and methyl sulfide in THF at the reflux temperature of the solution, which is about 80"C, the reaction is completed in about 2 hours to 48 hours depending on the precise substrate. The Z-H substrates can be obtained commercially or can be made by processes known to those skilled in the art. The specific examples are carried out in accordance with the detailed procedures disclosed below.

Method 7. Acylated derivatives of formula XX of Method 6 can be reduced in saturated alkyl chain derivatives of the formula IVA.

The process for carrying out this conversion is the same as that described in Method 6 for the conversion of a compound of formula XXII into a compound of formula XXIII. The preferred reagent is the borane and methyl sulfide complex. A compound of the formula IVA can be converted to a white compound of the formula XVI, as described above.

An alternative route for the compounds of the structure (XXII) also begins with the compound (XVIII). The initial reaction with a reagent of the amine protecting group, preferably BOC anhydride, produces the N-t-butyloxycarbonyl derivative of the formula XXVIII.

As above, the reaction occurs preferably at the nitrogen atom furthest from the group Ar2- The reaction of this intermediate with a reagent of the structure (XIV) as described above leads to the halo derivative (XXIX). The reaction of (XXIX) with Z-H, again as described above, produces the intermediate (XXX) which can be deprotected to produce (XXXI). Suitable reagents include trifluoroacetic acid and HCl - The reaction of (XXXI) with a carboxylic acid (XIX) under these coupling conditions as described above leads to the products of the formula (XXII).

Method 7a. The synthesis of the compounds of the invention wherein the suspended aromatic r 2 group, or the suspended aromatic Ar 2 group and its secondary chain are placed at the position of the alternative ring with respect to the compounds of the formula XXII (i.e. compounds of the formula C which is presented below), can be prepared using compounds of the formula XXVIII of the method 7, as starting materials. The coupling of the compounds of the formula XXVIII with any of the Rc acids » r ^ - (CH) 1CO2H under normal coupling conditions, for example using HOBT, Et3N and DEC in CH2CI2 produce intermediate (A). The removal of t-BOC or another protecting group under normal conditions releases the free amine (B). Acylation of (B) and further reaction with Z-H is continued as described in Method 6 for the conversion of (XX) through (XXI) to (XXII), to produce the compound (C) of the invention.

Method 8. A method for introducing a group, Rc, into the secondary chain of a compound of the invention, starts with a previously prepared compound of the formula (XX). This can be coupled with an appropriately protected amino acid derivative of the formula (XXXII) wherein the t-BOC group is used as a representative protecting group. The use of a relatively reactive coupling agent such as B0P-C1 of the formula (XXXIII), it is of course preferred and the reaction is carried out under normal coupling conditions well known to a person skilled in the art. Appropriate conditions include the use of CH2Cl2 and / or DMF as the solvent, with triethylamine or a Hünig Base, and a temperature between 0 ° C initially and the Ambient Temperature. The usual treatment conditions yield the protected intermediate of the formula (XXXIV). In the case of (XXXIV), where the N-protecting group is t-BOC, the usual conditions for the removal of this group can be used to release the function of the amine. Various concentrations of CF3C? 2H in CH2Cl2 will usually be sufficient. In some substances, a fairly diluted solution will suffice (e.g. 2N), while in other cases, a more concentrated solution up to net TFA may be necessary. In addition, other N-protective groups can be used and removed - - by methods bif > n known in the art. An example is the use of N-C z that can be removed already under acidic or hydrogenolytic conditions. The result of the deprotection is the amine intermediate of the formula (XXXV).

The conversion of the intermediate of the formula (XXXV) into compounds of the invention is then carried out by a reductive alkylation process. The group Z is introduced into the molecule using a ketone to be bound to the amino group of the formula (XXXV). An example of this intermediate is a compound of the formula (XXXVI).

After the reaction this group becomes the group Z of the compounds of the invention, ie the group "Y-NH" shown in the compounds of the formula (XXXVII) just indicated below XXXVII which is equivalent to the group "Z" shown in the Compendium of the Invention. The conditions of this reductive amination procedure are known in the art and exemplified by the use of NaBH3CN in MeOH with the addition of several equivalents of acetic acid. In general, the reaction is carried out at room temperature and left to react overnight.

The product is isolated by normal means such as the decomposition of the excess of the reagent with H 2 O and the extraction of the product in an organic solvent such as CH 2 Cl 2 or a mixture of Et 2? and CH2Cl2. Using procedures similar to those described above, or using procedures known to those skilled in the art, all compounds of the formula I of the invention can be produced. For example, compounds of the invention of the formula I can be obtained in which the Rc residue is in several carbon atoms of the piperazine ring. The in vi tro and in vi vi activity of the compounds of formula I can be determined by the following procedures.

In vitro procedure to identify the activity of NK1 The test compounds were evaluated due to their ability to inhibit the activity of the Substance P agonist of NK1 in the vas deferens of the isolated guinea pig. Freshly cut deferent vessels are removed from male Hartley guinea pigs (230 to 350 grams) and suspended in 25 milliliter tissue baths containing Kreb's Henseleit solution heated at 37 ° C and aerated constantly with 95 O2 percent and 5 percent CO2. The tissues are adjusted to 0.5 gram and allowed to equilibrate for a period of 30 minutes. The vas deferens are exposed to an electric field stimulus (Grass Stimulator S48) every 60 seconds to one. intensity that causes the tissue to contract up to 80 percent of its maximum capacity. All responses are recorded isometrically by means of a Grass force displacement transducer (FT03) and a Harvard electronic recording device. Substance P inhibits the induced contractions stimulated by the electric field of the guinea deferent's vas deferens. In studies that are not even, all tissues (control or drug treated) were exposed to cumulative concentrations of Substance P (1X10-10 M - 7X10-7 M). The single logarithm concentrations of the test compounds are provided to the separated tissues and allowed to equilibrate for 30 minutes before the concentration response curve of the P substance is generated. At least 5 separate tissues are used for each control and concentration of individual drug for each drug trial. Inhibition of Substance P is demonstrated by a shift to the right of its concentration response curve. These offsets are used to determine the value of pA2. which is defined as the negative logarithm of the molar concentration of the inhibitor which would require that the agonist be used twice more to allow a selected response. This value is used to determine the relative antagonistic potency.

NK2 Test of the Marmot Isolated Trachea The general methodology and characterization of marmot trachea responses to neurokinin agonists as provided to provide a monoracerecyl NK2 assay is found in C.A. Maggi, and others. Eur. J. Pharmacol. 166 (1989) 435 and J.L. Ellis, and others, J. Pharm. Exp. Ther. 267 (1993) 95. Continuous isometric tension monitoring is achieved with the Grass FT-03 force displacement transducers connected with Buxco Electronics pre-amplifiers constructed on a Graphtec Linearcorder Model WR 3310. The Charles River marmots LAK.LVG (SYR ), from 100 to 200 grams of food weight, they are stunned by a sharp blow to the head, the loss of corneal reflex is ensured, the marmots are sacrificed by means of a toractomy and the cutting of the heart. The segments of the cervical trachea are removed to a Krebs stabilizer at room temperature of pH 7.4, aerated with 95 percent O2 gas and 5 percent CO2 and cleaned of adherent tissue. The segments are cut into two ring segments of length of 3 to 4 millimeters. The tracheal rings are suspended from transducers and are retained in 15.0 milliliter water-jacketed body baths by means of 6-0 stainless steel and silk hooks. The bathrooms are filled with the Krebs stabilizer, pH 7.4, maintained at 37 ° C and continuously aerated with 95 percent O2 and 5 percent CO2 gas. The tracheal rings are placed under an initial tension of 1.0 gram and are left for a 90-minute equilibration period with four 1-micron NKA challenge wash and recovery cycles at 20 minute intervals. The 30-minute vehicle pretreatment is followed by cumulative additions of high doses of NKA (final concentration of 3 nM - 1 micrometer, intervals of minutes between additions). The final NKA response is followed by a 15 minute wash and recovery period. The 30 minute pretreatment with a test compound or its vehicle is followed by cumulative additions of NKA wash doses (3 nM and 10 micron final concentration if necessary, 5 minute intervals between additions). The final response of NKA is followed by a challenge of 1 mM carbachol to obtain a maximum stress response in each tissue. The tissue response to NKA is recorded as positive pen displacements above the baseline and converted to voltage in grams by comparison with normal weights. The responses are normalized as a percentage of the maximum tissue tension. They are calculated from the ED50 for NKA of the control and the dose responses of NKA treated and compared. The test compounds that result in an agonist dose ratio of > 2 at a selection concentration of 1 micrometer (ie, pA2 > - ß.O) are considered active. The additional dose response data is obtained for the maneuver assets that can be calculated from the calculation of apparent pA2. The pA2 is calculated either by calculation of K¿ as described by Furchogott (where pA2 = - Log K-1, RF Furchgott, Pharm. Rev. 7 [1995] 183) or by Trace Analysis Shild (O. Arunlakshana &HO Shild, Br. J. Pharmacol. 14 [1959] 48) if the data is sufficient.

