MXPA01003560A - Naphthalenecarboxamides as tachykinin receptor antagonists - Google Patents

Abstract

A compound having formula (Ia) and any pharmaceutically-acceptable salt thereof, and their use for treating depression, anxiety, asthma, rheumatoid arthritis, Alzheimer's disease, cancer, schizophrenia, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, anxiety, emesis, Huntington's disease, psychoses including depression, hypertension, migraine, bladder hypermotility, or urticaria and compositions including such compounds and processes for making the compounds.

Description

NAFTALENOCARBOXAMIDAS AS ANTAGONISTS TAQUICININE RECEPTORS Background The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the central and peripheral nervous system. The three main neurokinins are substances P (SP), Neurokinin A (NKA) and Neurocinin B (NKB). There are also extended N-terminal forms of NKA. At least three types of receptors are known for the three main neurokinins. Based on their relative selectivities favoring the neurokinin antagonists SP, NKA, and NKB, the receptors are classified as neurokinin 1 (NKi), neurokinin 2 (NK2), and neurokinin 3 receptors.

(NK3), respectively. In the periphery, SP and NKA are located in afferent sensory neurons C, which are characterized by unmyelinated nerve endings known as C fibers, and are released by selective depolarization of these neurons, or selective stimulation of C fibers. C fibers are located in the epithelium of respiratory fibers, and tachykinins They are known to cause intense effects that clearly equate many of the symptoms seen in asthmatics. The effects of the release or introduction of tacinins into the mammalian airways include REF: 128137 bronchoconstriction, increased microvascular permeability, vasodilation, increased secretion of mucus and activation of mast cells. Thus, tacininas are implicated in the pathophysiology and hypersensitivity of the airways observed in asthmatics; and blocking the action of released tacinins may be useful in the treatment of asthma and related conditions. A cyclopeptide antagonist (FK-224) selective for both NKi and NK2 receptors has demonstrated clinical efficacy in human patients suffering from asthma and chronic bronchitis. M. Ichinose et al., Lancet, 1992, 340, 1248.

Description This invention relates to N-substituted naphthalenecarboxamide compounds by a substituted phenylpiperidinylbutyl group, to pharmaceutical compositions containing such compounds, as well as to their uses and processes for their preparation. These compounds antagonize the pharmacological actions of the endogenous neuropeptide tachykinins known as neurokinins, particularly the receptors neurokinin 1 (NKi), and neurokinin 2 (NK2). These compounds are useful at any time such antagonism is desired. Thus, such compounds are of value in the treatment of those diseases in which substances P and Neurocinin A are involved, for example in the treatment of asthma, anxiety, depression, emesis, urinary incontinence and related conditions. The N-substituted naphthalenecarboxamide compounds of the present invention show a high degree of antagonistic activity at NK_ and / or NK2 receptors. Additionally, by manipulation of the substituents on the naphthalene and piperidine rings of the formula (I), the percentage of activity at the NKi and NK2 receptors can be modified as desired, providing compounds that are predominantly active at the receptors. NKi or NK2 or providing compounds with a balanced activity and, as such, are particularly useful when the combined antagonism of both receptors is desired. In particular, the compounds of the present invention also possess a high degree of antagonism to NKi and / or NK2 by oral administration. Accordingly, the present invention provides the compounds of the general formula (I): (I) where: R1, on the one hand, has the formula wherein R7 is as defined below to give the general formula (la). (la) R2 is hydrogen, hydroxy, C_6 alkoxy, C? _ alkanoyloxy, C? -6 alkanoyl, C? _6 alkoxycarbonyl, C? -6 alkanoylamino, C? -6 alkyl, carbamoyl, C? _6 alkylcarbamoyl or di-C? -6 alkylcarbamoyl. R3 is hydrogen or Ci-β alkyl, for example methyl, ethyl, n-propyl or cyclopropyl. Preferably, R3 is methyl.

R4, R5 and R6 are each independently hydroxy; cyano; nitro; trifluoromethoxy; trifluoromethyl; C? _6 alkylsulfonyl for example methylsulfonyl; halo for example chlorine, bromine, fluorine or iodine; C__6 alkoxy for example methoxy, ethoxy or propoxy; C? _6 alkyl for example methyl or ethyl; cyano C? -6 alkyl for example cyanomethyl; C2-6 alkenyl for example ethenyl, prop-1-enyl or prop-2-enyl; C2_6 alkynyl for example ethynyl; carboxy, C6-alkoxycarbonyl for example methoxycarbonyl; carbamoyl; Ci-e alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C? -6 alkylcarbamoyl for example di-methylcarbamoyl; C? _6 alkanoyl for example acetyl or propionyl; C6-alkanoylamino for example acetylamino or propionylamino; aminosulfonyl; and C ?_6 substituted alkyl for example methyl substituted by any of the substituents mentioned herein. In addition, R ° may be hydrogen. Fably, CL-6 is alkyl, for example methyl or ethyl; C? -6 alkoxy for example methoxy or ethoxy, or halo for example fluorine, chlorine, bromine and iodine. Preferably, R 4 is methyl, ethyl, methoxy, ethoxy or fluorine.

More preferably, R 4 is methoxy ethyl, more preferably, methoxy. Preferably, R5 is cyano or nitro; more preferably, R5 is cyano. Preferably, R is hydrogen, methoxy, cyano nitro.

R7 is -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. M is -C (= 0) - or -S (= 0) 2-. L is NH or CH2. The compounds of the invention have a number of chiral centers, in -CH (Ph-X ^ X2) -, and possibly in the optional substituents (for example the MeSO- substituent) in (or both) of the phenyls and naft groups -1-ilo. The present invention covers all isomers, diastereomers and mixtures thereof which antagonize NKi and / or NK2. The preferred configuration in -CHÍPh-x x2) - is shown in formula (Ib) below: (Ib) X1 and X2 are independently hydrogen or halo, provided that at least one of X1 or X2 is halo. Fably, X1 and X2 are both chlorine. In a preferred aspect Ph-X1, X2 is 3,4-dichlorophenyl. R2 is hydrogen; hydroxy; C6-alkoxy for example methoxy or ethoxy; C? _6 alkanoyloxy for example acetyloxy or propionyloxy; C? _6 alkanoyl for example acetyl or propionyl; C? _6 alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; C6-alkanoylamino for example acetylamino; C? _6 alkyl for example methyl or ethyl; carbamoyl; C? -6 alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl or di-C? _6 alkylcarbamoyl for example dimethylcarbamoyl. Preferably, R 2 is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. More preferably R2 is hydrogen or methylcarbamoyl. A preferred class of compounds is that of formula (II): (II) where R3 is as defined above and R-R6 are selected from hydrogen, cyano, nitro, methoxy, methyl, ethyl and fluorine. The most preferred structure is The particular compounds of this invention are provided as the Examples below. CQ-Z alkyl, unless otherwise specified, means an alkyl chain containing a minimum Y of total carbon atoms and a maximum Z of total carbon atoms. These alkyl chains can be branched or unbranched, cyclic, acyclic or a combination of cyclics and acyclics. For example, the following substituent would be included in the general description * C4-7 alkyl ": The pharmaceutically acceptable salts can be prepared from the corresponding acid of. conventional way. The non-pharmaceutically acceptable salts may be useful as intermediates and as such are another aspect of the present invention. The compounds of the present invention are capable of forming salts with various organic and inorganic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camforate, camphorsulfonate, citrate, cyclohexyl, sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyoleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate , nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), and undecanoate. Basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, salts of alkaline rare earth metals such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N -methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and the like. Also basic groups containing nitrogen can be converted to quaternaries with agents such as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides such as benzyl bromide and others. Non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in the isolation or purification of the product. The salts can be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by cold drying or by exchange of anions of an existing salt with another anion in a suitable ion exchange resin. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for therapeutic treatment (including prophylactic treatment) of mammals including humans, this is normally formulated in accordance with standard pharmaceutical practice as a - Pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention can be administered in standard manners for the condition of the disease to be treated, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention can be formulated by means known in the prior art in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulizers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more valuable pharmacological agents in the treatment of one or more disease conditions referred to herein. . The pharmaceutical compositions of this invention will be administered in a normal manner to humans so that, for example, a daily dose of 0.01 to 25 mg / kg of body weight (and preferably 0.1 to 5 mg / kg of body weight) is received. This daily dose can be given in divided doses as necessary, the precise amount of the compound received and the route of administration depends on the weight, age and sex of the patient to be treated and the particular disease condition to be treated in accordance with the principles known in the art. Typically dosage forms per unit will contain from about 1 mg to 500 mg of a compound of this invention. For example, a tablet or capsule for oral administration may conveniently contain above 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt thereof can be administered in a daily dose range of 5 to 100 mg, in a single dose or divided in two to four doses daily In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing above 10% w / w (and typically 5% w / w) of a compound of the formula can be used. (I) or a pharmaceutically acceptable salt thereof. Therefore in a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of therapeutic treatment of the human or animal body.

