WO2005025498A2

WO2005025498A2 - Substituted acetanilides and benzamides for the treatment of asthma and pulmonary inflammation

Info

Publication number: WO2005025498A2
Application number: PCT/US2004/028063
Authority: WO
Inventors: William R Baker; Marcin Stasiak; David Macleod
Original assignee: Corus Pharma
Priority date: 2003-09-08
Filing date: 2004-08-26
Publication date: 2005-03-24
Also published as: WO2005025498A3

Abstract

Substituted acetanilide or benzamide compositions or formulations for delivery by aerosolization are described. The formulation contains an efficacious amount of acetanilide or benzamide compound able to inhibit inflammation in asthmatic lungs. Compounds of the invention are formulated in 5 ml solution of a quarter normal saline having pH between 5.0 and 7.0. The method for treatment of respiratory tract inflammation by a formulation delivered as an aerosol having mass medium average diameter predominantly between 1 to 5 µ, produced by nebulization or dry powder inhaler.

Description

SUBSTITUTED ACETANILIDES AND BENZAMTDES FOR THE TREATMENT OF ASTHMA AND PULMONARY INFLAMMATION

Field of the Invention The current invention relates to the preparation of novel benzamides and acetanilides as mediators of eosinophil apoptosis. In particular, the invention concerns the synthesis, formulation and delivery of substituted benzamides and acetanilides such that when delivered topically these compounds cause cellular (eosinophil) apoptosis. The compounds of the invention are formulated as either liquids or dry powders and the formulation permits and is suitable for delivery of substituted acetanilides or benzamides to the lung endobronchial space of airways in an aerosol having a mass medium average diameter predominantly between 1 to 5 μ. The formulated and delivered efficacious amount of substituted acetanilides or benzamides is sufficient to deliver therapeutic amounts of compounds of the invention for treatment of acute/chronic respiratory tract inflammation associated with eosinophil infiltration in mild to severe asthma, bronchitis, chronic obstructive pulmonary disease (COPD), and pulmonary infections such as cystic fibrosis and pneumonia. Background of the Invention i Asthma is a chronic inflammatory disease of the airways resulting from the infiltration of pro-inflammatory cells, mostly eosinophils and activated T lymphocytes

(Poston, 1992; Walker, 1991) into the bronchial mucosa and submucosa. The secretion of potent chemical mediators, including cytokines, by these pre- inflammatory cells alters mucosal permeability, mucus production, and causes smooth muscle contraction. All of these factors lead to an increased reactivity of the airways to a wide variety of irritant stimuli (Kaliner, et al, 1988).

Glucocorticoids, which were first introduced as an asthma therapy in 1950 (Carrier, et al, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, 1985). Available evidence suggests that at least one mechanism by which they exert their potent anti-inflammatory properties is by inhibiting the release and activity of cytokines, which recruit and activate inflammatory cells such as eosinophils (Schleimer, 1990). Ordinarily, eosinophils undergo the phenomenon of apoptosis or programmed cell death, but certain cytokines such as interleukin-5 (IL-5), interleukin- 3 (IL-3), and granulocyte-macrophage colony stimulating factor (GM-CSF) increase eosinophil survival from 1 or 2 days to 4 days or longer and cause eosinophil activation (Kita, 1992). Wallen, et al. were the first to show that glucocorticoids potently block the cytokine 's ability to enhance eosinophil survival in a concentration-dependent manner (Wallen, et al, 1991). Unfortunately, glucocorticoids are associated with profoundly undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman). The side effects of glucocorticoid therapy have led to interest in agents, which exhibit similar anti-inflammatory effects. A variety of such agents have been tested. For example, preparations of cyclosporin (Szczeklik, 1991; Mungan, 1995), methotrexate (Dyer, 1991), troleandomycin (TAO) (Wald, 1986; Shivaram, 1991), and gold (Szczeklik, 1991; Dykewicz, 2001; Bernstein, 1988) have been used in attempts to wean patients off of orally-administered steroids. Similarly, leukotriene receptor antagonists (e.g., montelukast [Singulair^®] and zafirlukast [Accolate^®]) (Korenblat,

2001; Dykewicz, 2001; Wechsler, 1999), colchicine (Fish, 1997), salmeterol (Lazarus, 2001; Lemanske, 2001), and anti-immunoglobulin E (IgE) (Dykewicz, 2001) have been used with limited success in efforts to wean patients off inhaled steroids. However, to date, no completely satisfactory substitute for glucocorticoid therapy has been identified.

Serendipitously, Ohnishi, et al. (Ohnishi, et al, 1996) discovered that eosinophil survival is inhibited by lidocaine in a potent and concentration-dependent manner similar to that of corticosteroids. Lidocame was shown to be effective at low concentrations, which can easily be achieved in the airways by nebulization. The potent activity of lidocame, combined with its established record of low toxicity when administered to the airways, inspired use of this agent in preliminary clinical trials to determine its effects in patients with severe, glucocorticoid-dependent asthma. Results of these studies demonstrated that treatment with inhaled lidocaine allowed the majority of patients to significantly reduce, or discontinue, their oral glucocorticoid use without any concurrent increase in their asthma symptoms. In consideration of all the problems and disadvantages connected with the local anesthetic properties of lidocame and related local anesthetic compounds (numbing effect), it would be highly advantageous to provide an analog of lidocaine that causes eosinophil apoptosis and is non-numbing. Such a compound would be effectively delivered to the endobronchial space by aerosolization thereby delivering to the site of inflammation a therapeutic amount of drug. It is therefore a primary object of this invention to provide a composition and method for synthesis of potent acetanilides and benzamides, which are stable as a liquid or solid dosage form for nebulization or dry powder delivery. Such composition contains sufficient, but not excessive, concentration of the drug which can be efficiently aerosolized by nebulization in jet, ultrasonic, pressurized, or vibrating porous plate nebulizers or by dry powder into aerosol particles predominantly within the 1 to 5 μ size range, and which salinity and pH are adjusted to create a therapeutic aerosol well tolerated by patients, and which formulation further has an adequate shelf life. Summary of the Invention The present invention concerns the synthesis and use of, and formulation for substituted acetanilides and benzamides delivered by inhalation to treat asthma and pulmonary inflammation. The present invention also relates to compounds of the formula

wherein: X and Y are independently selected from the group consisting of NH, O, S0₂, and CO; n is 1-5; W and Z are independently selected from the group consisting of H, NH, NR where R is alkyl or alkenyl, alkenyl, substituted alkenyl, O, and CH₂; provided that when Z is H, Rj-W is absent and when W is absent, RI is bonded directly to Z; A and B are independently selected from the group consisting of H, NH, CH₂ and CO provided that when A is H, R₆-B is absent and when B is absent, R₅ is bonded directly to A; Ri and Re are independently selected from the group consisting of hydrogen, alkylheterocycle, alkylaryl, substituted alkylaryl, biaryl, arylalkyl, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkoxyaryl, substituted arylalkyl and substituted alkyl; R₂ and R₃ are independently H or CH₃; R₄ and R₅ are hydrogen or loweralkyl or R₄ and R₅ can be linked such that a nonaromatic cyclic ring is formed having 2-10 atoms selected from C, O, S and N where the ring can be optionally substituted with alkyl, heterocycle, or aryl groups; and the pharmaceutically acceptable salts thereof. More specific embodiments of this invention include compounds of formula 1 wherein wherein X is NH; Y is CO; Z is NH; W is CH₂ or CO; A is H; Rj is alkoxyaryl, arylaklyl, substituted alkyl or alkoxyalkyl; R₂ and R₃ are CH₃, R₄ and R₅ are ethyl or Rj and R₅ form a 6-membered piperidine ring which the 4-position is substituted with a cycloalkyl or heterocycle and n is 1. Other specific embodiments of this invention include compounds of formula 1 wherein X is CO; Y is NH; Z is H; A is NH; B is CH₂ or CO; R₆ is alkoxyaryl, arylaklyl, substituted alkyl or alkoxyalkyl; R₂ and R₃ are H; R* and R₅ are CH₂CH₃; and n is 1-4. Examples of presently preferred compounds of this invention include: Tetradecanoic acid [3 -(2-diethylamino-acetylamino)-2,4-dimethyl-phenyl] - amide; 2-Diethylamino-N-(2,6-dimethyl-3-tridecylamino-phenyl)-acetamide; 2-Diethylamino-N-{2,6-dimethyl-3-[5-(4-phenyl-butoxy)-pentylamino]- phenyl} -acetamide; N-(2-Diethylamino-ethyl)-4-(4-trifluoromethoxy-benzylamino)-benzamide; N-(2-Diethylamino-ethyl)-4-(4-trifluoromethoxy-benzoylamido)-benzamide; N-(2-Diethylamino-ethyl)-4-(4-phenyl-benzoylamido)-benzamide; 2-[l,4']Bipiperidinyl-r-yl-N-[2,6-dimethyl-3-(4-phenyl-butylamino)-phenyl]- acetamide; 2-[ 1 ,4'jBipiperidinyl- 1 '-yl-N- {2,6-dimethyl-3-[2-(4-trifluoromethoxy-phenyl)- ethylamino]-phenyl}-acetamide; and 2-[ 1 ,4']Bipiperidinyl- 1 '-yl-N-(2,6-dimethyl-phenyl)-acetamide and the pharmaceutically acceptable salts of the foregoing compounds. The invention also relates to a pharmaceutically acceptable composition for the treatment of a disorder selected from severe to mild asthma, bronchitis, COPD, and pulmonary inflammation associated with cystic fibrosis which comprises a therapeutically effective amount of a compound of formula 1 or a pharmaceutically accepted salt thereof, and a pharmaceutically accepted carrier. The invention also relates to a liquid or dry powder formulation of substituted anilides and benzamides for the treatment of a disorder selected from severe to mild asthma, bronchitis, COPD, and pulmonary inflammation associated with cystic fibrosis which comprises a therapeutically effective amount of compound of formula