Effect of NK1 Antagonists on Microvascular Respiratory Tract Escape Induced by Substance P in Guinea Pigs Studies were conducted on male Hartley guinea pigs ranging in weight from 400 to 650 grams. The animals are administered with food and water ad libi tum. The animals were anesthetized by intraperitoneal injection of dialurethane (containing 0.1 gram per milliliter of diallylbarbituric acid, 0.4 gram per milliliter of ethylurea and 0.4 gram per milliliter of urethane). The trachea is channeled just below the larynx and the animals are ventilated (VT / = 4 milliliters, f = 45 breaths per minute) with a Harvard rodent respirator. The jugular vein is channeled for drug injection. The Evans blue dye technique (Danko, G. et al., Pharmacol, Commun., 1, 203-209, 1992) is used to measure microvascular leakage of airways (AML). Evans blue is injected intravenously (30 milligrams per kilogram) followed 1 minute later by intravenous injection of substance P (10 micrograms per kilogram). Five minutes later, the thorax opens and a blunt-ended 13-gauge needle passes into the aorta. An incision is made in the right atrium and the blood is expelled by washing with 100 milliliters of saline solution through an aortic tube. The lungs and trachea are removed en-bloc and the trachea and bronchi are then dried with filter paper and weighed. The Evans blue is extracted by incubating the tissue at 37 ° C for 18 hours in 2 milliliters of formamide in capped tubes. The absorbance of formamide dye extracts is measured at 620 nm. The amount of the dye is calculated by interpolating a normal curve of Evans blue within the range of 0.5 to 10 micrograms per milliliter in formamide. The concentration of the dye is expressed in ng dye per milligram of net weight of the tissue. The test compounds were suspended in a cyclodextran vehicle and administered intravenously 5 minutes before substance P.

Activity Measurement NK2 In Vivo Hartley male guinea pigs (400 to 500 grams) with ad lib access. Food and water are anesthetized with an intraperitoneal injection of 0.9 milliliter per kilogram of dialurethane (containing 0.1 gram per diallylbarbituric acid, 0.4 gram per ml of ethylurea and 0.4 gram per ml of urethane). After the induction of a surgical plane of anesthesia, tracheal, esophageal and jugular venous cannulas are implanted to facilitate mechanical breathing, measurement of esophageal pressure and drug administration, respectively. The guinea pigs are placed inside a full body plethysmograph and the probes are connected to the exit holes in the wall of the plethysmograph. The air flow is measured using a differential pressure transducer (Validyne, Northridge CA, model MP45-1, scale + 2 cm H2O) that measures the pressure through a wire mesh screen that covers a hole of 2.54. centimeters in the wall of the plethysmograph. The air flow signal is electrically integrated to a signal proportional to the volume. The transpulmonary pressure is measured as the pressure difference between the trachea and the esophagus using a differential pressure transducer (Validyne, Northridge, CA, model MP45-1, scale + 20 cm H2O). Volume, airflow and transpulmonary pressure signals are monitored by means of a pulmonary analysis computer (Buxco Electronics, Sharon, CT, model 6) and are used for the derivation of pulmonary resistance (LR) and dynamic lung elasticity (Crj >vn).

Bronchoconstriction Due to NKA Increased intravenous doses of NKA are administered at logarithm intervals (0.01-3 micrograms per kilogram) allowing recovery to baseline pulmonary mechanics between each dose. Maximum bronchoconstriction occurs within 30 seconds after each dose of the agonist. The dose response stops when Cpyn is reduced from 80 percent to 90 percent of the baseline. A dose response to NKA is carried out on each animal. The test compounds are suspended in a cyclodextran vehicle and administered intravenously 5 minutes before the initiation of the NKA dose response.

For each animal, dose response curves are constructed to NKA plotting the percentage increase in RL or the decrease in Cnyn against the logarithmic dose of the agonist. The dose of NKA that increased RL by 100 percent (RL 100) or decreased Cfjyn by 40 percent (C) and n40) of the baseline values are obtained by logarithmic linear interpolation of the dose response curves.

Neurokinin Receptor Ligament Assay (s) The cells of the China Marmot (CHO) ovary transfected with the coding regions for human neurokinin 1 (NK1) of human neurokinin 2 (NK2) receptors are grown in a minimum essential Dulbecco medium supplemented with 10 percent fetal calf serum, 0.1 mM non-essential amino acids, 2 mM glutamine, 100 units per milliliter of penicillin and streptomycin, and 0.8 milligram of G418 / milliliter at 37 ° C in a humid atmosphere containing 5 percent CO2. The cells are separated from the T-175 flasks with a sterile solution containing 5 mM EDTA in phosphate-stabilized saline. The cells are harvested by centrifugation and washed in RPMI medium at 40 ° C for 5 minutes. The pellet is resuspended in Tris-HCl (pH 7.4) containing 1 micron of phosphoramidon and 4 micrograms per milliliter of chymostatin at a cell density of 30 x 10 ^ cells per milliliter. The suspension is then homogenized in a Brinkman Polytron (setting of 5) for 30 to 45 seconds. The homogenate is centrifuged at 800 x gram for 5 minutes at 4 ° C to collect the unbroken cells and nuclei. The supernatant fluid is centrifuged in a Sorvall RC5C at 19,000 revolutions per minute (44.00 x g) for 30 minutes at 4 ° C. The granule is resuspended, an aliquot is removed for a protein determination (BCA) and washed again. The resulting granule is stored at -80 ° C. The binding of the test receptor, 50 microliters of [3H] -Substance P (9-Sar, 11-Met [02]) (specific activity of 41 Ci / mmol) (Dupont-NEN) (0.8 nM of the assay for NK- 1) or [3H] -Neuroquinine A (specific activity of 114 Ci / mmol) (Zenca) (1.0 nM for the NK-2 assay) is added to the tubes containing the stabilizer (50 mM Tris-HCl (pH of 7.4) with 1 mM of MnCl2 and 0.2 percent of Bovine Serum Albumin) and either a DMSO compound or test. The bond is initiated by the addition of 100 microliters of the membrane (10-20 micrograms) containing the human NK-1 or NK-2 receptor in a final volume of 200 microliters. After 40 minutes at room temperature, the reaction is stopped by rapid filtration in Whatman GF / C filters that have been pre-soaked in 0.3 percent polyethylenimine. The filters were washed 2 times with 3 milliliters of 50 mM Tris-HCl (pH 7.4). The filters are added to 6 milliliters of a Ready-Safe liquid scintillation cocktail and quantified by liquid scintillation spectrometry in a LKB 1219 RackBeta counter. The non-specific binding is determined by the addition of either 1 micrometer of CP-99994 (NKX) or 1 micrometer of SR-48968 (NK2) (both synthesized by the chemistry department of Schering-Plow Research Institute). The IC50 values are determined from the competition binding curves and Ki values are determined according to Cheng and Prusoff using the experimentally determined value of 0.8 nM for the NK ^ receptor and 2.4 nM for the NK2 receptor. For all the compounds of the invention, the bond of NK ^ is within the scale of approximately 0 percent to 100 percent inhibition at 1 micrometer concentration. For all compounds of the invention, the binding of NK2 is within the range of about 0 to 100 percent inhibition to 1 micrometer of concentration. It should be understood that even when the NK bond for certain compounds of the invention is as low as 0 to 1 micrometer in concentration, at higher concentrations these compounds are expected to have NK-binding inhibiting activity. The Kj_ of a compound is that concentration at which the compound caused a 50 percent inhibition of either NK ^ or NK2. For those compounds of the invention that have more than 50 percent inhibition of NK] _, the Kj_ for NK] _ were determined. The Kj_ for NK ^ for these compounds were within a range of about 0.1 nM to about 1 micron. For those compounds of the invention having more than 50 percent inhibition of NK2, the K- for NK2 were determined. The Kj_ for NK2 for these compounds were within the range of about 0.1 nM to about 1 micron. The compounds of the formula I exhibit NK] _ and NK2 antagonist activity up to several degrees, ie, certain compounds have intense K antagonist activity but weaker NK2 antagonist activity. Others are the strong NK2 antagonists, but the weaker NK] _ antagonists. Certain compounds have intense antagonistic activities of both NK_ and NK2. Some compounds can also be NK antagonists.