In yet a further aspect the present invention provides a method of treating a disease condition wherein antagonism of the Ki and / or NK2 receptors which comprises the administration to a warm-blooded animal of an effective amount of a compound is beneficial. of the formula (I) or of a pharmaceutically acceptable salt thereof. The present invention also provides the use of a compound of the formula (I) of a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein the antagonism of Ki and / or NK2 receptors is beneficial. . The compounds of the formula (I) and their pharmaceutically acceptable salts can be made by processes as described and exemplified herein and by processes similar to these and by processes known in the chemical art. If they are not commercially available, the initiator materials for these processes can be made by methods that are selected from the prior art using techniques that are similar or analogous to the synthesis of known compounds. In another aspect the present invention provides a process for the preparation of a compound of the formula (I) of a pharmaceutically acceptable salt thereof which process comprises: a) reacting a compound of the formula (III) with a compound of the formula (IV): (III) (IV) wherein R2-R7, L, M, Xi and X2 are as defined above; and L and L 'are the reductive amination groups of the compounds of formulas (III) and (IV) which form an N-C bond; or b) reacting a compound of the formula (V) with a compound of the formula (VI): (V) (VI) wherein R2-R7, L, M, Xi and X2 are as defined above; and L "is a leaving group; where any other functional group is protected, if necessary, and: i) removal of any protection group; ii) optional formation of a pharmaceutically acceptable salt. Protection groups can generally be chosen from any of the groups described in the literature or known by experienced chemists as appropriate for the protection of the group in question, and can be introduced and removed by conventional methods; see for example Protecting Groups in Organic Chemistry; Theodora W. Greene. The removal methods are chosen in such a way to effect the removal of the protection group with the least alteration of the groups in another part of the molecule. It will also be appreciated that some of the many optional substituents on the compounds of the formula (I) can be introduced by standard aromatic substitution reactions or generated by conventional modifications of functional group either prior to or following the processes described above. Reactants and reaction conditions for such procedures are well known in the prior art of chemistry. The compounds of the formula (III) and (IV) are reacted under reductive amination conditions. Typically in the compounds of the formula (III) L is hydrogen. Typically in the compounds of the formula (IV) L 'is an oxo group that forms an aldehyde moiety. The reaction is typically carried out at a non-extreme temperature, for example from 0 to 100 ° C, suitably at room temperature in an inert solvent substantially, for example, dichloromethane. Typically, reducing agents include borohydrides such as sodium cyanoborohydride. The compounds of the formula (III) are known or prepared in a conventional manner. The compounds of the formula (IV) can be prepared, for example, by the reaction of a compound of the formula (VI) with a compound of the formula (VII): (VII) wherein L ', R3, X1 and X2 are as defined above under conventional acylation conditions.

The compounds of the formula (V) and (VI) can be reacted under conventional acylation conditions wherein is an acid or an activated acid derivative. Such activated acid derivatives are well known in the literature. These can be formed in situ from the acid or can be prepared, isolated and subsequently reacted. Typically L '' is chlorine with which it forms the acid chloride. Typically the acylation reaction is carried out in the presence of a non-nucleophilic base, for example, diisopropylethylamine, in an inert solvent substantially at a non-extreme temperature. The compounds of the formula (VII) are known or can be prepared in a conventional manner. Certain compounds of the formula (IV) and (V) are novel and form part of the present invention. In particular, the compounds of the formula (VI) are novel, in which the naphth-1-yl group is replaced by a methoxy group in the 2-position and by a cyano group in the 3-position.

Accordingly, in another aspect the present invention provides a compound of the formula (VIII): (VIII) where L "is found as defined above; preferably L "is hydrogen or a leaving group such as chlorine. In another aspect the present invention provides a compound of the formula (IX): (IX) where R3, X1, X2 and L 'are as defined above. It is well known in the prior art how to prepare optically active forms (e.g., by resolution of the racemic form or by the synthesis of optically active initiator materials) and how to determine the properties of NKi and NK2 antagonists by standard tests known in the prior art and those described below. Some individual compounds within the scope of this invention may contain double bonds. Representations of the double bonds in this invention are proposed to include both the E-isomer and the Z-isomer of the double bond. Additionally, some species within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of optically pure stereoisomers as well as any combination of stereoisomers. The following biological methods, data and examples serve to further illustrate and describe the invention. The utility of a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter collectively referred to as a "compound") can be demonstrated by standard tests and clinical studies, including those disclosed in the publications described below.

Receptor Binding Assay SP (Test A) The ability of a compound of the invention to antagonize SP binding to the NKX receptor can be demonstrated using a test using the human NKL receptor expressed in Mouse Erythroleukemia (MEL) cells. The human NKi receptor was isolated and characterized as described in: B. Hopkins, et al. Isolation and characterization of the human lung NKi cDNA receptor "Biochem Biophys, Res. Comm., 1991, 180, 1110-1117, and the NK_ receptor was expressed in Mouse Erythroleukemia (MEL) cells using a procedure similar to that described in test B below.

Receptor Binding Assay Neurokinin A (NKA) (Test B) The ability of a compound of the invention to antagonize the binding of NKA to the NK2 receptor can be demonstrated using an assay using the human NK2 receptor expressed in mouse erythroleukemia cells.

(MEL), as described in: Aharony, D., et al. "Isolation and Pharmacological Characterization of a Hampster Neurokinin A Receptor cDNA "Molecular Pharmacology, 1994, 45, 9-19. The selectivity of a compound for binding to NKi and NK2 receptors can be shown by determining its binding to other receptors using standard assays, for example, one using a tritiated NKB derivative in a tissue preparation selective for NK3 receptors. . In general, the compounds of the invention that were tested showed statistically significant binding activity in Test A and Test B with a Ki of 1 mM or much less being typically measured.

Rabbit Pulmonary Artery: In vitro Ki Functional Test (Test C) The ability of a compound of the invention to antagonize the action of the antagonist [Arg6, Sar9, Met (02) 11] Substance P (6-11), ASMSP, in a lung tissue can be demonstrated as follows. New Zealand white male rabbits were sacrificed by intravenous injection into the ear vein with 60 mg / kg of Nembutal (50 mg / mL). Preceding the Nembutal, Heparin was applied into the vein (1000 units / mL) at 0.0025 mL / kg for anticoagulation purposes. The thoracic cavity opens from the end of the costal arch to the sternum and the heart, lungs and part of the trachea are removed. The pulmonary arteries are isolated from the rest of the tissues and cut in half to serve as pairs. The segments are suspended between stainless steel stirrups, so that nothing is removed from the endothelium, and they are placed in water-filled tissue tubs (37 ° C) containing physiological saline of the following composition (mM): NaCl, 118.0; KCl, 4.7; CaCl2, 1.8; MgCl2, 0.54; NaH2P04, 1.0; NaHCO 3, 25.0 glucose, 11.0; indomethacin, 0.005 (to inhibit cyclooxygenase); and dl-Propanolol, 0.001 (to block β receptors); they are gasified continuously with 95% 02-5% C02. The answers are measured in a Grass polygraph via Grass FT-03 transducers. The initial tension placed on each fabric is 2 grams, which is maintained throughout the equilibrium period of 1.0 hour. The tissues are washed with physiological saline at 15 minute intervals. After 30 and 45 minutes of washing, the following treatments were added: 1 x 10 ~ 6 M of thiorphan (to block EC3.4.24.11), 3 x 10"8 M of (S) -N- [2- (3, 4-dichlorophenyl) -4- [4- (2-oxoperidropyrimidin-1-yl) piperidino] butyl] -N-methylbenzamide (to block NK2 receptors), and the given concentration of the compound to be tested.At the end of 1.0 hour of equilibrium, 3 x 10"6 M of phenylephrine hydrochloride is added during 1.0 hour. At the end of 1.0 hour, a dose relaxation curve for ASMSP is formed. Each tissue is treated individually and is considered finished when it fails to relax after two additional consecutive doses. When a tissue is completed, a maximum of 1 x 10"3 M Papaverine is added for maximum relaxation.The percent inhibition is determined when a tested compound produces a statistically significant reduction (p <; 0.05) of total relaxation which is calculated using the total relaxation of Papaverine as 100%. The potencies of the compounds are determined by calculating the apparent dissociation constants (KB) for each concentration tested using the standard equation: KB = [antagonist] / (proportion of the dose - 1) where the proportion of the dose = antilogt (agonist-log molar EC50 without compound) - (-log molar EC5o with compound)]. KB values can be converted to negative logarithms and expressed as -log molar KB (for example pKB). For this evaluation, the concentration-response curves for the agonist obtained in the absence and presence of the compound tested using paired pulmonary artery rings are completed. The agonist's potency is determined at 50% of its own maximum relaxation at each curve. The EC5u values are converted to negative logarithms and are expressed as -log molar EC50.