1 or a pharmaceutically accepted salt thereof. Brief Description of the Figures Figure 1, Figure 2 and Figure 3 depict reaction schemes for the preparation of compounds of the invention. Detailed Description of the Invention The term "alkyl" as used herein refers to a branched or straight chain comprising two to twenty carbon atoms, which also comprises one or more atoms, selected from O, S, and NH. Representative alkyl groups include methyl, butyl, hexyl, 3,6-dioxaheptyl, 3,6,9-trioxadecyl, and the like. As used herein "loweralkyl" includes both substituted or unsubstituted straight or branched chain alkyl groups having from 1 to 10 carbon atoms. Representative lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, ra-butyl, tert-butyl and the like. Representative halo-substituted and hydroxy-substituted lower alkyl include chloromethyl, chloroethyl, hydroxyethyl, aminoethyl, etc. The term "alkoxy" as used herein refers to RO- wherein R is alkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, and the like. The term "alkylamino" as used herein refers to R_{1 2}-N- wherein Ri and R₂ are alkyl or H as defined above. Representative examples of alklyamino groups include butylamino, dimethylamino, methoxyethoxyethylamino, and the like. The term "aryl" as used herein is defined as an aromatic ring substituted with

1-3 groups selected from hydrogen, amino, hydroxy, halo, haloalkyl, alkyl, O-alkyl and NH-alkyl. Aryl can be one or two rings either fused to form a bicylic aromatic ring system or linear as in biphenyl. Aryl groups can be substituted with N, S, or O in the ring to produce a hetrocyclic system.

As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups. As used herein, the term "alkanoyl" refers to O wherein R₇ is alkyl or lower alkyl. As used herein, the term "alkanoylamido" refers to

wherein R₈ is alkyl or ower alkyl.

As used herein, the term "alkanoyloxy" refers to

wherein R₉ is alkyl or lower alkyl. As used herein, the term "alkylsulfonyl" refers to

wherein Rio is alkyl or lower alkyl. The term "heterocycle" as used herein refers to an aromatic ring system composed of 5 or 6 atoms including the heteroatoms nitrogen, oxygen, and sulfur. The heterocycle may be composed of one or more heteroatoms that are either directly connected such as pyrazole or connected through carbon such as pyrimidine. Heterocycles can be substituted or unsubstituted with one, two or three substituents independently selected from amino, alkylamino, halogen, alkyl acylamino, loweralkyl, aryl, and alkoxy. The term "substituted heterocycle" or "heterocyclic group" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein the 5-membered ring has 0-2 double bounds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atom may be optionally oxidized; wherein the nitrogen and sulfur heteroatoms may be optionally quartemized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring as defined above. Heterocycles in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocycles include: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imid- azolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methyl piper- azinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazo- lidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl. Heterocycles can be unsubstituted, monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (C=O), alkylimino (RN==, wherein R is a lower alkyl or alkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl, aryl, heterocycle or haloalkyl. The most preferred heterocyclics include imidazolyl, pyridyl, piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, piperidinyl and benzoxazolyl. As used herein, the term "pharmaceutically acceptable salts" refers to the nontoxic acid or alkaline earth metal salts of the compounds of Formula 1. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula 1, or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively. Representative acid salts include the hydrochloride, hydrobromide, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, tartrate and the like. Representative alkali metals of alkaline earth metal salts include sodium, potassium, calcium, and magnesium salts. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as

"treating" is defined immediately above. The term "normal saline" means water solution containing 0.9% (w/v) NaCl. The term "diluted saline" means normal saline containing 0.9% (w/v) NaCl diluted into its lesser strength. The term "quarter normal saline" or "'Λ NS" means normal saline diluted to its quarter strength containing 0.225% (w/v) NaCl. The compounds of the invention may comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the invention comprising mixtures of stereoisomers at a particular asymmetrically substituted carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration, as used herein, are as defined by the IUPAC 1974 RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl. Chem. 45:13-30 (1976). The terms α and β are employed for ring positions of cyclic compounds. The α-side of the reference plane is that side on which the preferred substituent lies at the lower numbered position. Those substituents lying on the opposite side of the reference plane are assigned β descriptor. It should be noted that this usage differs from that for cyclic stereoparents, in which "α" means "below the plane" and denotes absolute configuration. The terms α and β configuration, as used herein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE-APPENDIX IV (1987) paragraph 203. The present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.

I. PREPARATION OF THE COMPOUNDS OF THE INVENTION In general, the compounds of the present invention can be prepared by the processes illustrated in reaction scheme I (Figure 1), reaction scheme II (Figure 2), and reaction scheme III (Figure 3). Referring to reaction scheme I shown in Figure 1, chloroacetanilide 1 (R₂ and R₃ = CH₃) serves as the starting material for the preparation of analogs 2. Reaction of chloroamide 1 with secondary or primary amines for example ethylamine, piperidine, morpholine, N-methyl homopiperazine and N-methyl piperazine and the like in either tertrahydrofuran, toluene or benzene at room temperature or reflux temperature produced the alkylated tertiary or secondary amines 2 which were converted to the 3-amino acetanilides 3 by a two-step process. First, nitration of 2 with 70% nitric acid at 0-5 degrees C using the procedure of Keenaghan et al. (1972), afforded the 3-nitro intermediate. Second, the nitro intermediate was then reduced to the aniline 3 using iron power in 6N HCl or hydrogen in presence of Pd/C catalyst in methanol. Usually the 3-amino acetanilide is obtained by recrystallization from hot ethyl acetate/hexane as a tan solid in good overall yield. Reaction of 3-amino-2,4-dimethylacetanilides with activated carboxylic acids such as acid chlorides, acylimidazoles, N-hydroxysuccinate esters and the like in pyridine, tetrahydrofuran, or dioxane afforded 3-substituted amides 4 in good yield. Urea derivatives 6 were prepared in a similar fashion by the reaction of aniline 3 with alkyl and aryl isocyanates. Dialkyl amino analogs 7 and monalkylamino derivatives 5 were prepared by treatment of 3 with alkyl bromides or iodides in THF at room temperature and sodium triacetoxyborohydride and aldehyde in dichloromethane 0-25 degrees C, respectively. Referring to reaction scheme II shown in Figure 2, additional 3 -substituted acetanilides of the invention are prepared. Lidocaine (2, Ri and R₂ = CH₃, P^ and R₅ = ethyl) is brominated with bromine in acetic acid to give 3 -bromo lidocaine 8 which serves as a key intermediate for the preparation of 3-alkyl (10), 3-alkyloxy (11), and 3- aminomethyl (12) analogs as illustrated in the Scheme. Referring now to reaction Scheme IH in Figure 3, 4-substituted bezamides 14,

15, and 16 are prepared by reaction of procainamide 13 with activated carboxylic acids, i.e. acid chlorides; alkyl or aryl isocyanates, and reductive alkylation (NaBH(OAc)₃, RiCHO). II. AEROSOL DELIVERY DEVICES The use of acetanilides and benzamides with a suitable formulation for liquid nebulization, or as a dry powder provides sufficient amount of therapeutic compound to the lungs for a local therapeutic effect. Acetanilides and benzamides are suitable for aerosolization using jet, electronic, or ultrasonic nebulizers as well as for delivery by dry powder or metered dose inhaler. The pure powder form has long-term stability permitting the drug to be stored at room temperature. The aerosol formulation comprises a concentrated solution of 10 to 500 mg/mL of acetanilide or benzamide or its pharmaceutically acceptable salts, dissolved in aqueous solution having a pH between 4.0 and 7.5. Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as they may cause less pulmonary irritation.

The therapeutic amount of the pure acetanilide or benzamide is delivered to the lung endobronchial space by nebulization of a liquid aerosol or dry powder having an average mass medium diameter between 1- 5 μ. A liquid formulation may require a separate prodrug salt from the appropriate diluent that can be reconstituted prior to administration because the long-term stability of acetanilide or benzamide in aqueous solutions may not provide a commercially acceptable shelf-life. An indivisible part of this invention is a device able to generate an aerosol from the formulation of the invention into aerosol particles predominantly in the 1-5 μ size range. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within the 1-5 μ size range.

Typical devices include jet nebulizers, ultrasonic nebulizers, vibrating porous plate nebulizers, and energized dry powder inhalers. A jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets. An ultrasonic nebulizer utilizes a piezoelectric crystal that shears a liquid into small aerosol droplets. A pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets. A vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes. However, only some formulations of acetanilides or benzamides can be efficiently nebulized, as the devices are sensitive to the physical and chemical properties of the formulation. The formulations, which can be nebulized typicaly must contain large amounts of acetanilides or benzamides, which are delivered in large volumes (up to 5 ml) of aerosol. III. UTILITY The compounds of the invention are useful (in humans) for treating pulmonary inflammation by inhibiting eosinophil survival. The mechanism(s) by which this inhibition process occurs is not completely known, however protein kinase B/Akt-1 (PKB/Akt-1) and sigma receptors 1 and 2 have been implicated as targets for these compounds (unpublished results). Furthermore, several compounds of the invention display reduced inhibition of sodium channel activity (reduced numbing) when compared to lidocaine in the Xenopus oocyte model while demonstrating increased inhibition of eosinophil survival. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. This small volume, high concentration formulation of substituted acetanilides and benzamides can be delivered as an aerosol, oral preparation, or topical and be delivered at efficacious concentrations. The solid dosage formulation is stable, readily manufactured, and very cost effective. Furthermore, the formulation provides adequate shelf life for commercial distribution. The foregoing may be better understood from the following examples, which are presented for the purposes of illustration and are not intended to limit the scope of the inventive concepts. Example 1 N-(2,6-Dimethyl-phenyl)-2-(4-methyl-piperazin- 1 -vD-acetamide

A solution of 2,6-dimethylchloroacetanilide 1 (10.6 g, 53.8 mmol), N- methylpiperazine (38.0 g, 380 mmol) in 250 mL of dry benzene was heated at reflux temperature for five hours according to the procedure of Dahlbom and Harms (1961).