- The binding values Ki and the binding values of K2 for certain compounds of the invention are the following: has a K¿ for K ^ linkage of 5.3 nM; and has K¿ for NK2 binding of 51 L nM. has k¿ for NK ^ binding of 23.3 nM; and K¿ for NK2 binding of 29.1 nM. has for NKX link of 3.3 nM; and K¿ for NK2 binding of 93 nM. has K¿ for NK ^ binding of 9.6 nM; and K¿ for NK2 binding of 87 nM. has K¿ for NK ^ binding of 7.0 nM; and K ± for NK2 binding of 40 nM. has K¿ for K ^ linkage of 71 nM; and K¿ for NK2 binding of 5.5 nM.

(Enantiomer B) has K¿ for NK ^ binding of 67 nM; and K¿ for NK2 binding of 18 nM.

(Racemic Compound) has K_ for NK ^ binding of 3 nM; and Kj_ for l ± gazón de NK2 of 25 nM. Many of the compounds of formula I have an asymmetric center and therefore exist as a pair of enantiomers. In these cases, one enantiomer may have different biological activity than the other. For example, one enantiomer may have intense K ^ activity and weak NK2 activity while the other enantiomer has weak NK] _ activity and strong NK2 activity. Certain compounds of the formula I have been found to be antagonists of both the NK] and NK2 receptors and are therefore useful for treating conditions caused or aggravated by the activity of the receptors.

NK and NK2. The present invention also relates to a pharmaceutical composition consisting of a compound of the formula I and a pharmaceutically acceptable carrier. The compounds of this invention can be administered in conventional oral dosage forms such as capsules, pills, powders, wafers, suspensions or solutions or 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 formulation techniques. The pharmaceutically acceptable excipients and additives include non-toxic and chemically compatible fillers or fillers, binders, disintegrating agents, stabilizers, preservatives, anti-oxidants, lubricants, flavoring agents, thickeners, coloring agents, emulsifiers and the like.

The daily dose of a compound of the formula I for treating asthma, cough, brochiospasm, inflammatory disease migraine, nociception and gastrointestinal disorders is from about 0.1 milligram to about 20 milligrams per kilogram of body weight per day, preferably from about 0.5 to about 15 milligrams per kilogram, more preferably from 0.5 to about 5 milligrams per kilogram. For an average body weight of 70 kilograms, the dosage scale therefore is from about 1 to about 1500 milligrams of drug per day, preferably from about 50 to about 100 milligrams which is administered in a single dose or 2 to 4 divided doses. The exact dose, however, is determined by the physician and depends on the potency of the compound administered, the age, weight, condition and response of the patient. The invention disclosed herein is exemplified by the following examples, which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention will be apparent to those skilled in the art.

EXAMPLE 1 Salt of dihydrochloride or (+/-) -1 - [[3,5-bis (trifluoromethyl) phenyl] ethyl] -3-phenyl-piperazine.

H Chloropyrazine (20.68 grams, 177 mmol) and [1,2-bis (diphenylphosphino) ethane] nickel (II) chloride (41.08 gm, 77.8 mmol) in THF s were mixed. co (2.5 liters) and stirred for 80 minutes in a flask (cooled with a water layer) under a nitrogen atmosphere. A solution of phenylmagnesium bromide (3M in Et20) (103 milliliters, 309 mmol) was slowly added through a dropping funnel into a brick red-cooled, thick suspension at room temperature under a nitrogen atmosphere over a period of time. 3.5 hours After being stirred at room temperature overnight, TLC showed that the reaction was complete. 3 N of HCl (100 milliliters) was added slowly through a dropping funnel under a nitrogen atmosphere and the mixture was stirred for one hour. The THF layer was separated from the aqueous layer. The aqueous layer was adjusted to a pH of 12 with 6 N NaOH and extracted with EtOAc (100 milliliters, 3x). The organic fractions (THF and EtOAc) were combined and dried through MgS? , filtered and concentrated to provide a solid. The product was purified by flash chromatography on 300 grams of evaporation grade silica gel in 2.5 percent EtOAc / CH2Cl2 to provide 10.79 grams (69 millimoles, 39 percent) of 2-phenyl-pyrazine, fusion of 69 ° C to 70 ° C; FAB MS [M + 1] + 157; Found, C, 76.55; H, 5.22; N, 17.71. Calculated for C10H8 2, C, 76.90; H, 5.16; N, 19.93. To a solution of 2-phenylpyrazine (11.64 grams, 74.53 mmol) in acetic acid (58.2 milliliters) was added palladium acetate Pd (OAc) 2 (2.33 grams, 9.94 mmol). The mixture was hydrogenated at 3.52 kilograms per square centimeter for 4 hours. After the reaction was completed, the catalyst was filtered and rinsed with a small portion of acetic acid. The filtrate was concentrated under vacuum to provide a black-brown solid which was suspended in deionized water (300 milliliters) and adjusted to a pH of 13 with a 20 percent solution of NaOH. The product was extracted from an aqueous solution with EtOAc (200 milliliters, 3x), dried through MgS? , filtered and evaporated to dryness to provide 2-phenylpiperazine (7.2 grams). An additional 1.6 grams of 2-phenylpiperazine was obtained by evaporating the aqueous fraction to a solid and triturating the solid with CH2Cl2. The total yield of 2-phenylpiperazine was 73 percent. The crude material was crystallized from EtOAc and hexane to characterize melting temperature of 86 ° to 88 ° C; FAB MS [M + 1] + 163; Found, C, 74.04; H, 8.66; N, 17.15. Calculated for C10H14N, C, 74.04; H, 8.69; N, 17.26. To a solution of 2-phenylpiperazine (4.0 grams, 24.65 mmol) in CH2C12 (200 milliliters) at -78 ° C under a nitrogen atmosphere was added Et3N (5.15 milliliters, 36.97 mmol) followed by the dropwise addition of a solution of CH2Cl2 (46.60 milliliters) of bis (trifluoromethyl) benzyl bromide (4.66 milliliters, 24.65 millimoles). The flask was maintained at -78 ° C and then gradually warmed to room temperature overnight. After the TLC showed that the reaction was complete, the material was washed with brine (150 milliliters, 2x), dried through MgSO 4, filtered and evaporated in vacuo to yield a tan solid. The crude product was purified by evaporation silica gel chromatography (150 grams), eluting with 2.5 percent MeOH / CH2Cl2 to provide (+, -) 1- [[3,5-bis (trifluoromethyl) phenyl] methyl] -3-phenylpiperazine (6.96 grams, 17.92 millimoles, 72.7 percent) as an oil. A portion of this oil (0.5 gram, 1287 millimoles) was converted into its hydrochloride salt by dissolving the oil in CH2CI2 (20 milliliters) and treating it with 2.3 M of HC1-EtOH (1.3 milliliters, 2.99 millimoles). After stirring at room temperature for 10 minutes, all the solvents were removed under a high vacuum and the residue was dried overnight, melting temperature of 229 ° C to 233 ° C; FAB MS [M + 1] + 389; Found, C, 48.83; H, 4.28; N, 5.87; Cl, 14.77; F, 24.03. Calculated for C19H18N2F6-2 HC1-0.25 H20, C, 48.99; H, 4.43; N, 6.01; Cl, 15.22; F, 24.47.