Functional test of NK2 in vitro (Test D) The ability of a compound of the invention to antagonize the action of the agonist [ß-ala8] NKA (4-10), BANK, in a lung tissue can be demonstrated as follows. New Zealand white male rabbits are sacrificed by intravenous injection into the vein of the ear with 60 mg / kg of Nembutal (50 mg / mL). Preceding Nembutal, Heparin was administered into the vein (1000 units / mL) at 0.0025 mL / kg for anticoagulation purposes. The thorax cavity opens from the end of the costal arch to the sternum and a small incision is made in the heart so that the left and right pulmonary arteries can be canalized with polyethylene tube PE260 and PE190 respectively). The pulmonary arteries are isolated from the rest of the tissues, then rubbed on an intimate surface to remove the endothelium, and cut in half to serve as pairs. The segments are suspended between stainless steel stirrups and placed in water-filled tissue tubs (37 ° C) containing physiological saline of the following composition (mM): NaCl, 118.0; KCl, 4.7; CaCl2 > 1.8; MgCl2, 0.54; NaH2P0, 1.0; NaHCO, 25.0 glucose, 11.0; indomethacin, 0.005 (to inhibit cyclooxygenase); it is gasified continuously with 95% 02-5% C02. The answers are measured in a Grass polygraph via Grass FT-03 transducers. The initial tension placed on each fabric is 2 grams, which is maintained throughout the equilibrium period of 1.0 hour. The tissues are washed with physiological saline at 15 minute intervals. After the equilibration period of 45 minutes, 3 x 10"2 M KCl is added for 60 minutes to test the viability of the tissues.The tissues are then washed extensively for 30 minutes.The concentration of the compound to be tested is Then, over 30 minutes, at the end of 30 minutes, a cumulative dose response curve was made for BANK, each tissue is treated individually and is considered finished when it fails in contraction after two consecutive doses. When a tissue is complete, 3 x 10"2 M BaCl2 is added for maximum concentration. The percent inhibition is determined when a tested compound produces a statistically significant reduction (p <0.05) of the total shrinkage which is calculated using the total BaCl2 shrinkage as 100%. The potencies of the compounds were determined by calculating the apparent dissociation constants (KB) for each concentration tested using the standard equation: KB = [antagonist] / (proportion of dose - 1) where the proportion of the dose = antilogt (agonist-log molar EC50 without compound) - (-log molar EC5u without compound)]. KB values can be converted to negative logarithms and expressed as -log molar KB (for example pKB). For this evaluation, the concentration-response curves for the agonist obtained in the absence and presence of the compound tested using paired pulmonary artery rings are completed. The agonist's potency is determined at 50% of its own maximum relaxation at each curve. The EC50 values are converted to negative logarithms and expressed as -log molar EC50.

Functional assay of NKi and NK2 in vivo (Test E) The activity of a compound as an antagonist of NKL and / or NK2 receptors can also be demonstrated in vivo in laboratory animals as described in: Buckner et al., * Differential Blockade by Tachykinin NKi and NK2 Antagonist Receptor of Bronchoconstriction Induced by Direct -Acting Agonist and the Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotonin in the Anesthetized Guinea Pig. "J. Pharm. Exp. Ther., 1993, Vol 267 (3), pp. 1168-1175. They are carried out as follows The compounds are tested in anesthetized guinea pigs pretreated with intravenous indomethacin (10 mg / kg, 20 minutes), propranolol (0.5 mg / kg, 15 minutes), and thiorphan (10 mg / kg, 10 minutes). Antagonists or vehicles are administered intravenously and orally, 30 and 120 minutes prior to the increase of agonist concentrations, respectively. The agonists used in these studies are ASMSP (Ac- [Arg6, Sar9, Met (02) 1J-] - SP (6-ll)) and BANK (ß-ala-8 NKA4-10). Administered intravenously, ASMSP is selective for NKi receptors, and BANK is selective for NK2 receptors. The maximum response is defined as zero conductance (G L, 1 / Rp). The values of ED0 are calculated (the dose of agonist that results in a reduction of GL to 50% of the baseline), and converted to the negative logarithm (-logED50). The ED50 values obtained in the presence (P) and absence (A) of antagonist, are used to calculate a Dose Ratio (P / A), a power expression. The data are expressed as mean + SEM and the statistical differences are determined using ANOVA / Tukey-Kramer and Student's t-test, with p <; 0.05 considered statistically significant. The compounds of the present invention exhibit marked activity in the preceding tests and are considered useful for the treatment of those diseases in which the NKL and / or NK2 receptor is involved, for example, in the treatment of asthma and related conditions.

Clinical studies Clinical studies to demonstrate the efficacy of a compound of the invention can be carried out using standard methods. For example, the ability of a compound to prevent or treat asthma symptoms or asthma-like conditions can be demonstrated using a challenge of cold air inhalation or allergen and evaluation by standard pulmonary measurements, such as, for example, FEVi (forced expiratory volume in one second) and FVC (forced vital capacity), analyzed by standard methods of statistical analysis. It will be understood that the implications of the activity of the compounds in the Tests described above are not limited to asthma, but rather, that the Tests provide evidence of general antagonism of both SP and NKA. SP and NKA have been implicated in the pathologies of numerous diseases that include: rheumatoid arthritis, Alzheimer's disease, cancer, schizophrenia, edema, allergic rhinitis, inflammation, pain, hypermotility-gastrointestinal, aging, emesis, Huntington's disease, psychosis including depression , hypertension, migraine, hypermotility of the bladder and urticaria. Accordingly, a feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease in a human or other mammal in need of those in which SP or NKA is involved and he wants the antagonism of his action. Asthma is characterized by chronic inflammation and hypersensitivity of the airways. The NKi receptor is known as a mediator of inflammation and mucus hypersecretion in the airways; and the NK2 receptor is involved in the control of bronchial smooth muscle tone. Thus, the agents capable of antagonizing the action of SP and NKA, and of the NKi and NK2 receptors, respectively, are capable of reducing both chronic inflammation and hypersensitivity of the airways that are symptomatic of asthma. It has been suggested that an antagonist having mixed affinity for the NKi and NK2 receptors could be therapeutically superior to a selective receptor antagonist. C.M. Maggi 'Tachykinin Receptors and Airway Pathophysiology "EUR, Respir J., 1993, 6, 735-742 to 739. Also, it has been suggested that a synergistic effect against bronchoconstriction may result from the simultaneous application of an NKi antagonist and one of NK2 DM Foulon, et al. * NK? and NK2 Receptors Mediated Tachykinin and Resiniferatoxin-induced Bronchospasm in Guinea Pigs "American Revie of Respiratory Disease, 1993, 148, 915-921. Accordingly, another feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of asthma in a human or other animal in need thereof. There is a possible role for P antagonists in the treatment of depression. Accordingly, another feature of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of depression in a human or other mammal in need thereof.

Because of the range of effects attributable to the actions of SP and NKA, compounds that are able to block their actions may also be useful as tools to further evaluate the biological actions of other neurotransmitters in the tachykinin family. As a result, another feature of the invention is provided by the use of a compound of formula I or a salt thereof as a pharmacological standard for the development and standardization of new disease models or assays for use in the development of new agents Therapeutics for the treatment of diseases in which SP or NPCA are involved or for tests for their diagnosis.

EXAMPLES The invention will now be illustrated by the following non-limiting examples, in which, unless otherwise indicated: (i) the temperatures are given in degrees Celsius (° C); unless otherwise stated, the operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 ° C; (ii) the organic solutions were dried in anhydrous magnesium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascal, 4.5-30 mm Hg) with a bath temperature above 60 ° C; (iii) chromatography means silica gel spectrum chromatography; thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of reactions was followed by TLC and the reaction times are given only by way of illustration; (v) the melting points are uncorrected and (dec) indicates decomposition; (vi) the final products have satisfactory proton nuclear magnetic resonance (NMR) spectrum; (vii) when given, the NMR data are in the form of delta values for the highest proton diagnosis, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using chloroform deuterated (CDC13) as a solvent; conventional abbreviations are used for signal configuration; for the AB spectrum the changes observed directly are reported; the coupling constants (J) are given in Hz; Ar designates an aromatic proton when such an assignment is made; (viii) the reduced pressures are given as absolute pressures in Pascales (Pa); the high pressures are given as bar pressure gauge pressures; (ix) the percentages of solvent are given in terms of volume: volume (v / v); and (x) the mass spectra (MS) were run using an automated system with chemical ionization of atmospheric pressure (APCI). Generally, only the spectrum where the original masses are observed and represented. The lower bulk mass ion is reported for molecules where the splitting of the isotope results in multiple peaks of spectral mass (for example when chlorine is present).