The reaction was cooled and solvents were removed by rotoevaporation under reduced pressure. The crude residue was redissolved in chloroform and the chloroform solution was washed with dilute KOH, water, and dried (MgSO₄). Evaporation gave an oil which solidified upon standing at room temperature (rt). The crude solid was recrystallized from hot ethyl acetate/hexane to give the title

compound as an off-white solid in good yield: ^lΗ. NMR (400 MHz, CDC1₃): δ 8.66 (brs IH), 7.27 (brm 3H), 3.20 (s 2H), 2.73 (brs 4H), 2.51 (brs 4H), 2.31 (s 3H), 2.23 (s

6H). LC/MS (M+H)⁺ 262. Anal. Calcd for Cι₅H₂₃N₃0: C, 68.93; H, 8.87; N, 16.08.

Found: C, 69.05; H, 8.66; N, 16.26. Example 2 N-(2,6-Dimethyl-phenyl)-2-(4-methyl-f 1.4]diazepan- 1 -yl)-acetamide

A solution of 5.2 g (26.5 mmol) of 2,6-dimethylchloroacetanilide 1 and N-methyl homopiperazine (4.54 g, 39.5 mmol) in 100 mL of dry tetrahydrofuran (THF) was allowed to stir at room temperature for 3 days. TLC [30:70:1, ethyl acetate:hexane:triethylamine (TEA)] showed complete reaction. Solvents were removed by rotoevaporation and the residue redissolved in chloroform, washed with dilute KOH, water, and dried (MgS0 ). Evaporation of solvents afforded crude amine in good yield. Recrystallization from ethyl acetate/hexane at -20° C gave the

title compound as a white solid: ^ΪH NMR (400 MHz, CDC1₃): δ 8.76 (brs IH), 7.26

(brm 3H), 3.33 (s 2H), 2.93 (brs 4H), 2.68 (brs 4H), 2.38 (s 3H), 2.23 (s 6H), 1.89 (m 2H). LC/MS (M+H) 276. Anal. Calcd for Cι₅H₂₃N₃0: C, 69.78; H, 9.15; N, 15.26.

Found: C, 70.03; H, 9.38; N, 15.15. Example 3 N-(2,6-Dimethyl-phenyl)-2-morpholin-4-yl-acetamide

Using the procedure in Example 47 and replacing ethylamine with morpholine gave the title compound. The product was purified by trituration with ether. Yield:

0.436 g (88 %); H NMR (400 MHz, CDC1₃): δ 8.6 (bs, IH), 7.07 - 7.11 (m, 3H),

3.77 - 3.80 (m, 4H),3.21 (s, 2H), 2.70 -2.72 (m, 2H), 2.23 (s, 6H); LC/MS (M+H)⁺

249 Anal. Calcd for Cι₄H₂₀N₂O₂: C, 67.71; H, 8.12; N, 11.28. Found: C, 67.58; H, 8.33; N, 11.30. Example 4 N-(2,6-Dimethyl-phenylV2-pyrrolidin-l-yl-acetamide

Using the procedure in Example 47 and replacing ethylamine with pyrrolidine gave the title compound. The product was purified by trituration with hexane.Yield:

0.460 g (99%); ^XH NMR (400 MHz, CDC1₃): δ 8.63 (bs, IH), 7.08 - 7.10 (m, 3H), 3.35 (s, 2H), 2.76 -⁵2.79 (m, 4H), 2.24 (s, 6H), 1.84 - 1.88 (m, 4H); LC/MS (M+H)⁺ 233. Anal. Calcd for Cι H₂₀N₂O: C, 72.38; H, 8.68; N, 12.06. Found: C, 71.81; H, 8.51; N, 11.93. Example 5 N-(2,6-Dimethyl-phenyl)-2-piperidin- 1 -yl-acetamide

Using the procedure in Example 47 and replacing ethylamine with piperidine gave the title compound. The product was purified by trituration with hexane.Yield: 0.445 g (90%); !H NMR (400 MHz, CDC1₃): δ 8.63 (bs, IH), 7.08 - 7.10 (m, 3H),

3.14 (s, 2H), 2.61 - 2.64 (m, 4H), 2.24 (s, 6H), 1.65 (quint, 4H, J = 5.6Hz), 1.48 -

1.52 (m, 2H); LC/MS (M+H)⁺ 247. Anal. Calcd for Cι₅H₂₂N₂0: C, 73.13; H, 9.00; N,

11.37. Found: C, 72.83; H, 9.17; N, 11.30. Example 6 2-f 1.4'1Bipiperidinyl-l '-yl-N-(2,6-dimethyl-phenyl>acetamide

Using the procedure in Example 51 and replacing 4-(4- trifluoromethyl)phenoxypiperidine hydrochloride with 4-piperidinylpiperidme gave the title compound. Crude residue was crystallized from dichloromethane/hexane.

Yield: 0.128 g (19%). ^lB NMR (400 MHz, CDC1₃): 8.72 (bs, IH), 7.06 - 7.10 (m,

3H), 3.17 (s, 2H), 3.05 - 3.10 (m, 2H), 2.51 (bt, 4H, J = 4.8Hz), 2.29 - 2.35 (m, 3H),

2.23 (s, 6H), 1.87 - 1.93 (m, 2H), 1.56 - 1.63 (m, 6H), 1.40 - 1.48 (m, 2H); LC/MS ((MM++HH))⁺⁺ 333300.. AAnnaall.. CCaalcd for C₂₀H₃₁N₃O C, 72.91; H, 9.48; N, 12.75. Found: C, 72.86; H, 9.50; N, 13.23

Example 7 2-ri.4'lBipiperidinyl- -yl-N-(2,6-dimethyl-3-nitro-phenvD-acetamide

Using the procedure described in Example 8 and replacing lidocaine with the compound prepared in Example 6 gave the title compound. The product was

recrystallized from ethyl acetate:hexane (90:10) at 0 C. Yield 14.0 g (60%): ^ΪH NMR (400 MHz, CDC1₃): δ 8.98 (s IH), 7.75 (d IH), 7.22 (d IH), 3.19 (s 2H), 3.08-3.05

(brm 2H), 2.53-2.50 (brt 4H), 2.39 (s 3H), 2.39-2.28 (m 2H), 2.30 (s 3H), 1.94-1.91

(br d 2H), 1.64-1.57 (m 6H), 1.46-1.43 (m 2H). LC/MS (M+H)⁺ 375.

Example 8 2-Diethylamino-N-(2,6-dimethyl-3-mtro-phcnyl')-acetamide

A 70% solution of nitric acid was prepared by adding 20 mL of water to 80 mL of fuming nitric acid (>90%) cooled in an ice- water bath (0-5 C). Lidocaine free-base

(15 g, 64 mmol) was added to the mechanically stirred solution in 3-5 portions at a rate so that the internal temperature did not exceed 25° C. After addition was complete, 8 mL of concentrated sulfuric acid was added in one portion and the reaction was stirred for an additional 30 min. TLC (30:70:2 ethyl acetate :hexane: TEA) showed complete reaction. The entire reaction time was 45 minutes The reaction was quenched by adding solid ice (300-400g), while cooling the reactor in an ice-water bath. Solid potassium hydroxide was added to neutralize the acids and at a rate to keep the internal temperature below 40° C and to achieve pH between 9-12. Ethyl acetate was then added and the two-phase solution was separated. The aqueous layer was washed two times with ethyl acetate and the combined ethyl acetate solutions were dried (MgSO ) and evaporated to give a yellow-orange oil. The product (3-nitro-lidocaine) was obtained as an off-white solid by recrystallization from hot ethyl acetate/hexane. Yield 9.8 g (first crop) and 5.5 g

(second crop) 15.3 g total yield (86%): 1H NMR (400 MHz, CDC1₃) δ 9.10 (brs IH), 7.73 (d IH), 7.21 (d IH), 3.24 (s 2H), 2.71 (q 4H), 2.38 (s 3H), 2.30 (s 3H), 1.15 (t

6H). LC/MS (M+H)⁺ 279.

Example 9 N-(3-Amino-2.6-dimethyl-phenylV2-diethylamino-acetamide

Hydrochloric acid (6N, 210 mL) was stirred (mechanically) and cooled in an ice-water bath to 5° C, while powdered solid 3-nitro-lidocaine (27.0 g, 96.9 mmol) was added. To the resulting solution was added iron powder (25 g, 447 mmol), portionwise over 3-5 minutes. The rate of addition was such that the internal temperature did. not exceed 10° C. Gas evolution was observed (hydrogen). The reaction mixture was stirred an additional 30 minutes at 10-30° C then 30 minutes at 30 °C using an external ice- water bath. Solid ice was added (400 g) followed by slow addition of solid NaOH until the reaction pH was 12 (internal temperature did not exceed 40° C during the neutralization process). The entire contents of the reaction flask were filtered through a bed of celite and the residual solids were washed with ethyl acetate (3 x 200 mL). The organic layer was separated, dried (MgS0₄) and evaporated to give 19.0 g of a light yellow solid after recrystallization from ethyl

acetate/hexane. Yield 70%. 1H NMR (400 MHz, CDC1₃) δ 8.89 (brs IH), 6.88 (d IH), 6.55 (d IH), 3.53 (bs 2H), 3.21 (s 211), 2.68 (q 4H), 2.13 (s 3H), 2.01 (s 3H),

1.13 (t 6H). LC/MS (M+H)⁺ 250.