EXAMPLE 2 (+, -) -4- [[3,5-bis (trifluoromethyl) phenyl] methyl] -1- [2- (4-hydroxy-4-phenyl-1-piperidinyl) acetyl] -2- dihydrochloride salt phenylpiperazine To a solution of (+, -) -1- [[3,5-bis (trifluoromethyl) phenyl] methyl] -3-phenylpiperazine (0.76 g, 1.975 mmol) in CH2C12 (15.2 milliliters) at -78 ° C was added Et3N (0.286 milliliter, 2.055 millimoles) followed by the dropwise addition of bromoacetyl bromide (0.179 milliliter, 2.055 millimoles). After being stirred at -78 ° C for 4 hours, the reaction mixture was diluted with CH2Cl (200 milliliters), washed with brine (100 milliliters, 2xj and dried through MgSO4). The solvent was removed to give a light yellow solid which was used without further purification FAB MS [M + 1] + 509.2 (79 Br) The product of the above reaction (2.0 grams, 3,928 mmol) dissolved in dry CH2C12 (20 milliliters) and cooled to -78 ° C under a nitrogen atmosphere.To this cooled solution were added 4-hydroxy-4-phenyl-piperidine (0.8 gram, 4.49 millimoles) and diisopropylethylamine (0.787 milliliter, 4.492 millimoles). The reaction was gradually warmed to room temperature overnight under a nitrogen atmosphere. After completion, CH2Cl2 (300 milliliters) was added and the organic layer was washed with brine (100 milliliters, 2x), dried through MgSO4 and filtered. The filtrate was evaporated in vacuo to provide a crude oil which was purified by flash chromatography on evaporative grade silica gel (100 grams), eluting with 4.0 percent NH3-MeOH-2.5 percent EtOH / CH2Cl2 for provide a light yellow oil (2.24 grams, 2.38 millimoles, 94 percent). A portion of the oil (0.40 gram, 0.661 millimole) was converted to its hydrochloride salt by dissolving in CH2CI2 (8 milliliters) and treating it with 2.3 M HCl-EtOH (0.632 milliliter, 1.454 millimoles). After being stirred at room temperature for 30 minutes, the solvent was evaporated and the residue was dried under vacuum overnight, at a melting temperature of 185 ° C to 187 ° C; FAB MS [M + 1] + 606.6; Found, C, 54.58; H, 5.44H N, 5.75; Cl, 9.71; F, 16.11. Calculated for C32H3302N3F6 • 2 HCl -1.5 H20, C, 54.47; N, 5.96; Cl, 10.05; F, 16.16.

EXAMPLE 3 By a process analogous to that described in Example 2, using the heterocyclic derivatives - - Suitable (group Z), as mentioned below, instead of 4-hydroxy-4-phenylpiperidine, the following compounds were prepared.

EXAMPLE 4 Salt of (+, -) -1- [2- [4- [[3,5-bis (trifluoromethyl) phenyl] methyl] -2-phenyl-l-piperazinyl] -4-piperidinol trihydrochloride salt.

- To a solution of (+, -) -4- [[3,5-bis (trifluoromethyl) phenyl] -methyl] -1- [2- (4-hydroxy-4-phenyl-1-piperidinyl) acetyl] -2 phenylpiperazine (0.74 g, 1.222 mmol) in THF (18.5 milliliters) was added 10 M of BH3 • S (CH3) 2 (0.85 milliliter, 8.5 mmol). The mixture was heated in an oil bath at 80 ° C under a nitrogen atmosphere overnight. After completion, the excess BH was decomposed by the droplet addition of MeOH to the cooled solution under a nitrogen atmosphere. The MeOH was evaporated and the residue redissolved in EtOH (22.2 milliliters). K2C03 (0.31 gram, 2.69 mmol) was added and the mixture was subjected to. reflux at 80 ° C for five hours. After the TLC showed that the reaction was complete, the solid was filtered and the filtrate was evaporated in vacuo. The residue was redissolved in EtOAc (200 milliliters), washed with brine (100 milliliters) and dried through MgSO 4. Filtered and evaporated in vacuo to provide an oil which was purified by flash chromatography on evaporative grade silica gel (100 grams), eluting with 10 percent NH3-MeOH / CHCl2 to provide the material desired as an oil (0.504 gram, 0.852 millimole, 69.8 percent). A portion of the oil (0.35 gram) was converted to its hydrochloride salt by dissolving in CH2Cl2 (17.5 milliliters), followed by the addition of 2.3 M HCl-EtOH (0.84 milliliter). The solvents were removed after being stirred at room temperature for 0.25 hour and the residue was dried under vacuum, melting temperature from 215 ° C to 220 ° C.; FAB MS [M + 1] + 592.1; Found, C, 53.17; H, 5.51; N, 5.77; Cl, 14.37; F, 15.62. Calculated for C33H38N F6-3 HC1-H20, C, 53.45; H, 5.61; N, 5.84; Cl, 14.79; F, 15.85. EXAMPLE 5 By a process analogous to the process described in Examples 2 and 4, using the appropriate heterocyclic derivatives (group Z), listed below, instead of 4-hydroxy-4-phenylpiperidine, the following compounds were prepared.

EXAMPLE 6 Salt of (+, -) - N- [1- [2- [4- [[3,4-bis (trifluoromethyl) funyl] methyl-2-phenyl-1-pipera ini 1] ethyl] -4 trihydrochloride salt -phenyl-4-piperidinJ 1] acetamide, hydrate 1.5.

To a solution of the product of Example 4 (free form) (0.66 gram, 1116 millimoles) in 5.0 milliliters of acetonitrile was added dropwise concentrated sulfuric acid (2.44 milliliters) at room temperature under a nitrogen atmosphere. After 4 hours, water (100 milliliters) was added to the reaction, and the solution was adjusted to a pH of 9 with a 10 percent solution of NaOH. The product was extracted from the aqueous solution with EtOAc (100 milliliters, 3x). The organic fractions were combined and washed with brine (100 milliliters), dried through MgSO 4, filtered, and concentrated in vacuo to provide an oil. The product was purified by flash evaporation chromatography on silica evaporation (80 grams) and eluted with 10 percent NH3-MeOH / CH2Cl2 to provide an oil (0.40 gram, 0.774 millimole, 69 percent). A portion of this oil (0.4 gram, 0.632 millimole) was dissolved in CH2Cl2 (20 milliliters) and treated with 2.3 M HCl-EtOH (2528 millimoles). After being stirred at room temperature for 0.5 hour, the solvents were removed in vacuo to give a white solid, with a melting temperature of 245 ° to 247 ° C; FAB MS [M + 1] + 633.4; Found, C, 53.27; H, 5.80; N, 7.23; Cl, 13.91; F, 14.55. Calculated for C34H38ON4F6 • 3 HCl • 1.5 H20, C, 53.09; H, 5.76; N, 7.28; Cl, 13.83; F, 14.82.