Terms and abbreviations: The solvent mixture compositions are given as percentages of volume or volume ratio. In cases where the NMR spectrum is complex, only diagnostic signals are reported, atm; atmospheric pressure, Boc; t-butoxycarbonyl, Cbz; benzyloxycarbonyl, DCM; methylene chloride, DIPEA: diisopropylethylamine, DMF; N, N-dimethylformamide, DMSO; dimethylsulfoxide, Et20; diethyl ether, EtQAc; ethyl acetate, h; hour (s), HPLC: high pressure liquid chromatography, min; minutes, NMR; nuclear magnetic resonance, psi; pounds per square inch; TFA; trifluoroacetic acid, THF; tetrahydrofuran. Standard reductive amination refers to the typical procedure in which a solution of an amine (1-1.2 equivalents), an aldehyde (1-1.2 equivalents) and acetic acid (2 equivalents) are stirred in methanol for 5 to 60 min before the addition of NaBH3CN (1.7 equivalents). After 1-16 h the reaction is optionally concentrated, dissolved in DCM, and washed with saturated sodium bicarbonate and then purified by chromatography. The standard Swern oxidation conditions refer to the oxidation of an alcohol to the corresponding aldehyde according to Mancuso, AJ; Huang, SL; Swern, D; J. Org. Chem .; 1978, 2840. The standard formation of an acid chloride refers to the typical procedure in which a solution of a naphthoic acid or substituted naphthoic acid in DCM is mixed with 1-1.2 equivalents of oxalyl chloride and a catalytic amount of DMF for 1 -12 h, concentrated under reduced pressure, and used without purification.

Standard acylation refers to the typical procedure in which an acid chloride (1-1.2 equivalents) is added to a mixed solution of an amine (1-1.2 equivalents) and triethylamine (2 equivalents) in DCM. After 1-16 h the reaction is optionally concentrated, dissolved in DCM, and washed with saturated sodium bicarbonate and then purified by chromatography. Where it was noted that a final compound was converted to the citrate salt, the free base was combined with citric acid (1.0 equivalents) in methanol, concentrated under reduced pressure and dried under vacuum (25-70 ° C). When it was indicated that a compound was isolated by Et20 filtration, the citrate salt of the compound was mixed for 12-18 h, removed by filtration, washed with Et20, and dried under vacuum at 25-70 ° C. Where it was noted that a final compound was converted to the hydrochloride salt, a solution of HCl in Et20 was added, with stirring to a solution of the purified free base in DCM or methanol. The resulting precipitate was collected by filtration and dried under vacuum. Each compound bearing a 2-substituted naphthamide was presented as a mixture of conformational isomers (atropisomers); it is believed that this results from the slow rotation around the amide and / or aryl bonds. Such compounds showed multiple peaks in the HPLC chromatograms and highly complex NMR spectrum. In some cases, the individual components of an atropiomeric mixture could be purified by reverse phase HPLC and the properties could be evaluated independently.

Example 1 N- [(S) -2- (3,4-Dichlorophenyl) -4- [4- [tetrahydro-2-oxo-1 (2H) -pyrimidinyl] -1-piperidinyl] butyl] citrate methyl-2-methoxy-3-cyano-l-naphtamide.

Using standard acylation conditions, N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [tetrahydro-2-oxo-l (2H) -pyrimidinyl] - was reacted (0.130 g). 1-piperidinyl] butyl] -N-methylamine (Miller, SC; WO 9505377) with 2-methoxy-3-cyano-l-naphthoyl chloride (prepared from 3-cyano-l-naphthoic acid and oxalyl chloride) (0.065 g). The free base was converted to citrate salt. MS m / z 622 (M + H).

The required 2-methoxy-3-cyano-l-naphthoic acid was prepared as follows, (a) 3-Hydroxy-4-iodo-2-naphthoic acid A mixture of NaOH (2.12 g) in methanol (100 mL) was stirred until the solution was homogeneous. Sodium iodide (3.98 g) and 3-hydroxy-2-naphthoic acid (5.00 g) were added and stirred for 30 minutes. The resulting suspension was cooled to 0 ° C and an aqueous solution of sodium hypochlorite at 5.25% (w / v) was added dropwise and the mixture was continued for 1 h. Saturated sodium thiosulfite (25 mL) was added and after 5 minutes the solution was acidified to a pH of 2 by the addition of 6 N of HCl resulting in the formation of a yellow precipitate which was filtered and washed with water (50 ml). mL). The precipitate was transferred to a round bottom flask, dissolved in methanol (70 mL) and toluene (100 mL), concentrated, redissolved in methanol (70 mL) and toluene (100 mL) and concentrated to provide the product as a yellow solid (6.26 g). MS m / z 313 (M-1). -H NMR (DMSO-de): d 12.41 (broad, 1H), 8.63 (s, 1H) 8.05-7.97 (m, 2H), 7.70 (m, 1H), 7.42 (m, 1H). (b) Methyl 3-methoxy-4-iodo-2-naphthoate. A solution of 3-hydroxy-4-iodo-2-naphthoic acid (8.0 g), dimethyl sulfate (8.03 g), potassium carbonate powder (8.80 g) and dry acetone (150 mL) was heated under reflux for 18 hours . The solution was cooled to room temperature, triethylamine (15 mL) was added, and stirring was continued for 30 min. The solution was filtered through a pad of Celite and washed with dry acetone (50 mL). The filtrate was concentrated to a yellow oil, diluted with EtOAc, and washed successively with IN of HCl (100 mL), saturated aqueous sodium bicarbonate (100 mL), and saline (100 mL). The organic phase was dried (sodium sulfate), filtered, concentrated, and purified by chromatography (0-10% ETOAc in hexanes) to give the product as a yellow oil (5.53 g) XH NMR (DMSO-d6 ): d 8.47 (s, 1H), 8.09 (m, 2H), 7.74 (m, 1H), 7.61 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H). (c) l-iodo-2-methoxy-3-cyanonaphthalene. Based on the procedure of Wood, JL; Khatri, NA; Weinreb, SM; Tetrahedron Lett; 51, 4907 (1979), methyl 3-methoxy-4-iodo-2-naphthoate (5.0 g) was suspended in xylenes (100 mL), cooled to 0 ° C, dimethylaluminum amide solution (approximately 37 mmol) was added. and the solution was heated under reflux for 2.5 h. The solution was then cooled to 0 ° C and acidified to a pH of 2 by the addition of IN of HCl and extracted with ETOAc (3 x 100 L). The combined ETOAc extracts were washed with saturated aqueous sodium bicarbonate (150 mL) and saline (150 mL), dried (sodium sulfate), filtered, concentrated, and purified by chromatography. (1: 1 ETOAc: DCM, then 10% 20% ETOAc in DCM) to provide the product as a white solid (3.29 g). 1 HOUR NMR (DMSO-de): d 8.69 (s, 1H), 8.24-8.04 (m, 2H), 7.91-7.81 (m, 1H), 7.76-7.75 (m, 1H), 3.99 (s, 3H); MS m / z 311 (M + H). (d) Methyl 2-methoxy-3-cyano-l-naphthoate. Through a suspension of l-iodo-2-methoxy-3-cyanonaphthalene (0.250 g), Pd (Oac) 2 (0.018 g), triethylamine, (0.081 g) and methanol (20 mL) was bubbled with carbon monoxide for 25 minutes, then stirred at 70 ° C under carbon monoxide (1 atm) for 18 hours. The solution was cooled, filtered, rinsed with methanol (20 L) and DCM (20 mL), concentrated, preabsorbed in silica (1 g) and purified by chromatography (0-10% ETOAc in hexanes) to provide the product as a white solid (0.113 g). X NMR (DMSO-de): d 8.78 (s, 1H), 8.12-8.09 (m, 1H), 7.84-7.78 (m, 2H), 7.70-7.63 (m, 1H), 4.02-4.01 (m, 6H ); GO (cirA): 2228, 1724, 1296, 1236, 1208, 1017. (e) 2-methoxy-3-cyano-l-naphthoic acid A solution of methyl 2-methoxy-3-cyano-l-naphthoate (0.113 g) and LiOH »H20 (0.0196 g) THF (3 mL), water (1 mL) and methanol (1 mL) was stirred overnight at room temperature, the solution was diluted with saturated sodium bicarbonate and extracted with Et20. The aqueous layer was acidified to a pH of 2 by the addition of IN of HCl and extracted with Et20. The organic layer was washed with water (30 mL) and saline (40 mL), dried (sodium sulfate), filtered, and concentrated to a white solid. X NMR (DMSO-d6): d 14.06 (broad, 1H), 8.08-8.02 (m, 1H), 7.83-7.76 (m, 2H), 7.69-7.63 (, 1H), 4.02 (s, 3H); MS m / z: 226 (M-1).