Example 10 N-(3-Amino-2,6-dimethyl-phenvD-2-f 1.4'^"|bipiperidinyl- 1 '-yl-acetamide

Using the procedure in Example 9 and substituting with the compound prepared in Example 7 gave the title compound after recrystallization from ethyl

acetate/hexane. Yield 3.0 g (50%): LC/MS (M+H)⁺ 345. Example 11 Tetradecanoic acid [3-(2-diethylamino-acetylamino^')-2.4-dimethyl-phenyll-amide

3-Amino-lidocaine (220 mg, 0.88 mmol) prepared in Example 9 was dissolved in 1.2 mL of dry pyridine and the solution was cooled in an ice-water bath. Neat myristoyl chloride (250 mg, 1 mmol) was added and the reaction stirred for 18 hours while warming up to room temperature. Excess pyridine was removed by rotoevaporation under reduced pressure. The residue was redissolved in chloroform, washed with saturated copper sulfate, water, and dried (MgS0₄). Evaporation of the

CHCI₃ gave a solid product which was purified by recrystallization from hot ethyl acetate/hexane. Yield 115 mg. 1H NMR (400 MHz, CDC1₃) δ 8.07 (brs IH), 7.34 (d

2H), 7.20 (brs IH), 7.05 (d 2H), 3.22 (s 2H), 2.69 (q 4H), 2.35 (t 2H), 2.19 (s 3H), 2.04 (s 3H), 1.70 (m 2H), 1.38-1.31 (brm 20H), 1.13 (t 6H) 0.88 (t 3H); LC/MS

(M+H)⁺ 460. Anal. Calcd for C₂₈H₄₉N₃0₂: C, 73.16; H, 10.74; N, 9.14. Found: C,

71.55; H, 10.97; N, 8.86. Example 12 4-Acetylamino-N-(2-diethylamino-ethylVbenzamide

A suspension of procainamide hydrochloride (2.71 g, 10 mmol) in 10 mL of anhydrous pyridine was cooled in an ice- water bath. To the suspension was added 0.8 g (10 mmol) of acetyl chloride. The reaction was stirred for 18 hours while allowing to warm up to room temprature. Excess pyridine was removed using rotoevaporation, CHCI₃ was added and the chloroform solution was washed with saturated NaHC0₃, water, saturated copper sulfate solution and dried with MgS0₄. Product was recrystallized from hot ethyl acetate/hexane (8:2) to give 566 mg of the title

compound. Yield 20%; 1H NMR (400 MHz, CDC1₃) δ 8.07 (brs IH), 7.34 (d 2H),

7.20 (brs IH), 7.05 (d 2H), 3.22 (s 2H), 2.69 (q 4H), 2.35 (t 2H), 2.19 (s 3H), 2.04 (s

3H), 1.70 (m 2H), 1.38-1.31 (brm 20H), 1.13 (t 6H), 0.88 (t 3H); LC/MS (M+H)⁺

460. Anal. Calcd for ₅H₂₃N₃O₂: C, 64.95; H, 8.36; N, 15.15. Found: C, 65.30; H, 8.70; N, 15.13. Example 13 N-(2-Diethylamino-ethyl)-4-pentanoylamino-benzamide

Using the procedure described in Example 12 and substituting acetyl chloride with valeryl chloride (1.2 g, 10 mmol) gave the title compound in good yield after

recrystallization from hot ethyl acetate/hexane. Yield 764 mg; 1H NMR (400 MHz,

CDC1₃) δ 7.74 (d 2H), 7.67 (brs IH), 7.60 (d 2H), 6.98 (brs IH), 3.48 (q 2H), 2.66 (t 2H), 2.57 (q 6H), 2.83 (t 2H), 1.71 (m 2H), 1.39 (m 2H), 1.04 (t 6H), 0.94 (t 3H);

LC/MS (M+H)⁺ 320. Anal. Calcd for Cι₈H₂₉N₃0₂: C, 67.68; H, 9.15; N, 13.15.

Found: C, 67.61; H, 9.41; N, 13.00. Example 14 N-(2-Diethylamino-ethyr)-4-nonanoylamino-benzamide

Using the procedure described in Example 12 and substituting nonanoyl chloride (1.8 g, 10 mmol) for acetyl chloride gave the title compound in good yield

after recrystallization from hot ethyl acetate/hexane. Yield 2.2 g; *H NMR (400

MHz, CDCI₃) δ 7.74 (d 2H), 7.67 (brs IH), 7.60 (d 2H), 6.98 (brs IH), 3.48 (q 2H), 2.66 (t 2H), 2.57 (q 6H), 2.83 (t 2H), 1.71 (m 2H), 1.39 (m 2H), 1.04 (t 6H), 0.94 (t

3H); LC/MS (M+H)⁺ 320. Anal. Calcd for C₂₂H₃₇N₃0₂: C, 70.36; H, 9.93; N, 11.19.

Found: C, 70.56; H, 9.81; N, 11.22. Example 15 N-r3-(2-Diethylamino-acetylaminoV2.4-dimethyl-phenyl]-3-|2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy}-propionamide

Using the procedure described in Example 12 and substituting 3-{2-[2-(2- methoxy-ethoxy)-ethoxy]-ethoxy}-propionyl chloride [1.06 mg, 4.2 mmol, prepared from 3-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-propionic acid (Ig) and thionyl chloride (3 mL) by refluxing for 1 hour; bp 153-155° C 1 mmHg] for acetyl chloride, 900 mg (3.6 mmol) of 3-amino-lidocaine and pyridine (4 mL) gave the title compound in good yield. The product was purified by silica gel chromatography

using CHCl₃/2-propanoVTEA as eluent. 'H NMR (400 MHz, CDC1₃) δ 8.95 (brs IH), 8.29 (brs IH), 7.08 (d 2H), 3.84 (t 2H), 3.71-3.49 (m 12H), 3.35 (s 3H), 3.21 (s 2H),

2.71-2.66 (m 6H), 2.20 (s 3H), 2.10 (s 3H), 1.13 (t 6H); LC/MS (M+H)+ 468. Anal. Calcd for C₂₄H₄iN₃O₆: C, 61.65; H, 8.84; N, 8.99. Found: C, 61.56; H, 8.80; N, 8.84. Example 16 4-(3-Chloro-benzoylamidoVN-(2-diethylamino-ethyl')-benzamide

Using the procedure described in Example 12 and substituting 3- chlorobenzoyl chloride (3.5 g, 20 mmol) for acetyl chloride, procainamide (5.4 g, 20 mmol) and pyridine (25 mL) gave the title compound in good yield after

recrystallization from hot ethyl acetate/hexane. Yield 3.8 g; ^ΪH NMR (400 MHz, CDCI3) δ 8.88 (brs IH), 7.89 (t IH), 7.79-7.70 (m 5H), 7.49-7.48 (m IH), 7.35 (dd

IH), 7.02 (bit IH), 3.42 (q 2H), 2.62 (t 2H), 2.55 (m 6H), 1.03 (t 6H); LC/MS

(M+H) 374. Anal. Calcd for C₂₀H₂₄ClN₃O₂: C, 64.25; H, 6.47; N, 11.24. Found: C,

64.29; H, 6.50; N, 11.37. Example 17 2-Diethylamino-N-[3-(2-methoxy-acetylamino)-2,6-dimethyl-phenyl1-acetamide

Preparation of methoxyacetyl chloride. A solution of methoxyacetic acid (6 g , 66 mmol) and thionyl chloride (10 mL) was heated at reflux temperature for 1 hour. Excess thionyl chloride was removed by distillation at atmospheric pressure to give 4.0 g of acid chloride (bp 90-95 ° C). Using the procedure described in Example 12 and substituting methoxyacetyl chloride (350 mg, 3.2 mmol) for acetyl chloride, 500 mg (2 mmol) of 3-amino- lidocaine and pyridine (4 mL) gave the title compound in good yield . The product was purified using silica gel chromatography using CHCl₃/2-propanol/TEA as eluent:

!H NMR (400 MHz, CDC1₃) δ 8.99 (brs IH), 7.67 (brs IH), 8.17 (brs IH), 7.66 (d

2H), 7.10 (d 2H), 4.05 (s 2H), 3.52 (s 3H), 3.22 (s 2H), 2.68 (q 4H), 2.21 (s 3H), 2.12

(s 3H), 1.13 (t 6H); LC/MS (M+H)⁺ 322. Anal. Calcd for Cι₇H₂₇N₃0₃: C, 63.53; H,

8.47; N, 13.07. Found: C, 63.79; H, 8.39; N, 12.83. Example 18 2-Diethylamino-N-(3 - (2- [2-(2-methoxy-ethoxyVethoxy1 -acetylamino I -2,6-dimethyl- phenvD-acetamide

Preparation of [2-(2-methoxy-ethoxy)-ethoxy1-acetyl chloride. A solution of [2-(2-methoxy-ethoxy)-ethoxy] -acetic acid (1 g , 5.6 mmol) and thionyl chloride (3 mL) was heated at reflux temperature for 1 hour. Excess thionyl chloride was removed by distillation at atmospheric pressure. The residue was purified by short path distillation under high vaccum to give 910 mg of acid chloride which was used in the next step without further purification. Using the procedure described in Example 12 and substituting [2-(2-methoxy- ethoxy)-ethoxy]-acetyl chloride (632 mg, 3.2 mmol) for acetyl chloride, 500 mg (2 mmol) of 3-amino-lidocaine and pyridine (4 mL) gave the title compound in good yield. The product was purified using silica gel chromatography using CHCl₃/2-

propanol/TEA as eluent. 1H NMR (400 MHz, CDC1₃) δ 8.98 (brs IH), 8.61 (brs IH), 7.53 (d 2H), 7.09 (d 2H), 4.13 (s 2H), 3.80 (m 2H), 3.72 (m 2H), 3.66 (m 2H), 3.48 (m 2H), 3.24 (s 3H), 2.69 (q 4H), 2.21 (s 3H), 2.13 (s 3H), 1.37 (t 6H); LC/MS

(M+H)⁺ 410. Anal. Calcd for C_2.H₃₅N₃O₅: C, 61.59; H, 8.61; N, 10.26. Found: C,

61.50; H, 8.41; N, 9.89.