EXAMPLE 7 Dihydrochloride salt of (+, -) -1- [(2-methoxyphenyl) meryl] -3-phenyl-piperazine • 2 HCl • H20 To a solution of l-hydroxymethyl-2-methoxy-benzene (28.7 grams, 0.207 mol) in CH2Cl2 (574 milliliters) at 0 ° C under a nitrogen atmosphere was slowly added PBr3 (13.66 milliliters, 0.145 mol). After stirring for an additional 1.5 hours, MeOH (13.66 milliliters) was added and stirred for 5 minutes. To this mixture was added dropwise a 10 percent solution of Na2CO (2 milliliters) and stirred for 5 minutes. The mixture was then washed with 10 percent Na2CO3 (50 milliliters, 2x) and brine (100 milliliters). It was dried through MgSO4, and filtered. The filtrate was removed under vacuum to provide an oil (40 grams) of l-bromomethyl-2-methoxy-benzene. This material was used without purification. To a solution of (+, -) -2-phenyl-piperazine (2.83 grams, 17.44 mmol) (which is described in Example 1) in dry CH2Cl2 (141.5 milliliters) at -78 ° C was slowly added a solution of -bromomethyl-2-methoxy-benzene (3.507 grams 17.44 millimoles) in dry CH2CI2 (35 milliliters) under a nitrogen atmosphere. The reaction mixture was stirred at -78 ° C and gradually warmed to room temperature overnight. After completion, the product was diluted with CH2Cl2 (200 milliliters), washed with brine (100 milliliters), dried through MgSO4 and filtered. The filtrate was removed under vacuum to provide an oil. The product - - was purified by flash evaporation chromatography on evaporation grade silica gel (150 grams), eluting with 4 percent MeOH / CH2Cl2 to give the header compound as an oil (2.68 grams, 54 percent). A portion of this oil (0.33 gram, 1168 millimoles) was dissolved in CH2CI2 (10.0 milliliters) and treated with 2.3 M HCl (1.1 milliliter, 2.53 moles). After stirring at room temperature for 10 minutes, the solvents were vacuum stripped to provide a melting temperature of 152 ° C to 156 ° C; FAB MS [M + l] 283.2. Found, C 58.18; H, 7.23; N, 7.33; Cl, 18.89, Calculated for 18H22ON2 '2HC1 * H20' C '57.91; H, 7.02; N, 7.50; Cl, 18.99. EXAMPLE 8 Salt of (+, -) -1 - [(4-hydroxy-4-phenyl-1-piperidinyl) acetyl] -4- [(2-metaxyphenyl) methyl] -2- phenylpiperazine dihydrochloride salt.

The bromoacetyl derivative of the product of Example 7 was prepared according to the procedure described in Example 2. This intermediate was used for the next reaction without further purification. The compound E2 of the header was prepared using a process analogous to that described in Example 3, through a bromoacetyl derivative of (+, -) -1- [(2-methoxyphenyl) methyl] ~ 3 ~ phenyl-piperazine to provide a solid. Melting temperature from 183 ° to 186 ° C. FAB MS [M + l] + 500; Found C, 61.30; H, 7.54; N, 6.98; Cl, 11.65. Calculated for C31H37N303-2 HCl, C, 61.18; H, 7.12; N, 6.90; Cl, 11.65.

EXAMPLE 9 (+, -) - l- [2- [4- [(2-methoxyphenyl) methyl] -2-phenyl-1-piperizinyl] ethyl] -4-phenyl-4-piperidinol.

The product of Example 8 (free form) (0.7 gram, 1.4 mmol) was used to prepare the header compound using a procedure analogous to the procedure of Example 4. The header compound was a melting temperature solid of 63 ° C at 65 ° C; FAB MS [M + 1] + 486; Found, C, 75.86; H, 8.52; N, 8.54. Calculated for C31H39N3 ° 2 'c' 75-54; H, 8.14; N, 8.53.

EXAMPLE 10 2- (3,4-dichlorophenyl) piperazine A. Synthesis: METHOD 1 2- (3,4-Dichlorophenyl) pyrazine was prepared according to the analogous method described in Example 1. Melting temperature from 118 ° C to 119 ° C; F? B MS [M +]] + -15 Cl 225. To a solution of 2- (3,4-dichlorophenyl) pyrazine (10 grams, 44.43 mmol) in dry THF (150 milliliters) was slowly added a solution of DIBAL- H (1M in THF, 444.3 milliliters) through a dropping funnel at 10 ° C under N2. The color of the solution became a red wine color at the end of the addition. The solution was gradually warmed to room temperature overnight. After completion of the reaction (checked by TLC) the reaction mixture was slowly cooled slowly by the addition of a saturated Na 2 S 4 solution until the H2 was released. The white precipitate material was formed after being stirred for 1.0 hour. The precipitated material was filtered, rinsed with THF, dried through MgS? and evaporated to dryness. The crude material (10 grams) was purified by flash chromatography on 300 grams of evaporation grade silica gel in 7.5 percent NH3-MeOH / CH2Cl2 to provide 4.11 grams (17.77 millimoles, 40 percent) of 2- (3, 4-dichloro-phenyl) piperazine, with a melting temperature of 74 ° C to 76 ° C; FAB MS [M + l] + 231.

METHOD 2. 2- (3,4-Dichlorophenyl) piperazine was also synthesized according to the method published in J. Med. Chem., 9, 181, 1966. The general method for the synthesis of 2-aryl derivatives -piperazine: R1 = Cl, H or other substituents, that is, OCH3, CF3, Br, I, F, etc. R ^ = Cl, H or other substituents, that is, OCH, CF3, Br, I, F, etc.

B. Resolution of 2- (3,4-dichlorophenyl) piperazine Step 1 A solution of 2- (3, 4-dichlorophenyl) piperazine (36.05 grams, 0.156 mol) in methanol (200 milliliters) was treated with a solution containing two equivalents of N-acetyl-L-leucine (54.02 grams, 0.312 mol) and heated until all the material dissolved. This EtOAc solution (2.2 liters) was added and allowed to stand at room temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo. This procedure was repeated using 37.88 grams of 2- (3,4-dichlorophenyl) -piperazine (0.164 mol) and 56.68 grams of N-acetyl-L-leucine (0.327 mol).

Step 2 The concentrated salts of both phases of the solvent in step 1 were combined and heated in methanol (550 milliliters) until all the material dissolved. EtOAc (2.75 liters) was added to this solution and allowed to stand at room temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo to provide ~ 95 grams of piperazine salt (72 percent ee of enantiomer A).

Step 3 The salt of the solvent phase in step 2 was dissolved in a solution of H 2 O (800 milliliters) and aqueous ammonia (400 milliliters) and extracted with CH 2 Cl 2 (4 x 400 milliliters). The combined organic layers were dried with MgSO 4 and concentrated to provide 37 grams of the piperazine free base. The free base was successively recrystallized from hexane (890, 600 and 450 milliliters) to provide 16 grams of piperazine (> 99.9 percent ee of the A-enantiomer). [a] D24-7 ° C = -45.0 ° (MEOH) Step 4 ¡9 - The precipitated salts from step 1 were combined and heated in methanol (220 milliliters until all the material dissolved.) EtOAc (2.2 liters) was added to this solution and allowed to stand at room temperature overnight. decanted from the precipitated salt and dried under vacuum to provide ~ 43 grams of piperazine salt (93 percent ee of the B-enantiomer).

Step 5 A portion of 12.3 grams of salt (75 percent ee of the B-enantiomer) prepared in a procedure analogous to that in step 4, was dissolved in 0.5 M NaOH (400 milliliters) and extracted with CH2Cl2 (4 x 155 milliliters). The combined organic layers were dried with MgS? and concentrated to provide 3.72 grams of the piperazine-free base. The free base was successively recrystallized from hexane (90 and 70 milliliters) to provide 2.1 grams of piperazine (98 percent ee of the B-enantiomer).

EXAMPLE 11 By procedures analogous to the procedures described in Examples 1 and 2 and 10 but using (+, -) -1- [[3,5-bis (trifluoromethyl) phenyl] -methyl] -3- (3,4-dichlorophenyl) -piperazine instead of (+, -) -1- [[3, 5- bis (trifluoromethyl) phenyl] methyl] -3-phenyl-piperazine, and using the appropriate heterocyclic reagents (group Z), which are listed below , the following compounds were prepared. .. __ ______ - Found Ph ^ N- free form 55-57 672 673. 1935 Ph. HiN Informa libres 105- 107 702 O EXAMPLE 12 (+, -) - 1 - [2- f 4- [[3,5-bi (tri fluoroethyl) phenyl] ethyl J-2- (3,4-dichloropheni-1) -1-piperazinyl] ethyl] -4-phenyl-4-piperidonol.