Example 2 N- [(S) -2- (3,4-Dichlorophenyl) -4-. { 4- (2-oxo-l-piperidinyl) -4- (N-methylaminocarbonyl)} -l-piperidinyl] butyl] -N-methyl-3-cyano-2-methoxy-1-naph amide. 4- (2-Oxo-l-piperidinyl) -4- (methylaminocarbonyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB; EP 739891) was reacted with N- [2- (S) - (3, 4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-2-methoxy-1-naphtamide according to the standard reductive amination methodology to give the title compound which was converted to the salt of citrate according to the standard procedure. 1 H NMR (300 MHz, DMSO-de) d 8.70-8.63 (m), 8.08-7.91 (m), 7.77-7.72 (m), 7.68 (s), 7.66-7.61 (m), 7.58-7.54 (m) , 7.49-7.47 (m), 7.39-7.33 (m), 7.06 (s), 7.03 (s), 6.88-6.79 (m), 6.30-6.28 (d), 4.55-4.47 (t), 4.12-3.99 ( m), 3.92 (s), 3.88 (s), 3.82-3.77 (m), 3.69 (s), 3.50-3.39 (m), 3.17-3.13 (m), 3.06-2.81 (m), 2.72-2.57 ( m), 2.22-2.01 (m), 1.79 (bs), 1.66-1.64 (m), 1.11-0.853 (m); MS APCI, m / z = 678 (M +); Analysis calculated for C36H41N5O.CI2, 1 citric acid, 1.34 water, C 56.36, H 5.82, N 7.82, found C 56.34, H 5.73, N 7.80. The required N- [2- (S) - (3, 4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-2-methoxy-1-naphthamide was prepared as follows: (a) N- [ 2- (S) - (3,4-dichlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-2-methoxy-1-naphthamide. A solution of N- [(S) -2- (3,4-dichlorophenyl) -4-hydroxybutyl] -N-methylamine (Miller, SC; WO 9512577) in DCM was combined with a 10% aqueous sodium bicarbonate solution. %. The mixture was cooled to 0 ° C and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 min. After stirring overnight at room temperature, the organic phase was concentrated and purified by column chromatography to achieve N- [2- (S) - (3,4-Dichlorophenyl) -4-hydroxybutyl] -N-methyl- 3-cyano-2-methoxy-1-naphthamide. [*? NMR (300 MHz, DMSO-d6) d 9.70-9.64 (m), 8.67-8.57 (m), 8.07-7.97 (m), 7.80 (s), 7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.33 (), 7.12-7.10 (d), 7.04-7.02 (d), 6.87-6.83 (m), 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00 (m), 3.94 ( s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m), 3.33 (s), 3.14 (s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m / z-455 (M +)]. (b) N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-2-methoxy-1-naphthamide. The alcohol from (a) was oxidized using oxalyl chloride and DMSO under standard Swern conditions to achieve the aldehyde [X NMR (300 MHz, DMSO-de) d 9.70-9.64 (m), 8.67-8.57 (m), 8.07 -7.97 (), 7.80 (s), 7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.33 (m), 7.12-7.10 (d), 7.04-7.02 (d), 6.87-6.83 () , 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00 (m), 3.94 (s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m) , 3.33 (s), 3.14 (s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m / z = 455 (M +)].

Example 3 N- [(S) -2- (3,4-dichloro-enyl) -4- [4- (2-oxo-l-piperidinyl) -4- (N-methylaminocarbonyl)] -1-piperidinyl citrate] butyl] -3-cyano-2-methoxy-1-na tamide. 3-Cyano-2-ethyl-4-methoxy-1-naphthoic acid (60 mg) was added to the anhydrous DCM (15 mL) and DIPEA (0.11 mL) was added and the mixture was stirred under nitrogen until the carboxylic acid It dissolved. Then tetramethyl fluoroformamidinium hexafluorophosphate (TFFH) (76 mg) was added in a single portion. After 20 min, a solution of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (N-methylaminocarbonyl)] was added. -1-piperidinyl] butyl] -amine, (120 mg) of DCM. After 1 h, water was added and the layers separated. The product was recovered as a white powder (100 mg, 57%) after chromatographic purification and extraction (10-20% methanol in DCM), and converted to the citrate salt under standard conditions. 1 H NMR (300 MHz, DMSO-de) d 8.72 (m), 8.62 (s), 8.01 (d), 7.67-7.50 (m), 7.39-7.36 (m), 7.14 (d), 4.11-4.09 (m ), 3.88 (s), 3.78-3.59 (m), 3.39-3.29 (m), 3.17-3.04 (m), 2.67-2.50 (m), 2.20-2.08 (m), 1.94-1.8 (), 1.79- 1.64 (m), 1.26-1.24 (d); MS APCI, m / z = 664.36 (M +). N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (N-methyl-aminocarbonyl)] -1-piperidinyl] butyl] -amine required was prepared as follows. (a) N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (N-methylamino-carbonyl)] -1-piperidinyl] butyl] -phthalimide. N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -phthalimide (Beein, PR; Miller, SC, EP 709376, 1996) was reacted with 4- (2-oxoyl) -piperidinyl) -4- (N-methylaminocarbonyl) -piperidine using standard reductive amination conditions to achieve the product as a white powder (200 mg, 52%) after chromatographic purification and extraction (5-10% methanol in DCM 1 H NMR (300 MHz, DMSO-de) d 7.81 (s), 7.53 (s), 7.47-7.42 (d), 7.20-7.14 (m), 3.86-3.72 (m), 3.49-3.27 (m), 3.21-3.14 (m), 2.55-2.47 (m), 2.44-2.27 (m), 2.18-2.14 (t), 2.08-1.99 (m), 1.95-1.84 (m), 1.74-1.59 (m), MS APCI, m / z = 584.18 (M-). (B) N- [(S) -2- (3,4-Dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- ( N-methylaminocarbonyl)] -1-piperidinyl] butyl] -amine This compound was synthesized from N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -phthalimide according to the method in step 4 for Example to achieve the amine as a white powder (120 mg, 91%) after filtering and co Concentrate the mother solution followed by the trituration of ether. X NMR (300 MHz, DMSO-de) d 7.54-7.51 (d), 7.45 (s), 7.21-7.14 (), 3.41-3.29 (m), 2.89-2.67 (m), 2.63-2.60 (m), 2.50 -2.40 (m), 2.38-2.26 (), 2.18-2.14 (t), 2.05-1.86 (m), 1.76-1.72 (m), 1.66-1.56 (m); MS APCI, m / z = 453.54 (M ").

Example 4 Citrate of N- [2- (S) - (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (N, N-dimethylaminocarbonyl)] -1- piperidinyl] butyl] -N-methyl-3-cyano-2-methoxy-1-naph amide.

Using standard reductive amination conditions, N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-2-methoxy-1-naphthamide (0.200 g) was reacted with 4- (2-oxo-1-piperidinyl) -4- (N, N-dimethylaminocarbonyl) piperidine (0.122 g) and converted to the citrate salt. X NMR (300 MHz, DMSO-de) d 8.70-8.63 (m), 8.08-6.82 (m), 6.32-6.29 (), 4.55-4.51 (), 4.125-3.69 (), 3.38-1.61 (m); MS APCI, m / z = 714 (M + Na).

Example 5 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- (tetrahydro-2-oxo-1 (2H) -pyrimidinyl) -4- (methylaminocarbonyl)] - Citrate piperidinyl] butyl] -N-methyl-3-cyano-2-methoxy-1-naphtamide.

Using standard reductive amination conditions, N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-2-methoxy-1-naphthamide (0.200 g) is reacted with N-methyl-4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -piperidine-4-carboxamide (Miller, SC, WO 9512577) (0.116 g) and converted to the citrate salt. X NMR (300 MHz, DMSO-d6) d 8.70-8.63 (m), 8.08-6.78 (), 6.35-6.30 (m), 4.54-4.46 (m), 4.11-1.87 (m); MS APCI, m / z = 701 (M + Na).

Example 6 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- (S, S-dioxo-tetrahydro-2H-l, 2-thiazin-2-yl) -4- citrate (methylaminosarbonyl)] -1-piperidinyl] butyl] -N-methyl-3-cyano-2-methoxy-1-naphtamide.