Example 19 2-Diethylamino-N-l3-[2-(2-methoxy-ethoxyVacetylamino1-2.6-dimethyl-phenyll- acetamide

Using the procedure described in Example 12 and substituting (2-methoxy- ethoxy)-acetyl chloride (456 mg, 3 mmol; prepared from (2-methoxy-ethoxy)-acetic acid and thionyl chloride as described in Example 15; bp 153-155° C 1 mmHg) for acetyl chloride, 500 mg (2 mmol) of 3-amino-lidocaine and pyridine (4 mL) gave the title compound in good yield. The product was purified using silica gel

chromatography using CHCl₃/2-propanol/TEA as eluent. ^lU NMR (400 MHz,

CDC1₃) δ 8.99 (brs IH), 8.57 (brs IH), 7.60 (d 2H), 7.11 (d 2H), 4.13 (s 2H), 3.78 (m 2H), 3.60 (m 2H), 3.38 (s 3H), 3.22 (s 2H), 2.69 (q 4H), 2.21 (s 3H), 2.13 (s 3H), 1.38

(t 6H). LC/MS (M+H)⁺ 366. Anal. Calcd for C₁₉H₃ιN₃0₄: C, 62.44; H, 8.55; N,

11.50. Found: C, 62.29; H, 8.27; N, 11.42. Example 20 Hexanoic acid r3-(2-diethylamino-acetylaminoV2.4-dimethyl-phenyl]-amide

Using the procedure described in Example 12 and substituting hexanoyl chloride (432 mg, 3.2 mmol) for acetyl chloride, 500 mg (2 mmol) of 3-amino- lidocaine and pyridine (4 mL) gave the title compound in good yield. The product

was purified by recrystallization from ethyl acetate/hexane. 1H NMR (400 MHz, CDCI3) δ 8.98 (brs IH), 7.35 (d 2H), 7.19 (brs IH), 7.06 (d 2H), 3.22 (s 2H), 2.69 (q 4H), 2.35 (t 2H), 2.19 (s 3H), 2.04 (s 3H), 1.73 (brm 2H), 1.36 (brm 4H), 1.13 (t 6H),

0.91 (brt 3H); LC/MS (M+H)⁺ 348. Example 21 4-Benzoylamido-N-(2-diethylamino-ethylVbenzamide

A solution of 1.35 g (5 mmol) of procainamide in 10 mL of dry pyridine was cooled in an ice-water bath. Benzoyl chloride (0.84 g, 6 mmol) was added and the reaction mixture was stirred at room temperature over 18 hours and quenched with aqueous KOH and CHCI3. The organic layer was separated, washed with water, saturated copper sulfate, dried (MgS0₄) and evaporated. The crude solid residue was recrystallized from hot ethyl acetate/hexane to give the title compound in good yield.

*H NMR (400 MHz, CDC1₃) δ 10.45 (s IH), 8.29 (brt IH), 7.97 (d 2H), 7.88-7.82 (q

4H), 7.61-7.52 (m 3H), 3.33-3.28 (m 2H), 2.53 (q 6H), 0.97 (t 6H); LC/MS (M+H)⁺

340. Anal. Calcd for C₂oH₂₅N₃0₂: C, 70.77; H, 7.42; N, 12.38. Found: C, 71.00; H, 7.30; N, 12.25. Example 22 N-(2-Diethylamino-ethyl)-4-(3-trifluoromethyl-benzoylamido)-benzamide

Using the procedure descrbed in Example 21 and substituting 3- trifluoromethylbenzoyl chloride (1.25 g, 6 mmol) for benzoyl chloride gave the title

compound in good yield. 1H NMR (400 MHz, CDCI3) δ 10.66 (brs IH), 8.34-8.27 (brm 3H), 7.98 (brd IH), 7.87 (brs 4H), 7.79 (brt IH), 3.34-3.29 (m 2H), 2.57-2.48 (m 6H), 0.97 (t 6H); LC/MS (M+H)⁺ 408. Anal. Calcd for C₂₁H₂₄F₃N₃0₂: C, 61.91; H,

5.94; N, 10.31. Found: C, 62.01; H, 6.15; N, 10.14. Example 23 N-(2-Diethylamino-ethylV4-(4-trifluoromethoxy-benzoylamidoVbenzamide

Using the procedure described in Example 21 and substituting 4- trifluoromethoxylbenzoyl chloride (1.34 g, 6 mmol) for benzoyl chloride gave the title

compound in good yield. ^lH NMR (400 MHz, CDC1₃) δ 10.60 (brs IH), 8.31 (t IH), 8.10 (brd 2H), 7.85 (brs 4H), 7.54 (brd 2H), 3.33-3.28 (m 2H), 2.56-2.48 (m 6H), 0.97

(t 6H); LC/MS (M+H)⁺ 424. Anal. Calcd for C₂ιH₂₄F₃N₃0₃: C, 59.57; H, 5.71; N,

9.92. Found: C, 58.30; H, 5.62; N, 9.44. Example 24 N-(2-Diethylamino-ethyl -4-(4-heptyl-benzoylamidoVbenzamide

Using the procedure described in Example 21 and substituting 4- heptylbenzoyl chloride (1.43 g, 6 mmol) for benzoyl chloride gave the title compound

in good yield. *H NMR (400 MHz, CDC1₃) δ 10.40 (brs IH), 8.30 (t IH), 7.91-7.82 (m 6H), 7.34 (brd 2H), 3.33-3.28 (m 2H), 2.66-2.63 (brt 6H), 1.61-1.57 (brm 2H), +

1.29-1.23 (brm 10H), 0.97 (t 6H), 0.85 (brt 3H); LC/MS (M+H) 438. Anal. Calcd

for C₂₇H₃₉N₃0₂: C, 74.10; H, 8.98; N, 9.60. Found: C, 72.85; H, 9.16; N, 9.21.

Example 25 4-[(Benzo[l,3]dioxol-5-carboxamido1-N-(2-diethylamino-ethyl)-benzamide

Using the procedure in Example 21 and substituting piperonyloyl chloride (1.1

g, 6 mmol) for benzoyl chloride gave the title compound in good yield. H NMR (400 MHz, CDC1₃) δ 10.27 (brs IH), 8.28 (brt IH), 7.85-7.80 (brm 4H), 7.91 (brd 2H), 7.59 (dd IH), 7.78-7.52 (brs IH), 7.07 (dd IH), 6.14 (s 2H), 3.33-3.28 (m 2H),

2.56-2.48 (m 6H), 0.97 (t 3H); LC/MS (M+H)⁺ 384. Anal. Calcd for C₂₁H₂₅N₃0₄: C,

65.78; H, 6.57; N, 10.96. Found: C, 65.31; H, 6.85; N, 10.62. Example 26 Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethylcarbamoylVphenyl] -amide

Using the procedure described in Example 21 and substituting 4- phenylbenzoyl chloride (1.3 g, 6 mmol) for benzoyl chloride gave the title compound in good yield. iH NMR (400 MHz, CDC1₃) δ 10.55 (brs IH), 8.33 (t IH), 8.09 (brd 2H), 7.91 (brd 2H), 7.86-784 (brd 4H), 7.78-7.76 (brd 2H), 7.54-7.50 (brt 2H), 7.45-

7.41 (brs IH), 3.34-3.29 (m 2H), 2.57-2.48 (m 6H), 0.97 (t 3H); LC/MS (M+H)⁺

416. Anal. Calcd for C₂₆H₂9N₃0₂: C, 75.15; H, 7.03; N, 10.11. Found: C, 71.46; H, 6.78; N, 9.18.

Example 27 N-r3-(3-Benzyl-ureidoV2.6-dimethyl-phenyl]-2-diethylamino-acetamide

A solution of amine prepared in Example 9 (300 mg, 1.2 mmol) in 10-15 mL of dry dioxane was cooled in an ice-water bath, while benzyl isocyanate (1.59 g, 1.2 mmol) was added. The reaction was stirred for 18 hours at room temperature.

Chloroform was added and the organic layer was separated, washed with saturated

NaHC0₃, dried (MgS0₄) and evaporated to give the title urea in good yield. ^H

NMR (400 MHz, CDC1₃) δ 8.94 (brs IH), 7.33-6.99 (brm 5H), 7.10 (d IH), 7.00 (d IH), 5.37 (brt IH), 4.37 (d 2H), 3.60 (m 2H), 3.13 (s 2H), 2.65 (q 4H), 2.13 (s 3H),

1.99 (s 3H), 1.07 (t 6H); LC/MS (M+H)⁺ 383. Anal. Calcd for C₂₂H₃₀N₄O₂: C,

69.08; H, 7.91; N, 14.65. Found: C, 69.26; H, 7.96; N, 14.93.

Example 28 2-Diethylamino-N-{2.6-dimethyl-3-[3-(4-trifluoromethoxy-phenylVureido1-phenyl}- acetamide

Using the procedure described in Example 27 and substituting 4- trifluoromethoxyphenyl isocyanate (500 mg, 2.4 mmol) for benzyl isocyanate, 610

mg of 3-amino-lidocaine gave the title compound in good yield. 1H NMR (400 MHz,

CDCI3) δ 9.09 (brs IH), 8.11 (brs IH), 7.41 (brd 2H), 7..08 (brd 2H), 6.98 (d IH), 6.87 dt IH), 6.79 (brs IH), 3.31 (s 2H), 2.72 (q 4H), 2.14 (s 3H), 1.95 (s 3H), 1.15 (t

6H); LC/MS (M+H)⁺ 453. Anal. Calcd for C₂₂H₂₇N₄0₃: C, 58.40; H, 6.01; N, 12.38.