- By a procedure analogous to the procedure described in Example 4, using the last compound of Example 11, a starting material was prepared, the header compound in a yield of 67 percent as a solid, melting temperature of 71 ° to 72 ° C; FAB MS [M + 1] + 660; Found, C, 58.08; H, . 14; M, 6.40; F, 17.37. Calculated for C3 H33M3C12F60, C, 58.19; H, 5.04; N, 6.36; F, 17.26.

EXAMPLE 13 (+, -) - [3,5-bis (trifluoromethyl) benzoyl] -3- (3,4-dichlorophenyl) piperazine To a cooled solution of CH2Cl2 (103 milliliters) containing 2- (3,4-dichlorophenyl) piperazine (1.15 grams, 5.0 mmol), 3,5-bis- (trifluoromethyl) benzoic acid (1.34 grams, 5.09 mmol) and N-hydroxybenzotriazole monohydrate (0.688 grams, 5.09 mmol) at -20 ° C were added with Et3N (0.711 milliliter). 5.09 millimoles) and N, N-dimethylaminopropyl ethylcarbodimide (DEC) (0.967 grams, 5.09 millimoles) under a nitrogen atmosphere. The reaction mixture was kept at -20 ° C for one hour and warmed to room temperature gradually overnight. After being stirred for 20 hours, the reaction was complete and CH 2 Cl 2 (200 milliliters) was added. The organic solution was washed with 5 percent NaHCO (80 milliliters) and brine (80 milliliters, 2x), dried through MgSO 4, filtered and concentrated in vacuo to provide 2.1 grams of the crude product. The product was purified by flash evaporation chromatography on silica gel. (120 grams), eluting with 2 percent NH3-MeOH / CH2Cl2 to provide a foam solid (1.25 grams, 2.65 millimoles, 53 percent), melting temperature of 50 ° to 53 ° C; FAB MS [M + 1] + 470.9; Calculated for C, 48.42; H, 2.99; N, 5.94; F, 24.19; Cl, 15.05. Found, C, 48.57; H, 2.90; N, 5.94; F, 23.90; Cl, 03.03.

EXAMPLE 14 (+, -) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -ll (4-hydroxy-4-phenyl-1-piperidini 1) ] acetyl] piperazine To a solution of (+, -) - [3,5-bis (trifluoromethyl) benzoyl] -3- (3,4-dichlorophenyl) piperazine (0.6 gram, 1.274 mmol) in dry CH2C12 (12.0 milliliters) at a temperature of - 78 ° C was added diisopropylethylamine (0.266 milliliter, 1.53 millimole) followed by the dropwise addition of bromoacetyl bromide (0.124 milliliter, .40 millimole). After being stirred at -78 ° C for 3.5 hours under a nitrogen atmosphere, additional diisopropylethylamine (0.234 milliliter, 1342 millimoles) and 4-amino-1-benzyl piperidine (0.279 milliliter, 1342 millimoles) were added at -78 ° C. . The reaction was gradually warmed to room temperature overnight. After completing the reaction, the reaction mixture was diluted with CH2Cl2 (200 milliliters), washed with brine (80 milliliters), 3x) and dried through MgSO4. After filtration, the solvent was removed in vacuo to provide a light yellow solid which was purified by flash chromatography on evaporative grade silica gel (150 grams), eluting with 5 percent NH3-MeOH / CH2Cl2 to provide the header compound that was prepared in a 72 percent yield as a solid, with a melting temperature of 104 ° C to 106 ° C, F7AB MS [M + l] + 688.1 Calculated for C32H29N303F6Cl2 • 0.25 H20, C , 55.45; H, 4.30; N, 6.06; F, 16.45; Cl, 10.23. Found, C, 55.40; H, 4.38; N, 6.05; F, 16.83; Cl, 10.63.

EXAMPLE 15 Using methods analogous to those described in Example 13 and Example 14 using appropriate alkylation reagents, the following compounds were obtained in accordance with the graphs shown below.

- Ar 3, 4-d purified at this stage 9. . FABMS | M + 1] FAB S [M + 1] < O r- O 708.0 Cl Cl EXAMPLE 16 (+, -) -2- (3,4-dichlorophenyl) -4- (2-methoxybenzoyl) -1 - [[(4-hydroxy-4-phenyl-1-piperidinyl)] acetyl] piperazine Using the analogous methods to those described in Example 13 and Example 15 and using 2-methoxybenzoic acid instead of bis (3,5-trifluoromethyl) benzoic acid, the title compound was prepared in a 71 percent yield as a solid, melting temperature of 112 ° C to 114 ° C, F7AB MS [M + l] + 582.0.

EXAMPLE 17 (+, -) -4- [3,5-bis (trifluoromethyl) benzoyl] -2-phenyl-1 - [[(4-hydroxy-4-phenyl-1-piperidinyl)] acetyl] piperazine Using methods analogous to those described in Example 13 and Example 15, and using 2-phenylpiperazine instead of 2- (3,4-dichlorophenyl) -piperazine, the title compound was prepared in a 90 percent yield as a solid: melting temperature of 101 ° C to 102 ° C, FAB MS [M + 1] + 620.4; Calculated for C32H29N303F6C12 • 0.25 H20, C, 61.57: H, 5.09; N, 6.73; F, 18.27. Found C, 61.41; H, 5.08; N, 6.71; F, 18.28.

EXAMPLE 18 ! +, -) [3, 5-dimethylbenzoyl] -3- (3,4-dichloro phenyl) piperazine To a cooled solution of CH2C12 (600 milliliters) containing 2- (3,4-dichlorophenyl) p! .. erazine (6.934 grams, 30 millimoles), 3, 5-dip.ethylbenzoic acid (4.55 grams, 30 millimoles), and N-hydroxybenzotriazole monohydrate (4.05 grams, 30 mmol) at -20 ° C were added Et3N (4.2 milliliters, 30 railimoles) and N, N-dimethylaminopropylethylcarbodiimide (DEC) (5.86 grams, 30 millimoles) under a nitrogen atmosphere. The reaction was maintained at -20 ° C for one hour and gradually warmed to room temperature overnight. After stirring 22 hours, the sc reaction was complete and CH 2 Cl 2 (200 milliliters) was added. The organic solution was washed with brine (150 milliliters, 3x), dried through MgSO4, filtered and concentrated in vacuo to provide 8.2 grams of the crude product. The product was crystallized from CH2Cl2 / Hexane to give a light yellow solid (6.3 grams, 17.34 mmol, 57.8 percent), melting temperature 1 -9 ° C-141 ° C; FAB M :. (M + l] 363.1.

EXAMPLE 19 (+) - [3,5-dimethylbenzoyl] -3- (R) - (3,4-dichlorophenyl) piperazine (Enantiomer B) The header compound was prepared by an analogous method to that described in Example 18 using (-) 2- (R) - (3,4-dichlorophenyl) piperazine instead of (+, -) - 2- (3, 4 -dichlorophenyl) piperazine, with a melting temperature of 97 ° C to 100 ° C; F7B MS [M + 1] + = 363.1; [a] D22-5 ° c = + 87.2 ° (MeOH).

EXAMPLE 20 (+, -) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -1 [1,2-dioxo-2- [4- (phenyl ethyl) -1- piperazinyl] ethyl] piperazine Step 1 A solution of 1-benzylpiperazine (1.75 milliliters, 10 mmol) in CH2Cl2 (60 milliliters) was treated with methyl acrylate (0.90 milliliter, 10 mmol) at room temperature for 2 days. The reaction mixture was concentrated to provide a clean Michael product (2.6 grams, 10 mmol, 100 percent).