Trifluoroacetate 4- (S, S-dioxo-tetrahydro-2H-1, 2-thiazin-2-yl) -4- (methylaminocarbonyl)] -1-piperidine was neutralized with triethylamine, then reacted with N- [2 - (S) - (3, 4-dichlorophenyl)] -4-oxobutyl-N-methyl-2-methoxy-3-cyano-1-naphthamide and triethylamine under standard reductive amination conditions to achieve the product (50% after two stages) and converted to the citrate salt. X NMR (300 MHz, DMSO-d6) d 8.64 (d), 8.11-7.30 (m), 7.05- • 6.77 (m), 6.32 (d), 4.50 (m), 4.10-3.93 (m), 3.93 ( d), 3.93-1.20 (m). MS APCI, m / z = (M +); 714. The required 4- (S, S-dioxo-tetrahydro-2H-1, 2-thiazin-2-yl) -4- (methylaminocarbonyl)] -1-piperidine was prepared as follows. (a) 4-Bromobutane-1-sulfonyl chloride. The sodium salt of 4-bromo-l-butane acid (1.25 g) was added to thionyl chloride (12.5 mL) with stirring under nitrogen. The reaction was heated under reflux for 3 h, cooled, and concentrated under reduced pressure. The residue was then diluted with diethyl ether, washed with water, dried, filtered and concentrated under reduced pressure to obtain 760 mg of a 7: 3 mixture of the desired product and the 4-chloro analogue (instead of 4-chloro). bromine). X NMR (300 MHz, CDC13) d 3.70 (t, 2H), 3.46 (t, 2H), 2.25 (m, 2H), 2.09 (, 2H). (b) 1-N-Cbz- [4- (4-Amino-4-methylaminocarbonyl)] -1-piperidine. The l-N-Cbz-4-amino-4-piperidylcarboxylic acid (3.0 g) was suspended in THF (100 mL) under nitrogen. To this was added, at 50 ° C with stirring, as a solution in THF, triphosgene (1.3 g), for 5 min. The reaction was stirred 0.5 h at 50 ° C, then allowed to cool to room temperature. It was then concentrated under reduced pressure and the residue was dissolved in 100 mL of THF. A solution of methylamine (8.1 mL, 2.0 M in THF) was added at 5 ° C and the reaction was allowed to stir overnight. It was then diluted with EtOAc, washed with water, then with saline, dried, filtered and concentrated under reduced pressure. The resulting oil was then passed through a plug of silica (5% MeOH in DCM) to obtain 1.65 g of the desired product as a white solid. X NMR (300 MHz, CDC13) d 7.63 (bs, 1H), 7.35 (m, 5H), 5.13 (s, 2H), 4.05 (d, 2H), 3.15 (t, 2H), 2.80 (d, 3H) , 2.18 (m, 2H), 1.37 (m, 4H); MS APCI, m / z = (M +); 292. (c) 1-N-Cbz- [4- [4-Bromobutylsulfonamido-4-methylamino-carbolnyl]] -1-piperidine. To a stirred solution of 940 mg of 1-N-Cbz- [4- (4-Amino-4-methylaminocarbonyl)] -1-piperidine and 750 mg of a 7: 3 mixture of 4-bromo-l-butanesulfonyl chloride and 4-chloro-1-butanesulfonyl chloride in 20 mL of DCM at 0 ° C under nitrogen was slowly added 0.49 mL of triethylamine. The reaction was stirred overnight at room temperature, then additional triethylamine (0.49 mL) was added. The mixture was stirred for 3 days, concentrated under reduced pressure, and purified by chromatography (3-4% MeOH in DCM) to provide 380 mg of the desired product as a mixture of alkyl bromide and alkyl chloride adducted. *? NMR (300 MHz, CDC13) d 7.36 (m, 5H), 6.22 (m, 1H), 5.13 (s, 2H), 4.69 (s, 1H), 3.84 (m, 2H), 3.57 (t, 2H), 3.45 (m, 4H), 3.06 (t, 2H), 2.87-2.79 (m, 3H), 2.01 (m, 8H). MS APCI, m / z = (M +); 446. (d) 4- [(S, S-Dioxo-tetrahydro-2H-1, 2-thiazin-2-yl) -4- (methylaminocarbonyl)] -1-N-Cbz-1-piperidine. To a stirred solution of 380 mg of 1-N-Cbz- [4- [4-bromobutylsulfonamido-4-methyl-aminocarbonyl]] -1-piperidine (containing the impure alkyl chloride from the previous step) in 5 mL of THF under nitrogen atmosphere was added 40 mg of sodium hydride (60% dispersion in mineral oil) and the reaction was heated under reflux for 6 hours . Additional sidium hydride (20 mg, 60% dispersion) was added and the reaction was heated under reflux overnight. Then it cooled; was diluted with EtOAc; it was washed with water, then with saline; dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography (3% MeOH in DCM) to provide 110 mg of the desired product as an oil, -H NMR (300 MHz, CDC13) d 7.35 (m, 5H), 6.57 (m, 1H), 5.07 (s, 2H), 3.71 (m, 2H), 3.56 (m, 2H), 3.40 (m, 2H), 3.09 (m, 2H), 2.85 (d, 3H), 2.20 (m, 6H), 1.73 (m, 2H). MS APCI, m / z = (M +); 410. (e) 4- [(S, S-Dioxo-tetrahydro-2H-l, 2-thiazin-2-yl) -4- (methylaminocarbonyl)] -piperidine trifluoroacetate 4- [(S, S-Dioxo -tetrahydro-2H-1, 2-thiazin-2-yl) -4- (methylaminocarbonyl)] -1-N-Cbz-1-piperidine (110 mg) was dissolved in 10 mL of TFA under nitrogen and heated under reflux for 40 min. The reaction was cooled and concentrated under reduced pressure, dissolved in DCM, and concentrated again to provide the desired product which was used directly in the subsequent reaction. 1 H NMR (300 MHz, CDC13) d 6.60 (m, 1 H), 3.46 (t, 2 H), 3.21 (t, 4 H), 3.12 (t, 2 H), 2.85 (d, 3 H), 2.40 (m, 4 H) , 2.20 (m, 2H), 1.75 (, 2H), 0.88 (, 1H). MS APCI, m / z = (M +); 276 Example 7 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- (methylsulfonyl- (N-methyl) amino) -4- (methylaminocarbonyl] -1-piperidinyl] butyl citrate ] -N-methyl-3-cyano-2-methoxy-1-naphtamide.

The 4- [4-methylsulfonyl- (N-methyl) amino) -4- (methylaminocarbonyl)] -piperidine trifluoroacetate was reacted with N- [2- (S) - (3,4-dichlorophenyl)] -4- oxobutyl-N-methyl-2-methoxy-3-cyano-1-naphthamide under standard reductive amination conditions in the presence of triethylamine to provide the product (90% over the two steps) and convert it to the citrate salt. X NMR (300 MHz, DMSO d-6) d 8.64 (d), 8.01 (m), 7.79-7.48 (m), 7.37 (m), 7.04 (d), 6.83 (m), 6.30 (d), 4.52 (t), 4.06-3.93 (d), 3.93 (d), 3.93-2.97 (m); 2.97 (d); 2.97-2.00 (m); MS APCI, m / z = (M +); 688. (a) 4- [4- (Methylsulfonylamino) -4- (methylaminocarbonyl)] -1-N-Cbz-piperidine. To a solution of 500 mg of 4- [4-amino-4- (methylaminocarbonyl)] -1-N-Cbz-piperidine in 10 mL of DCM at 5 ° C under nitrogen was added 0.15 mL of methanesulfonyl chloride, then 0.29 mL of triethylamine. The reaction was stirred at room temperature for 2 hours, diluted with DCM, washed successfully with 0.5 N of aqueous HCl, water, saline and then dried and filtered. The solution was concentrated under reduced pressure to provide 500 mg of the desired compound as a solid foam. X NMR (300 MHz, CDC13) d 7.35 (, 5H), 6.41 (m, 1H), 5.57 (s, 1H), 5.13 (s, 2H), 3.92 (d, 2H), 3.29 (t, 2H), 3.00 (s, 3H), 2.86 (d, 3H), 2.04 (m, 4H); MS APCI, m / z = (M +); 370. (b) 4- [4- (Methylsulfonyl- (N-methyl) amino) -4- (methylaminocarbonyl)] -1-N-Cbz-piperidine. To a solution of 80 mg of 4- [4- (methylsulfonylamino) -4- (methylaminocarbonyl)] -1-N-Cbz-piperidine in 10 mL of THF / DMF (1: 1) under nitrogen was added 32 mg of potassium t-butoxide, then 0.015 mL of iodomethane. The reaction was allowed to stir at room temperature for 3 hours. This was then diluted with EtOAc, washed with water, then with saline, dried, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 4- [4- (methylsulfonyl- (N-methyl) amino) -4- (methylaminocarbonyl)] -1-N- Cbz-piperidine as an oil (50% yield) . X NMR (300 MHz, CDC13) d 7.35 (m, 5H), 6.32 (bs, 1H), 5.13 (s, 2H), 3.93 (d, 2H), 3.40 (bs, 2H), 2.92 (s, 3H), 2.91 (s, 3H), 2.84 (b, 3H), 2.30 (d, 2H), 2.00 (bs, 2H) ); MS (APCI, negative ion mode) m / z = (M "); 382. This material was N-Cbz deprotected in accordance with the methods described by Example 6, step (e) to provide trifluoroacetate of 4- [4 -methylsulfonyl- (N-methyl) amino) -4- (methylaminocarbonyl)] -piperidine.