Found: C, 57.61; H, 6.60; N, 10.62. Example 29 (SV2-Diethylamino-N-{2.6-dimethyl-3-[3-(l-phenyl-ethyl')-ureido]-phenyl|- acetamide

Using the procedure described in Example 27 and substituting (S)-(-) alpha- methylbenzyl isocyanate (176 mg, 1.2 mmol) for benzyl isocyanate gave the title

compound in good yield: !H NMR (400 MHz, CDC1₃) δ 8.92 (brs IH), 7.31-7.21 (brm 5H), 7.06 (d IH), 6.98 (d IH), 6.28 (s IH), 5.39 (brd IH), 4.93 (m IH), 3.18 (dd

2H), 2.66 (q 4H), 2.13 (s 3H), 1.92 (s 3H), 1.40 (d 3H), 1.12 (t 6H); LC/MS (M+H)⁺

397. Anal. Calcd for C₂₃H₃₂N₄0₂: C, 69.67; H, 8.13; N, 14.13. Found: C, 69.35; H, 8.32; N, 13.93. Example 30 (R -2-Diethylamino-N-(2.6-dimethyl-3-r3-(l-phenyl-ethylVureido1-ρhenyll- acetamide

Using the procedure described in Example 27 and substituting (R)-(+) alpha- methylbenzyl isocyanate (176 mg, 1.2 mmol) for benzyl isocyanate gave the title

compound in good yield. iH NMR (400 MHz, CDC1₃) δ 8.92 (brs IH), 7.31-7.21

(brm 5H), 7.06 (d IH), 6.98 (d IH), 6.28 (s IH), 5.39 (brd IH), 4.93 (m IH), 3.18 (dd

397. Anal. Calcd for C₂₃H₃₂N₄0₂: C, 69.67; H, 8.13; N, 14.13. Found: C, 69.24; H, 8.34; N, 14.30. Example 31 2-Diethylamino-N- 2,6-dimethyl-3-(3-phenyl-ureido)-phenyl]-acetamide

Using the procedure described in Example 27 and substituting phenyl isocyanate (149 mg, 1.2 mmol) for benzyl isocyanate gave the title compound in good

yield. iH NMR (400 MHz, CDC1₃) δ 9.03 (brs IH), 7.82 (brs IH), 7.40-7.37 (brd

2H), 7.26-7.24 (brm 2H), 6.98-6.94 (brm 3H), 6.80 (s IH), 3.30 (s 2H), 2.72 (q 4H),

2.14 (s 3H), 1.96 (s 3H), 1.48 (t 6H); LC/MS (M+H) 369. Anal. Calcd for

C₂ιH₂₈N₄0₂: C, 68.45; H, 7.66; N, 15.21. Found: C, 68.45; H, 7.61; N, 14.97. Example 32 N-r3-r2-Diethylamino-acetylaminoV2,4-dimethyl-ρhenyl1-3-trifluoromethyl- benzamide

Using the procedure described in Example 27 and substituting 3- trifluorobenzoyl chloride (249 mg, 1.2 mmol) for benzyl isocyanate and diisopropylethyl amine (200 mg 1.3 mmol) gave the title compound in good yield.

*H NMR (400 MHz, CDC1₃) δ 9.04 (brs IH), 8.43 (brs IH), 8.24 (brs 2H), 8.11 (d IH), 7.79 (d IH), 7.61 (t IH), 7.28 (t IH), 7.06 (d IH), 3.22 (s 2H), 2.69 (q 4H), 2.19

(s 3H), 2.07 (s 3H), 1.13 (t 3H); LC/MS (M+H)⁺ 422. Anal. Calcd for C₂ιH₂₈N₄0₂:

C, 62.70; H, 6.22; N, 9.97. Found: C, 62.83; H, 6.48; N, 10.03. Example 33 2-Diethylamino-N-(2.6-dimethyl-3-tridecylamino-phenyl)-acetamide

To a solution of tridecanal (90%, 883 mg, 4.0 mmol), 3-amino-lidocaine (1.0 g, 4.0 mmol) dissolved in 25 mL of dichloromethane and cooled in an ice-water bath was added NaBH(OAc)₃ (1.2 g, 6 mmol). The reaction was stirred 3 hours at 0-5° C and quenched with saturated solution of NaHC0₃. After an additional 30 minutes of stirring (to decompose reducing reagent and borate intermediates), the organic layer was separated, and dried (MgS0 ). Evaporation gave a yellow oil, which was redissolved in diethyl ether and hexane and cooled to - 20° C The product crystallized and was collected by filtration. *H NMR (400 MHz, CDC1₃) δ 8.90 (brs

IH), 6.98 (d IH), 6.51 (d IH), 3.22 (s 2H), 3.10 (t 2H), 2.68 (q 4H), 2.14 (s 3H), 1.98 (s 3H), 1.63 (br m 3H), 1.41-1.30 (brm 20H),1.13 (t 6H), 0.88 (t 3H); LC/MS

(M+H)⁺ 433.

Example 34 Z-Tetradec-9-enoic acid [3-(2-diethylamino-acetylammoV2,4-dimethyl-phenyl]- amide

dimethylformamide and 358 mg (2.2 mmol) of carbonyl diimidazole were stirred at room temperature for 15 minutes. Then, solid 3-amino-lidocaine (550 mg, 2.2 mmol) was added to the solution and the reaction mixture was warmed to 50° C and kept at that temperature for 18 hours. After that it was cooled to room temperature and water was added. The precipitated solid was collected by filtration and dried to afford an

off-white solid in good yield. LC/MS (M+H) 458. Example 35 2-Diethylamino-N-[2.6-dimethyl-3-(3.7, 11 -trimethyl-dodeca-2,6.10-trienylamino)- phenyl^"|-acetamide (A) and N-(3-[Bis-f 3.7,1 l-trimethyl-dodeca-2,6 O-trienyl)- amino]-2.6-dimethyl-phenyll -2-diethylamino-acetamide (B)

A solution of 3-amino-lidocaine (880 mg, 3.5 mmol) and 3.5 mmol of diisopropylethylamine in 10 mL of THF was cooled to 0-5° C To this cooled solution was added 1.0 g (3.5 mmol) of farnesyl bromide. The reaction was stirred for 3 hours, followed by addition of saturated NaHCU₃ solution and ethyl acetate. The organic layer was separated, dried (MgS0₄) and concentrated. TLC (ethyl acetate:hexane:TEA) showed unreacted 3-amino-lidocaine and two less polar compounds. The crude product was redissolved in ethyl acetate/hexane and kept at - 20° C to remove the starting material, 3-amino lidocaine by precipitation. The mother liquor was concentrated and purified by silica gel chromatography to give two products (monoalkylated and dialkylated) as yellow oils in good yield.

Mononalkylated compound A: ^ΪH NMR (400 MHz, CDC1₃) δ 8.90 (s IH), 6.98 (d IH), 6.51 (d IH), 5.38-5.34 (m, IH), 5.13-5.07 (m 2H), 3.71-3.70 (brd 2H), 3.33(brs IH), 3.22 (s, 2H), 2.69 (q 4H), 2.14-1.98 (m 14H), 1.70-1.60 (s 12H), 1.13 (t 6H);

LC/MS (M+H)⁺ 454.

+

Dialkylated product B. LC/MS (M+H) 659.

Example 36 2-Diethylamino-N-r2.6-dimethyl-3-(4-phenyl-butylamino -phenyll-acetamide

4-Phenylbutyraldehyde. To a suspension of pyrdinium chlorochromate (PCC, 1.72 g, 8 mmol) in dichloromethane (30 mL) at room temperature was added 4- phenylbutanol (500 mg, 3.3 mmol). The reaction was stirred for 3 hours and then filtered through a cake of silica gel/celite. The dichloromethane filtrate was concentrated to give crude aldehyde which was used in the next step without further purification. The crude aldehyde was dissolved in 10 mL of dichloromethane and 825 mg (3.3 mmol) of 3-amino-lidocaine was added. The reaction was stirred at 0-5° C and solid NaBH(OAc)₃ (1.0 g, 5.0 mmol) was added. After stirring at 0-5° C for 4 hours, saturated NaHC03 solution was added and the organic layer was separated, dried

(MgS0₄) and concentrated. The product was purified by silica gel chromatography to

give a white solid. H NMR (400 MHz, CDC1₃) δ 8.89 (s IH), 7.30-7.26 (m 5H), 6.97 (d IH), 6.50 (d IH), 3.34 (brs IH), 3.14 (t 2H), 3.21 (s 2H), 3.13 (t 2H), 2.71-2.65 (m

6H), 2.13 (s 3H), 1.96 (s 3H), 1.77-1.56 (m 4H), 1.13 (t 6H); LC/MS (M+H)⁺ 383.

Anal. Calcd for C₂ H₃₅N₃0: C, 75.55; H, 9.25; N, 11.01. Found: C, 75.52; H, 9.33;

N, 10.71. Example 37 2-[1.4']Bipiperidinyl-l'-yl-N-{2.6-dimethyl-3-[6-(4-phenyl-butoxyVhexylaminol- phenyll -acetamide

Using the procedure described in Example 33 and replacing 3-amino-lidocaine with the compound prepared in Example 10 and tridecanal with 6-(4-Phenyl-butoxy)- hexanal (Skidmore et -7/.1991) gave after silica gel chromatography 408 mg of the title compound: LC/MS (M+H)+ 578.