Step 2 A solution of the product from step 1 (0.92 g, 3.5 mmol) in methanol (10 milliliters) was treated with 1 M LiOH (5.2 milliliters, 5.2 mmol) for 1 hour. The reaction mixture was concentrated in vacuo at 50 ° C and the residue was suspended in CH2Cl2 (25 milliliters), filtered and concentrated to obtain 0.72 gram of the desired acid (2.9 mmol, 83 percent).

Step 3 A solution of the product from step 2 (0.72 gram, 2.9 mmol) in benzene (12 milliliter) was treated with oxalyl chloride (300 milliliters, 3.4 mmol) and DMF (1 drop) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 90 minutes. The reaction mixture was concentrated in vacuo and the residue was suspended in CH2Cl2 (20 milliliters). To this suspension were added 1- [3, 5-bis (trifluoromethyl) benzoyl] -3- (3,4-dichlorophenyl) piperazine (1.4 grams, 2.9 mmol) in CH2C1 (14 milliliters) and triethylamine (0.80 milliliter, 5.7 millimoles). The reaction mixture was stirred for 1 hour and H 2 O (100 milliliters) was added. The mixture was extracted with CH2C12 (50 and 25 milliliters). The combined organic layers were washed with brine (50 milliliters), dried (MgSO) and concentrated. The crude material was purified by silica gel chromatography, eluting with CH2Cl: methanol (50: 1)) to obtain 0.64 gram (0.91 millimole, 31 percent) of the title compound as a colorless foam. HRMS (FAB, M + H +): m / e calculated for [C 32 H 29 Cl 2 F 6? 3] +: 701.1521, found 701.1513.

EXAMPLE 21 1- [3, 5-dimethylbenzoyl] -3- (R) - (3,4-dichloropheni, pipette (B-enantiomer) To a solution of glycine BOC (0.918 gram, 5.24 millimoles), (+) - (3,5-dimethylbenzoyl) -3- (R) - (3,4-dichlorophenyl) piperazine (enantiomer B) (1.80 grams, 4.95 millimoles ) (prepared in Example 19), DEC (0.983 gram, 5.13 millimoles), HOBT (0.687 gram, 5.07 millimoles) and the Hünig base (0.92 milliliter, 5.1 millimoles) in CH2CI2 (100 milliliters) was left stirring for 2.5 days. The reaction mixture was added to CH2Cl2 (200 milliliters) and washed with saturated NaHCO3 (3 times 100 milliliters), brine (100 milliliters), dried with MgSO.sub.0 was concentrated. The crude material was treated with HCl saturated with MeOH (25 milliliters) for 10 hours and concentrated. The residue residue was suspended in 0.3 N NaOH (150 milliliters) and extracted with CH2Cl2, (3 times 50 milliliters). The combined organic layers were washed with brine (50 milliliters), dried with MgSO 4, concentrated and purified by flash chromatography on silica gel, eluting with 20: 1: 0.2 CH2Cl2 / MeOH / concentrated aqueous to provide 0.95. gram of the product of the header as a white solid. HRMS (FAB, M + H +); m / e calculated [C31H24Cl2N302] +: 420.1246 found 420.1254.

EXAMPLE 22 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- [[4-carbethoxycyclohexyl) amino] acetyl] piperazine (enantiomer B) - - A solution of CH2Cl2 (2.0 milliliters) contains the amino compound of Example 21 (0.10 gram, 0.23 millimole) and l-carbethoxy-4-piperidone (39 milligrams, 0.23 millimole) was treated with NaBH (OAc) 3 (63 milligrams, 0.32 millimole) and acetic acid (15 milliliters, 0.26 millimole) and allowed to stir overnight. The reaction mixture was quenched with 1 N NaOH and extracted with H2 I2 (50 milliliters, 3 times). The combined organic layers were washed with brine, dried with MgSO 4 and chromatographed on silica gel eluting with 5 percent MeOH / CH 2 Cl 2 saturated with NH to provide ~6 milligrams of the header product as a white solid. HRMS (FAB, M + H +); m / e calculated [C30H38Cl2N5? 4] +: 574.2239, found 574.2250.

EXAMPLE 23 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- [[3-methylcyclohexyl) amino) acetyl] piperazine (diastereomers of B-enantiomer) Using an analogous method to that described in Example 22 using 3-methylcyclohexanone, the title compound was obtained. HRJMS (FAB, M + H +); m / e calculated [C28H36C12N302] +: 516.2185, found 516.2199.

EXAMPLE 24 1- [(cyclohexylamino) acetyl] -2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) piperazine (enantiomer B) Cl 0 Using the analogous method to that described in Example 22 using cyclohexanone, the header compound was obtained. HRMS (FAB, M + H +); m / e calculated paa [C27H3 C12N302] +: 502.2028, found 502.2025.

EXAMPLE 25 1- [(cycloheptylamino) acetyl] -2- (R) - (3,4-dichlorophenyl, -4- (3,5-dimethylbenzoyl) piperazine (enantiomer B) Using the analogous method to that described in Example 22 using cycloheptanone, the header compound was obtained. HRMS (FAB, M + H +); m / e calculated [c28H36cl2N3 ° 3l +: 516.2185, found 516.2177.

EXAMPLE 26 1- [[(4-cyano-4-phenylcyclohexyl) amino] acetyl] -2- (R) dichlorophenyl) -4- (3,5-dimethylbenzoyl) piperazine (enar.t omero B) Using the analogous method to that described in Example 22 using 4-cyano-4-phenylcyclohexanone, got the header compound. HRMS (FAB, M + H +); m / e calculated [C3 H37Cl2N? 2] +: 603.2294, found 503.2271.

EXAMPLE 26A (+/-) -2- (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1 - [[4-phenylcyclohexyl] amino] acetyl] -piperazine Using methods analogous to that described in Examples 21 and 22 using (+, -) - (3,5-dimethylbenzoyl) -3- (3,4-dichlorophenyl) -piperazine (enantiomer B) of Example 18 and 4-phenylcyclohexanone , the header compound was obtained. HRMS (FAB, M + H +); m / e calculated [C33H3gCl2N302] +: 578.2341, found 578.2327.

EXAMPLE 27 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- [3- [4- (2-keto-1-benzimidazolinyl) piperidinium] -1-oxopropyl] piperazine ( enantiomer B) A cooled solution of CH C12 (4 milliliters) containing (+) - (3,5-dimethylbenzoyl) -3- (3, -dichlorophenyl) piperazine (enantiomer B) of Example 19 (153 milligrams, 0.42 millimole) and the base of Hünig (0.12 milliliter), 0.86 millinol) at -78 ° C was treated with 3-chloropropionyl chloride (0.040 milliliter, 0.42 millimole) and heated at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and resuspended in acetonitrile (2 milliliters). To the reaction mixture was added 4- (2-cetc-1-bencimiaxolinyl) piperidine (104 milligrams, 0.48 millimole) and left to warm overnight at 70 ° C. The reaction mixture was concentrated and purified by silica gel chromatography eluting with 20: 1: 0 CH2Cl2 / eOH / concentrated aqueous to provide 104 milligrams of the overhead compound as a white solid (39 percent yield). HRMS (FAB, M + H +): calculated m / e [C H3sCl2N5? 3] +: 634.2352, found 634.2351.

EXAMPLE 28 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- [3- [4- (phenylmethyl) -1-piperidinyl] -l-oxopropyl] piperazine (enantiomer B) Using the analogous method to that described in Example 27 using 4-benzylpiperidine, the title compound was obtained. HRMS (FAB, M + H +); m / e calculated [C3 H or Cl2N302] +: 592.2498, found 592.2494.