Example 8 N- [2- (S) - (3,4-dichlorophenyl) -4- (3-morpholinon-4-yl) -4-methylaminocarbonyl-l-piperidinyl] butyl] -N-methyl-3- citrate cyano-2-methoxy-1-naphtamide 4- (3-Morpholinone-4-y-) -4-methylaminocarbonyl-piperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl-N-methyl-3- cyano-2-methoxy-1-naphtamide using standard amination conditions to provide the product (43% over the two steps) and convert it to citrate salt X NMR (300 MHz, DMSO-d6) d 8.65 (d), 8.03 (m), 7.78-7.31 (m), 7.07-7.79 (), 6.32 (d), 4.52 (t), 4.17-4.01 (m), 4.00 (d), 3.94 (d), 3.93-3.70 (m) 3.50-1.97 (m) MS APCI, m / z = (M +); 680. The requisite 4- (3-morpholinon-4-yl) -4-methylaminocarbonyl-piperidine was prepared as follows. (a) 4-Bromomethylcarbonylamino-4-methylaminocarbonyl-l-N-Cbz-1-piperidine. The 4-amino-4-methylaminocarbonyl-l-N-Cbz-1-piperidine (700 mg) was dissolved in THF (15 mL) under nitrogen and cooled to -10 ° C. Bromoacetyl bromide (0.22 mL) was added slowly, and then triethylamine (0.38 mL). The cold bath was removed and the reaction was allowed to stir for 1 hour. This was then diluted with EtOAc; was washed with water and saline; dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography (2-3% MeOH in DCM) to provide the desired product (740 mg) as a solid foam. X NMR (300 MHz, CDC13) d 7.35 (m, 5H), 6.83 (bs, 1H), 6.46 (s, 1H), 5.13 (s, 2H), 3.90 (m, 4H), 3.21 (m, 2H) , 2.81 (d, 3H), 2.13 (m, 4H),. MS APCI, m / z = (M + Na); 434. (b) 4-Chloroethoxymethylcarbonylamino-4-methylaminocarbonyl-l-N-Cbz-1-piperidine. To a stirred solution of 730 mg of 4-bromomethylcarbonylamino-4-methylamino-carbonyl-l-N-Cbz-1-piperidine in 10 mL of THF under nitrogen was added 0.32 mL of 2-chloroethanol. The reaction was then cooled to -10 ° C and 90 mg of 60% sodium hydride was added. It was then allowed to warm to room temperature for 1 hour after which a small amount of water was added. The reaction was then diluted with EtOAc; it was washed with water, then with saline, dried, filtered and concentrated under reduced pressure: The residue was purified by chromatography to provide 580 mg of the desired compound as a gum. ^? NMR (300 MHz, CDC13) d 7. 35 (m, 5H), 7.10 (m, 1H), 6.80 (s, 1H), 5.13 (s, 2H), 4.03 (s, 2H), 4.03 (s, 2H), 3.85 (, 4H), 3.70 (t, 2H), 3.24 (m, 2H), 2.80 (d, 3H), 2.15 (, 4H). MS APCI, m / z = (M +); 412 (c) 4- (3-Morpholin-4-yl) -4-methylaminocarbonyl-1-N-Cbz-1-piperidine.

To a solution of 4-chloroethoxymethylcarbonylamino-4-methylaminocarbonyl-1-N-Cbz-1-piperidine (580 mg) in THF under nitrogen was added sodium hydride (70 mg, 60% dispersion in mineral oil). The reaction was heated under reflux for an additional 2 hours and 30 mg (60%) of additional sodium hydride was added. The mixture was heated under reflux for an additional 2 h, cooled and quenched with water. The reaction was then diluted with EtOAc; washed with water, saline; dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography (3-5% MeOH in DCM) to provide the desired product (300 mg) as a solid foam. X NMR (300 MHz, CDC13) d 7.35 (m, 5H), 6.77 (m, 1H), 5.13 (s, 2H), 4. 16 (s, 2H), 3.80 (t, 2H), 3.66 (m, 2H), 3.49 (m, 2H), 3.41 (t, 2H), 2.81 (d, 3H), 2.40 (, 2H), 2.16 ( , 2H). MS APCI, m / z = (M "); 374. (d) 4- (3-morpholinone-4-yl) -4-methylaminocarbonyl-piperidine 4- (3-morpholinone-4-yl) -4-methylaminocarbonyl -lN-Cbz-1-piperidine (300 mg) was dissolved in 2-propanol (20 mL) under nitrogen and to this was added 10% palladium on carbon (170 mg). The mixture was placed at a pressure of 50 psi. of hydrogen, with stirring, for 1.5 hours. It was then filtered and concentrated under pressure to provide the desired compound which was used directly in the subsequent reaction. X NMR (300 MHz, CDC103) d 6.78 (m, 1H), 4.16 (s, 2H), 3.84 (t, 2H), 3.46 (t, 2H), 2.94 (m, 4H), 2.82 (d, 3H) , 2.40 (, 2H), 2.21 (m, 2H). MS APCI, m / z = (M +); 242 Example 9 N- [2- (S) - (3,4-Dichlorophenyl) -4- [4- (methylsulfonylamino) -4- (methylaminocarbonyl)] -1-piperinidyl] butyl] -N-methyl-3- citrate cyano-2-methoxy-1-naphthamide.

N (4- [4- (Methylsulfonylamino) -4- (methylaminocarbonyl) piperidine (Example 7) was reacted with N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N- methyl-3-cyano-2-methoxy-1-naphthamide under standard reductive amination conditions to provide a product (70% over two steps) and convert to citrate salt X NMR (300 MHz, DMS0-d6) d 8.64 ( d), 8.04 (m), 7.22-7.79 (m), 7.04 (d), 6.88 (d), 6.79 (d), 6.33 (d), 4.50 (t), 3.95-4.09 (), 3.94 (d) , 3.64-3.92 (), 2.90-3.51 (m), 2.89 (d), 2.46-2.87 (m), 2.04 (m), MS APCI, m / z = (M +), 674. The N- (4-) [4- (Methylsulfonylamino) -4- (methylaminocarbonyl) piperidine required was prepared by treatment of N- (4- [4- (methylsulfonylamino) -4- (methylaminocarbonyl) -N-1-Cbz-piperidine (Example 7, step ( a)) with TFA according to the procedure of Example 6, step (e) and the resulting trifluoroacetate salt was neutralized by the addition of triethylamine.

Example 10 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (pyrrolidin-1-yl-carbonyl)] -1 citrate -piperidinyl] butyl] -3-cyano-2-methoxy-1-naphtamide Using the standard reductive amination conditions, the N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl- N-methyl-3-cyano-2-methoxy-1-naphthamide (0.287 g) with 4- [4- (2-oxo-l-piperidinyl) -4- (pyrrolidin-1-yl-carbonyl)] -1- piperidine (Miller, SC; WO 9512577) (0.181 g). The resulting reaction mixture was purified by chromatography and the title compound was isolated as the citrate salt. MS m / z 718 (M +); -H NMR (DMS0-d6) d 8.6 (, 1H), 8.0 (m, 1H), 7.8-7.3 (m, 5H), 7.1-6.3 (m, 1H), 4.5 (t, J = 10 Hz, 1H ), 3.95 (s, 3H), 2.2 (m, 3H), 2.0-1.6 (m, 8H); mp 168-175 (d).

Example 11 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (hydroxyethylaminocarbonyl)] -1-piperidinyl] butyl] citrate 3-cyano-2-methoxy-1-naphtamide.

Using standard reductive amination conditions, N- [2- (S) - (3,4-dichlorophenyl)] -4-oxo-butyl-N-methyl-3-cyano-2-methoxy-1-naphthamide was reacted ( 0.173 g) with 4- [4- (2-oxo-l-piperidinyl) -4- (hydroxyethylaminocarbonyl)] - piperidine (0.181 g). The resulting reaction mixture was purified by chromatography to provide the desired product. MS m / z 708 (M +); X NMR (DMS0-d6) d 8.6 (m, 1H), 8.0 (m, 1H), 7.8-7.3 (m, 5H), 7.1-6.3 (m, 1H), 4.5 (t, J = 10 Hz, 1H), 4.4 (t, J = 5 Hz, 1H), 3.95 (s, 3H), 2.2 (m, 3H), 2.0-1.6 (m, 8H); mp 110-120 (d).