Example 38 N-(2-Diethylamino-ethyl)-4-(4-trifluoromethoxy-benzylamino)-benzamide

A solution of procainamide hydrochloride (1.35 g, 5 mmol), 4- trifluoromethoxybenzaldehyde (0.94 g, 5 mmol) and diisopropylethylamine (5 mmol) were stirred at 0-5° C for 20 minutes. Solid NaBH(OAc)₃ (1.0 g, 5 mmol) was added to the reaction and the reaction was stirred for 18 hours, while warming to room temperature. Saturated NaHC0₃ solution was added, the organic layer was separated, dried (MgS0₄) and concentrated to give a yellow oil, which was purified by silical gel

chromatography. *H NMR (400 MHz, CDC1₃) δ 8.44 (s IH), 7.96 (d 2H), 7.83 (d 2H), 7.33 (d 2H), 7.23 (d 2H), 6.93 (brs IH), 3.52-3.50 (m 2H), 2.66 (t 2H), 2.58 (q

6H), 1.05 (t 6H); LC/MS (M+H)+ 410. Example 39 2-Diethylamino-N-(2.6-dimethyl-3-phenethylamino-phenyl^')-acetamide

Using the procedure in Example 33 and replacing 4-phenylbutryaldehyde with phenylacetaldehyde (0.48 g, 4 mmol), NaBH(OAc)₃ (1.06 g, 5 mmol), and 3-amino-

lidocaine (1.27 g, 5 mmol) gave the product in good yield. *H NMR (400 MHz, CDC1₃) δ 8.88 (s IH), 7.33-7.21 (m 5H), 6.99 (d 2H), 6.56 (d 2H), 3.45-3.38 (m 3H), 3.21 (s 2H), 2.95 (t 2H), 2.68 (q 4H), 2.13 (s 3H), 1.88 (s 2H), 1.12 (t 6H); LC/MS

(M+H)⁺ 354.

Example 40 2-Diethylamino-N-r2,6-dimethyl-3-(4-trifluoromethoxy-benzylamino)-phenyl1- acetamide

Using the procedure described in Example 33 and replacing tridecanal with 4-

trifluoromethoxybenzaldehyde gave the title compound in good yield. ^H NMR (400 MHz, CDCl₃) δ 8.93 (s IH), 7.40-7.38 (d 2H), 7.19-7.17 (d 2H), 6.95-6.93 (d 2H), 6.44-6.42 (d 2H), 4.36 (s 2H), 3.90-3.80 (brs IH), 3.22 (s 2H), 2.72-2.66 (m 4H),

2.14 (s 3H), 2.04 (s 3H), 1.13 (t 6H); LC/MS (M+H)⁺ 424.

Example 41 N-f2,6-Dimethyl-3-nitro-phenyl)-2-f4-methyl-[1.41diazepan-l-yl)-acetamide

Using the procedure in Example 8 and replacing lidocaine with N-(2,6- dimethyl phenyl)-2-(4-methyl-[l,4]diazepan-l-yl)-acetamide prepared in Example 2 gave the title compound in good yield: LC/MS (M+H)⁺ 321. Example 42 N-(3-Amino-2.6-dimethyl-phenyl^')-2-(4-methyl-ri.41diazepan-l-ylVacetamide

Using the procedure in Example 9 and replacing 3-nitro-lidocaine with N-(2,6- dimethyl-3-nitro-phenyl)-2-(4-methyl-[l,4]diazepan-l-yl)-acetamide prepared in Example 41 gave the title compound in good yield : LC/MS (M+H) 291. Example 43 2-[^"1.4'1Bipiperidinyl-r-yl-N-[2,6-dimethyl-3-(4-phenyl-butylamino)-phenyl]- acetamide

Using the procedure from Example 36 for the preparation of 4- phenylbutyraldehyde and replacing 3-amino-lidocaine with 1.1 g, (3.3 mmol) the amine prepared in Example 10, NaBH(OAc)3 (1.0 g, 5.0 mmol) gave the title compound in good yield after silica gel chromatography using 70:30:2

(EtOAc:hexane:triethylamine): LC/MS (M+H)⁺ 477. Example 44 2-[l,4'1Bipiperidinyl-r-yl-N-(2.6-dimethyl-3-phenethylamino-ρhenyl)-acetamide

Using the procedure in Example 43 and replacing 4-phenylbutyraldehyde with phenylactealdehyde gives the product in good yield. Example 45 N-[2,6-Dimethyl-3-(4-trifluoromethoxy-benzylamino')-phenvn-2-(4-methyl- [ 1 ,4]diazepan- 1 -vD-acetamide

Using the procedure in Example 36 and replacing 4-phenylbutyrylaldehyde with 4-trifluoromethoxybenzaldehyde (448 mg, 2.3 mmol), NaBH(OAc)₃ (750 mg,

3.5 mmol), and the amine prepared in Example 42 (680 mg, 2.3 mmol) for 3-amino-

lidocaine gave the product in good yield: *H NMR (400 MHz, CDC1₃) δ 8.84 (s IH), 8.34 (s IH), 7.96-7.94 (m 2H), 7.32-7.30 (d 2H), 7.12-7.10 (d IH), 6.84 (d 2H), 3.35 (s 2H), 2.98-2.95 (m 4H), 2.71-2.67 (m 4H), 2.38 (s 3H), 2.26-2.24 (m 6H), 1.96-

1.88 (m 2H); LC/MS (M+H)⁺ 465.

Example 46 Tetradecanoic acid (2.4-dimethyl-3-[2-(4-methyl-[1.4]diazepan-l-yl)-acetylamino1- phenyl} -amide

Using the procedure described in Example 11 and substituting the amine prepared in Example 42 (300 mg, 1 mmol) for 3-amino-lidocaine and tetradecanoyl + chloπde (1 mmol) gave the title compound in good yield. LC/MS (M+H) 502.

Example 47 N-(2,6-Dimethyl-phenylV2-ethylamino-acetamide

2,6-Dimethylchloroacetanilide (3.95 g, 20 mmol) was treated with 2M ethylamine in THF (50 mL, 100 mmol) and resulting mixture was stirred at room temperature in a tightly sealed flask for 3 days. The precipitate formed was filtered off, solid was washed with diethyl ether and combined filtrates were evaporated to give a residue, which was recrystallized from diethyl ether/hexane. Yield: 3.028 g (73%); iHNMR (400 MHz, CDC1₃) δ 8.81 (bs, IH), 7.07-7.11 (m, 3H), 3.46 (s, 2H), 2.79 (qt, 2H, J = 7.2Hz), 2.23 (s, 6H), 1.18 (t, 3H, J = 7.2Hz); LC/MS (M+H) 207.

Anal. Calcd for Cι₂H_]8N₂0: C, 69.87; H, 8.80; N, 13.58. Found: C, 69.70; H, 9.00; N, 13.41. Example 48 2-Dimethylamino-N-(2.6-dimethyl-phenyl)-acetamide

Using the procedure in Example 47 and replacing ethylamine with dimethylamine gave the title compound. The product was purified by trituration with hexane. Yield: 0.259 g (63%); 1H NMR (400 MHz, CDC1₃) δ 8.63 (bs, IH), 7.08 - 7.10 (m, 3H), 3.15 (s, 2H), 2.45 (s, 6H), 2.24 (s, 6H); LC/MS (M+H)⁺ 207. Anal. Calcd for Cι₂Hι₈N₂0: C, 69.87; H, 8.80; N, 13.58. Found: C, 69.95; H, 9.06; N, 13.46.

Example 49 N-(2,6-Dimethyl-phenvD-2-(ethyl-methyl-amino^')-acetamide

Using the procedure in Example 47 and replacing ethylamine with ethylmethylamine gave the title compound. The product was isolated as the HCl salt, recrystallized from dichloromethane/hexane. Yield: 0.489 g (95%); ^lR NMR (400 MHz, CDC1₃) δ 11.59 (bs, IH), 10.07 (bs, IH), 7.02 - 7.10 (m, 3H), 4.35 (bs, 2H),

3.50 - 3.55 (m, IH), 3.37 - 3.41 (m, IH), 3.05 (d, 3H, J = 4.8Hz), 2.25 (s, 6H), 1.29 ((tt,, 33HH,, 77..22HHzz));; LLCC//MMSS ((MM++HH))⁺⁺ 222211.. AAnnaall.. CCaallccd for Cι₃H₂₁ClN₂0: C, 60.81; H, 8.24; N, 10.91. Found: C, 60.61; H, 7.91; N, 10.76.

Example 50 2-(Benzyl-ethyl-amino)-N-(2,6-dimethyl-phenyl)-acetamide

Compound 47 was stirred with benzaldehyde (1.05 equiv.) in 1 ,2-dichloroethane at room temperature for 10 minutes and then treated with sodium triacetoxyborohydride (1.5 equiv.) which was followed by stirring at room temperature overnight. Next day the reaction mixture was diluted with dichloromethane and quenched by stirring with 0.5 N NaOH.