EXAMPLE 29 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- [l-oxo-3- [4- (phenylmethyl) -1-piperidinyl] propyl] piperazine (enantiomer B ) Using an analogous method to that described in Example 27 using 1-benzyl-piperazine, the title compound was obtained. HRMS (FAB, M + H +); m / e calculated [C33H49Cl2N 02] +: 593.2450, found 593.2464. EXAMPLE 30 2- (R) - (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- 13- [4-hydroxy-4-phenyl-1-piperidinyl] -1-oxopropyl] piperazine ( enantiomer B) Using the analogous method to that described in Example 27 using 4-hydroxy-4-phenylpiperidine, the title compound was obtained. HRMS (FAB, M + H +); m / e calculated [C3 H3gCl2N303] +: 594.2290, found 594.::?5. EXAMPLE 31 The following examples were prepared in a manner analogous to the methods described in Example 27, using piperidine or an appropriate piperazine derivative instead of 4- (2-keto-1-bencimiaxolinyl (piperidine.

HR S measured calculated Cr - 593.2464 593.2450 592.2494 592.2498 ^ C - *** N N-575.2183 575.2192 -N / - < 580.2251 580.2246 - "• N- 609.2402 609.2399 -O 599.2550 599.2556 0 ~ H 112-117 585.2765 585.2763 223-226 643.3179 643.3182 187 aecom-.osed 629.2485 629.2484 127-130 599.2545 599.2556 159-16 634.307: 6843033 OO 578.2325 578.234 ' 97-99 5S3.3232 698.3240 94-97 670.3290 670.3291 78-80 570.2924 670.2927 82-84 581.2183 581.2199

Claims (14)

CLAIMS:

1. A compound represented by the structural formula each X is independently O, (H, H), NRd or S; n is from 0 to 2; u is from 0 to 2; I is from 0 to 2; m is 1, e and is from 1 to 3; or is 2 and Y is 0; each Rc is independently H, alkyl of 1 to 6 carbon atoms, - (CH2) ni-R4 is where ni is from 1 to 6; Kd is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, CN, ORa, phenyl, substituted phenyl, benzyl, substituted benzyl or allyl, and with the additional proviso that not more than one Rc is another other than H in the residue; Rc 'is H, alkyl of 1 to 6 carbon atoms or (CH2) nORa, with the proviso that no more than one Rc' is other than H; each Ra and Rb is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, benzyl, substituted C, allyl; or when Ra and Rb are attached to the same nitrogen atom, then Ra and Rb together with the nitrogen atom to which they are attached, form a 7-membered ring; where each R1 and R2 is independently H, alkyl of 1 to 6 carbon atoms, CF3, 0C II! 'C2F5, C !. Br, I, F, N02. ORa. CN, NRaRb, - c- • Ra, - O -Ra _ or fa Rb O Ra or 0"ii // i //?, R, - O - CN ~ Rb f - NC-ORa f - -C-Rb -C-ORa - r - - N-Rt H \ O O o and where Ra is not H -S R3 (_S_R2 (.SRa? And _s-NHRa; O O or Rb or II \ v // i íl -S-S-Ra -N-C-ORa • on 'or when Rl and R2 are on the adjacent carbon atoms in a ring, they can form where n 'is 1 or 2; and each R3 is independently H, alkyl of 1 to dxatomos carbon, CF3, -Ra O O Ra -O- Cll-Ra, _C, 1 _ ', 1R, cl / ßr ^ J f F / QRa r QCF3 Q feni? 0; Ap is a heteroaryl or substituted heteroaryl, Q is N or CH; Ar2 is heteroaryl, substituted heteroaryl, - - Z is where pi and p2 each is independently of 1 to 4 with the proviso that pi and p2 added together sen

2 to 6; ns is from 1 to 2; each Rs is independently selected from the group consisting of H, OH, c '', - Dna, alkyl of 1 to 6 carbon atoms, - (CHc) n? -R4 wherein neither is from 1 to 6 with the proviso that when it is not 1, R4 is not OH or NRaRb; also with the proviso that when ns is 2, Rs is alkyl of 1 to 6 carbon atoms and two Rs can be attached to the nitrogen atom to form a quaternary salt; each of Ra and Rb is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl; n3 from 0 to 4; each Re and Rf is independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl; or Re and Rf taken together with the carbon atom to which they are attached can also form a carbonyl group with the proviso that no more than one carbonyl group is in the residue of carbonyl. Rg is H, Or II < T0R-. -? - C-NRaRb? -? - -c - _ FL - $ - 0-C-Ra - -O-C- • N '• R. OR-?-. where Rb is not H, Ra_O Ra I II I - \ N-C-N-: R6 is H, alkyl of 1 to 6 carbon atoms, allyl, cycloalkyl of 3 to 6 carbon atoms, R6 may also be where X3 is 0, (H, H), NRd, or S; or Rβ is heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl when n3 is 0-4; or when Re, Rf taken together with the carbon atom to which they are fixed, form a carbonyl group and n3 is 1, Re can also be ORa where Ra is not H, and Re can also be - (NRa, Rb) , O-heteroaryl, substituted O-heteroaryl, O-heterocycloalkyl, O-heterocycloalkyl-substituted, -NRa-heteroaryl, -Nra-substituted heteroaryl, -NRa-heterocycloalkyl, heterocycloalkyl-NRa-substituted, or a pharmaceutically acceptable salt thereof . 2. A compound according to claim 1, wherein X is 0 or (H, H) and at least one X is O.

3. A compound according to claim 2, wherein both X are O.

4. A compound according to any claim 1, 2 or 3 wherein I is O; m is 1; and to 3; n is 1; u is O; where Q is N or CH; each Xi is independently 0, S or NRa; each X2 is independently CH or?; and n is O or 1; and Ar2 is or 5. A compound according to claim 1 of formula II where Rc is H; and is from 1 to 3; pi and p2 are 2; Re and Rf are

H, alkyl of 1 to 6 carbon atoms, cycloalkyl or allyl of 3 to 6 carbon atoms; n3 is 0-4; Rg is defined in claim 1; and Ap and AR2 both are

6. A compound according to claim 1, of formula III where Rc is H; and is from 1 to 3; pi and p2 are 2; n3 is 0-4; Re and Rf are H, alkyl of 1 to 6 carbon atoms, cycloalkyl or allyl of 3 to 6 carbon atoms; and Ap and Ar2 both are Ri R. R3

7. A compound according to claim 1 of formula IV where Rc is H; and is from 1 to 3; pi, p2 are 1-2; n3 is O to 4; Re and Rf are H, alkyl of 1 to 6 carbon atoms, cycloalkyl or allyl of 3 to 6 carbon atoms; and Ap and Ar2 are both

8. A compound according to claim 5 or 7 wherein R6 is or Re and Rf taken together with the carbon atom to which they are attached form a carbonyl group, n3 is 1 and R6 is

9. A compound according to the claim wherein Re is or Re, Rf taken together with the carbon atom to which they are attached form a carbonyl group, n3 is 1, Re is

10. A compound according to claim 9 wherein R6 is eleven . A compound according to claim 1 which is selected from the group consisting of wherein Z is or a compound selected from the group consisting of wherein Z is or a compound selected from the group consisting of where Z is or a compound selected from the group where Z is or or a compound that is selected from the group consisting of or a compound selected from the group consisting of wherein Z is or a compound selected from the group consisting of 29 -. 29 - or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising an antagonist effective amount of neurokinin of a compound according to any of claims 1 to 11 and a pharmaceutically acceptable carrier material. 13. The use of a compound of any of claims 1 to 11 for preparing a medicament useful for inducing neurokinin antagonism. The use of a compound of any of claims 1 to 11, for preparing a medicament useful for treating chronic respiratory diseases such as asthma, bronchospasm or allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrosites, osteoarthritis and rheumatoid arthritis; migraine; disorders of the central nervous system such as depression, psychosis, dementia, and Alzheimer's disease; Down's Syndrome; neuropathy; multiple sclerosis; ophthalmic disorders, conjunctivitis; autoimmune disorders; graft rejection; systematic lupus peritemosis: Gl disorders such as Crohn's disease and ulcerative colitis; disorders of the function of the vesicle; circulatory disorders such as angina, Raynaud's disease; vomit, cough and pain, which comprises administering an effective therapeutic amount of a compound according to claim 1.