The required 4- [4- (2-oxo-l-piperidinyl) -4- (hydroxyethylaminocarbonyl)] -piperidine was prepared as follows, (a) 4- [4- (2-Oxo-l-piperidinyl) -4- (hydroxyethylaminocarbonyl)] - lN-Cbz-piperidine. A solution of 4- [4- (2-oxo-l-piperidinyl) -4-carboxy] -1-N-Cbz-piperidine [Miller, SC; WO 9512577) (2.88 g) in DCM (20 mL) was reacted with diisopropylethylamine (3.05 mL) and tetramethylfluoroformamidine hexafluorophosphate (2.64 g) and stirred for 2 hours. To this was added a solution of 2-aminoethanol (0.128 g) in 5 mL of DCM containing diisopropylethylamine (0.364 g) and the reaction mixture was stirred for 2 hours. At the end of this period the reaction mixture was diluted with EtOAc, washed with 5% hydrochloric acid and saturated with sodium bicarbonate, dried, concentrated, under reduced pressure, and purified by chromatography to provide the product ( 0.475 g). MS (APCI, negative ion mode) m / z 402 (M ~); X NMR (CDC13) d 7.4 (m, 5H), 6.6 (t, J = 5 Hz, 1H), 5.1 (m, 2H), 3.8-3.2 (m, 10H), 2.4 (t, J = 10 Hz, 2H), 2.3-1.6 (, 11H). (b) 4- [4- (2-oxo-l-piperidinyl) -4- (hydroxyethylaminocarbonyl)] - piperidine. A solution of 4- [4- (2-oxo-l-piperidinyl) -4- (hydroxyethylaminocarbonyl)] -1-N-Cbz-piperidine (0.36 g) in ethanol (50 mL) containing acetic acid (0.1 mL) and 10% Pd / C (50 mg) over a hydrogen atmosphere at 40 psi for 16 hours. The mixture was filtered and concentrated under reduced pressure to give the product (0.268 g): MS m / z 270 (M +); X NMR (CDC13) d 6.9 (m, 1H), 3.6 (m, 1H), 3.4-3.1 (m, 8H), 2.4-2.2 (, 3H), 2.0-1.6 (m, 8H).

Example 12 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (aminocarbonylmethylaminocarbonyl)] -1-piperidinyl] butyl] citrate 3-cyano-2-methoxy-1-na tamide.

Using the standard reductive amination conditions, N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-2-methoxy-1-naphthamide was reacted (0.227). g) with 4- [4- (2-oxo-l-piperidinyl) -4- (aminocarbonylmethylaminocarbonyl)] - piperidine (0.375 g) (prepared according to the method described in example 11 with the exception that glycinamide was used instead of inoethanol). The resulting reaction mixture was purified by chromatography to provide the desired product: MS m / z 721 (M +); - "" H NMR (DMSO d6) d 8.6 (m, 1H), 8.0 (m, 1H), 7.8-6.3 (m, 9H), 4.5 (t, J = 10 Hz, 1H), 4.4 (t, J = 5Hz, 1H) , 3.95 (s, 3H), 2.2 (m, 3H), 2.0-1.6 (m, 8H); mp 140-145 (d).

Example 13 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -4- (cyanomethylaminocarbonyl)] -1-piperidinyl] butyl] citrate 3-cyano-2-me oxy-1-naph amide.

Using the standard reductive amination conditions, N- [2- (S) - (3, -dichlorophenyl)] - 4-oxobutyl-N-methyl-3-cyano-2-methoxy-1-naphthamide (0.316 g) was reacted ) with 4- [4- (2-oxo-l-piperidinyl) -4- (cyanomethylaminocarbonyl)] - piperidine (0.375 g) (prepared according to the method described in Example 11 with the exception that aminoacetonitrile was used instead of aminoethanol). The reaction of the resulting mixture was purified by chromatography to provide the desired product. MS m / z 703 (M +); 1H NMR (DMSO d6) d 8.6 (m, 1H), 8.0 (, 1H), 7.8-6.3 (m, 6H), 4.5 (t, J = 10 Hz, 1H), 4.4 (t, J = 5Hz, 1H), 3.95 (s, 3H), 3.3 (m, 4H), 2.2 (m, 3H), 2.0-1.6 (m, 8H); mp 130-145 (d).

Table 1. Experimental data selected for the tachykinin antagonists. The chiral center of 2-dichlorophenyl-butyl has the configuration (S). This material was prepared by reductive amination using the procedures and intermediates as described above in the text or elsewhere. Compounds containing a basic nitrogen were converted to citrate salts RJ IT R5 R "RR MS (m / z) 14 * -Me -OCH20-AS- (2-oxopiperidin-1-yl) C (0) NHMe 667 15 -Et -OMe -CNH- (2-oxopiperidin-1-yl) C (0) NHCH2CH20H 722 16 -Et -OMe -CNH- (2-oxopiperidin-1-yl) C (0) NHCH2C (0 ) NH2 735 17 -Et -OMe -CNH- (2-oxopiperidin-1-yl) C (0) NHCH2CN 717 18 -Et -OMe -CNH- (tetrahydro-2-oxo-l (2H) C (0) NHMe 693 pyrimidine-1-yl) (Jl s. 19 Et -OMe -CN -H- (2-oxopiperidin-1-yl) C (0) NHMe 692 20 Et -OMe -CN -H- (2-oxopiperidin-1-yl) H 635 21 Et -OMe -CN -H - (tetrahydro-2-oxo-l (2H) H 636 pyrimidine-1-yl) * Naphthol [2,3-d] -1,3-dioxool-carboxylic acid was prepared according to Dallacker, F.; et al .; Z. Naturforsch; 1979, 1434.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (9)

2. Having described the invention as above, the content of the following claims is claimed as property: 1. A compound having the formula characterized in that: R2 is hydrogen, hydroxy, C6-6 alkoxy, C6-6 alkanoyloxy, C6-alkanoyl, C6-6 alkoxycarbonyl, C6-alkanoylamino, C6-6 alkyl, carbamoyl, C6-alkylcarbamoyl or -C? -6 alkylcarbamoyl; R3 is H or C? _6 alkyl; R4 is independently selected from hydroxy, halo, C6-6alkoxy, Ci-βalkyl, cyanoC6-6alkyl, C2_6alkenyl, C2-alkynyl, carboxy, C6-6alkoxycarbonyl, carbamoyl, C6-6 alkylcarbamoyl, di-C? _6 alkylcarbamoyl, C? _6 alkanoyl, C? -6 alkanoylamino, and aminosulfonyl; R5 is independently selected from hydroxy, cyano, nitro, trifluoromethoxy, trifluoromethyl, C? _6 alkylsulfonyl, halo, C? -6 alkoxy, C? _6 alkyl, cyanoC? _6 alkyl, C2-6 alkenyl, C2-e alkynyl, carboxy, C? _6 alkoxycarbonyl, carbamoyl, C? _6 alkylcarbamoyl, di-C? _6 alkylcarbamoyl, C? -6 alkanoyl, Ci-e alkanoylamino, aminosulfonyl, and substituted alkyl; or R4 and R5 together form -OCH20- or -OC (CH3) 02-; R6 is selected from hydrogen, hydroxy, cyano, nitro, trifluoromethoxy, trifluoromethyl, C? -alkylsulfonyl, halo, C? -6 alkoxy, C? _6 alkyl, cyanoC? _6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carboxy , C? -6 alkoxycarbonyl, carbamoyl, C? _6 alkylcarbamoyl, di-C? -6 alkylcarbamoyl, C? -6 alkanoyl, C? -6 alkanoylamino, aminosulfonyl, and C? -6 substituted alkyl; R7 is -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. M is -C (= 0) - or -S (= 0) 2-. L is -NH- or -CH2-. X1 or X2 are independently H or halogen, wherein at least one of X1 or X1 are halogen; and any pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 characterized in that: R7 is -CH2CH2-CH2-.
3. 3. A compound according to claim 2 characterized in that: R2 is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl.
4. 4. A compound according to claim 3 characterized in that: M is -C (= 0) -; and L is -CH2-;
5. 5. A compound according to any of claims 2, 3, or 4 characterized in that: • R3 is hydrogen, methyl or ethyl; R4 is C4-4alkoxy, C4-4alkyl, halogen, -CH = CHCH3, -OS (0) nCH3, or -OS (0) 2CH3; R5 is cyano, nitro, hydrogen or halogen; R6 is hydrogen, methoxy, cyano or nitro; and 10 n is 0, 1 or 2.
6. 6. A compound according to claim 5 * characterized in that: R3 is hydrogen, methyl or ethyl; R 4 is methyl, ethyl, methoxy, ethoxy, hydroxy, or fluoro; R5 is cyano or nitro; and R6 is hydrogen.
7. 7. A compound according to claim 1 characterized in that it has the structure:
8. 8. A process for the preparation of a compound according to any of claims 1 to 7, characterized in that the process comprises the steps of: reacting a compound of the formula (III) with a compound of the formula (IV) under the conditions of reductive amination: (neither: (IV) wherein L, M, R2 to R7, Xx and X2 are as in claim 1; and L and L 'are the reductive amination groups of the compounds of the formula (III) and (IV) which form an N-C bond; or reacting a compound of the formula (V) with a compound of the formula (VI): (V) 15 (VI) wherein L, M, R2 to R7, Xi and X2 are as defined in claim 1; and L "'in a leaving group
9. 9. A pharmaceutical composition characterized in that it comprises a compound in accordance with any of the 20 claims 1 to 7. 25