Organic phase was separated, washed with sat. sodium bicarbonate, brine, dried over magnesium sulfate, decanted and evaporated. Crude residue was dissolved in diethyl ether, treated with 4N HCl in dioxane at room temperature and concentrated. The residue was rinsed with ether several times and finally recrystallized from 2-propanol/diethyl ether to yield title compound as a hydrochloride. LCMS: t_R= 3.404 min, (M+H)⁺ 297, (M+Na)⁺ 319. Anal. Calcd for Cι₉H₂₄N₂0 x HCl (Mol. Wt: 296.41): C, 68.56; H, 7.57; N, 8.42. Found: C, 68.59; H, 7.52; N, 8.39. Example 51 N-(2.6-Dimethyl-phenyl)-2-[4-(4-trifluoromethyl-phenoxy)-piperidin-l-yl]-acetamide

2,6-dimethylchloroacetanilide (0.475 g, 2.4 mmol) was dissolved in anhydrous THF

(5mL) and 4-(4-trifluoromethyl)phenoxypiperidine hydrochloride (Array Biopharma) (1.049 g, 3.7mmol) was added with stirring followed by N,N-diisopropylethylamine (1.25 mL, 7.2 mmol). The reaction mixture was stirred at room temperature for 3 days, during which formation of the precipitate was observed. Then diethyl ether (15 mL) was added and mixture was stirred for further 30 min. Then solid (starting material and polar impurities) was filtered off, washed with diethyl ether and combined filtrates were evaporated. The crude residue was crystallized from dichloromethane/hexane and then purified by chromatography (ethyl acetate/hexane 3:7). Yield: 0.512g (52%); LCMS: t_R = 4.564min, (M+H)⁺ 407, (M+Na)⁺ 429. Anal. Calcd for C22H25F3N2O2 (Mol. Wt: 406.44) C, 65.01; H, 6.20; N, 6.89. Found: C, 64.49; H, 6.19; N, 6.71. Example 52 2-(l-Benzyl-piperidin-4-ylamino)-N-(2.6-dimethyl-phenylVacetamide

Using the procedure described in Example 51 and replacing 4-(4- trifluoromethyl)phenoxypiperidine hydrochloride with 4-amino-l-benzylpiperidine gave the title compound. The crude residue was crystallized from dichloromethane/hexane and then purified by preparative HPLC 1H NMR (400 MHz, CDC1₃) δ 8.60 (b, IH), 7.33 - 7.43 ( , 5H), 7.07 - 7.10 ( , 3H), 3.71 - 3.80 (m, 2H), 3.48 (s, 2H), 3.04 - 3.09 (m, 2H), 2.62 - 2.65 (m, IH), 2.21 (s, 6H), 1.72 - 2.08 (bm, 611); LC/MS (M+H)⁺ 352.

Example 53 N-(2.6-Dimethyl-phenyl)-2-(4-phenyl-piperazin-l-ylVacetamide

Using the procedure described in Example 51 and replacing 4-(4- 1rifluoromethyl)phenoxypiperidine hydrochloride with N-phenylpiperazine gave the title compound. The crude residue was crystallized from diethyl ether/hexane and then purified by chromatography using 30% ethyl acetate in hexane. Yield: 0.295g (46%) H NMR (400 MHz, CDC1₃) δ 8.66 (b, IH), 7.27 - 7.32 (m, 2H), 7.08 - 7.13 (m, 3H), 6.87 - 6.97 (m, 3H), 3.26 - 3.29 (m, 6H), 2.86 - 2.90 (m, 4H), 2.25 (s, 6H); LLCC//MMSS ((MM++HH))⁺⁺ 332244.. AAnnaall.. CCaallccdd ffoorr CC₂₂₀₀HH₂₂₅₅NN₃₃OO (Mol. Wt.: 323.43) C, 74.27; H, 7.79; N, 12.99. Found: C, 74.21; H, 7.69; N, 12.71.

Example 54 N-(2,6-D-imethyl-phenyl)-2-(4-pyridin-2-yl-piperazin-l-yl -acetamide

Using the procedure described in Example 51 and replacing 4-(4- trifluoromethyl)phenoxypiperidine hydrochloride with N-(2-pyridinyl)piperazine gave the title compound. The crude residue was crystallized from diethyl ether/hexane and then purified by silica gel chromatography using 50% ethyl acetate in hexane. Yield: 0.324 g (50%); H NMR (400 MHz, CDC1₃) δ 8.67 (bs, IH), 8.20 - 8.22 (m, IH), 7.48 - 7.53 (m, IH), 7.09 - 7.13 (m, 3H), 6.64 - 6.69 (m, 2H), 3.61 - 3.64 (m, 4H), 3.27 (s, 2H), 2.81 - 2.84 (m, 4H), 2.25 (s, 6H); LC/MS (M+H)⁺ 325. Anal. Calcd for

C₁ H₂₄N₄O (Mol. Wt: 324.42) C, 70.34; H, 7.46; N, 17.27. Found: C, 70.47; H, 7.59; N, 16.95.

Example 55 N-(2.6-Dimethyl-phenylV2-(2-piperidin-l-yl-ethylamino^')-acetamide (dihvdrochloride) (A) and N-(2.6-Dimeτhyl-ρhenylV2- r(2.6-dimethyl- phenylcarbamoyD-methyll -(2-piperidin- 1 -yl-ethvD-amino] -acetamide (B

Using the procedure described in Example 51 and replacing 4-(4- trifluoromethyl)phenoxypiperidine hydrochloride with N-(2-aminoethyl) piperidine gave compound A. Compound A was purified by precipitating (with dichloromethane/hexane) compound B from the crude reaction product and then by preparative HPLC (obtained as bis-TFA salt). 1H NMR (400 MHz, DMSO-d6) δ 10.64 (bs, IH), 10.05 (s, IH), 9.54 (bs, IH), 7.08 - 7.12 (m, 3H), 4.11 (bs, 2H), 3.35 - 3.58 (bm, 8H), 2.17 (s, 6H), 1.68 - 1.84 (m, 4H), 1.30 - 1.50 (b, 2H); LC/MS (M+H)⁺ 290. Compound B was obtained by precipitating with dichloromethane/hexane from the crude residue after evaporation of reaction mixture. Yield: 0.130 g (29%) !H NMR (400 MHz, CDC13) δ 9.57 (s, 2H), 6.98 - 7.06 (m, 6H), 3.81 (s, 4H), 3.23 (bs, 4H), 2.60 - 2.90 (b, 4H), 2.20 (s, 12H), 1.70 - 1.95 (b, 6H); LC/MS (M+H)⁺ 451. Example 56 4-r(2,6-Dimethyl-phenylcarbamovπ-methyll-[1.4 diazepane-l-carboxylic acid tert- butyl ester

Using the procedure described in Example 51 and replacing 4-(4- trifluoromethyl)phenoxypiperidine hydrochloride with N-(Boc)-homopiperazine gave the title compound. The compound was obtained pure by chromatography (10-50% ethyl acetate in hexane). Yield: 0.521 g (72%); 1H NMR (400 MHz, CDC13) δ 8.64 (bs, IH), 7.07 - 7.11 (m, 3H), 3.46 - 3.59 (m, 4H), 3.34 (s, 2H), 2.84 - 2.92 (m, 4H), 2.23 (s, 6H), 1.89 - 1.93 (m, 2H), 1.45 (s, 9H); LC/MS (M+H)⁺ 362. Anal. Calcd for C₂₀H₃₁N₃O₃ (Mol. Wt.: 361.48) C, 66.45; H, 8.64; N, 11.62. Found: C, 67.15; H, 9.20; N, 11.61.

Example 57 2-(4-Benzo 1.31dioxol-5-ylmethyl-piperazin-l-yl)-N-(2.6-dimethyl-phenyl')- acetamide

Using the procedure described in Example 51 and replacing 4-(4- trifluoromethyl)phenoxypiperidine hydrochloride with l-benzo[l,3]dioxol-5- ylmethyl-piperazine gave the title compound. The product was purified by crystallization from diethyl ether/hexane, followed by silica gel chromatography using gradient of 50-90% ethyl acetate in hexane. Yield: 0.346 g (45%); ^lR NMR (400 MHz, CDCI₃) δ 8.66 (bs, IH), 7.07 - 7.11 (m, 3H), 6.86 (bs, IH), 6.75 (bs, 2H), 3.46 (s, 2H), 3.20 (s, 2H), 2.73 (bs, 4H), 2.54 (bs, 4H), 2.22 (s, 6H); LC/MS (M+H)⁺ 382. Anal. Calcd for C₂₂H₂₇N₃θ₃ (Mol. Wt.: 381.47) C, 69.27; H, 7.13; N, 11.02. Found: C, 69.26; 1-1, 7.28; N, 10.89.

Example 58 N-(2,6-Dimethyl-phenyl^")-2-{4-[(2.6-dimethyl-phenylcarbamoylVmethyl1-piperazin- 1-yll-acetamide (A andN-(2,6-Dimethyl-phenyl)-2-piperazin-l-yl-acetamide (B)

2,6-Dimethylchloroacetanilide (1.977 g, 10 mmol) was dissolved in anhydrous THF (10 mL) and finely powdered anhydrous sodium carbonate (1.5 g) was added with stirring followed by piperazine (0.431 g, 5 mmol). Reaction mixture was stirred at room temperature for 3 days. Solid material was filtered off, washed with ethyl acetate, triturated with IN HCl and filtered. The aqueous filtrate was brought to basic pH by addition of solid KOH and resulting solution was extracted 3 times with dichloromethane. Organic extracts were dried with magnesium sulfate, decanted and evaporated. Residue was subjected to chromatography using dichloromethane/methanol (95:5) as a solvent system separating compounds A and B. Compound A: 1H NMR (400 MHz, CDC1₃) δ 8.57 (b, 2H), 7.09 - 7.12 (m, 6H), 3.25 (s, 4H), 2.82 (bs, 8H), 2.24 (s, 12H); LC/MS (M+H)⁺ 409. Anal. Calcd for C₂₄H₃₂N₄0₂, Mol. Wt. 408.54; C, 70.56; H, 7.90; N, 13.71. Found: C, 70.29; H, 8.09; N, 13.53. Compound B: *H NMR (400 MHz, CDC1₃) δ 8.66 (bs, IH), 7.07 - 7.11 (m, 3H), 3.20 (s, 2H), 2.99 (t, 4H, J = 5Hz), 2.69 (bt, 4H, J = 5Hz), 2.23 (s, 6H); LC/MS (M+H)⁺ 248. Example 59

A solution of sodium azide (5.5 g, 85 mmol) and 2,6- dimethylchloroacetanilide (12.9 g, 65 mmol) in 40 mL of anhydrous DMSO was heated to 40-45° C for 24 hours. The reaction was cooled to room temperature, chloroform (350 mL) was added followed by 400 mL of water. The organic layer was separated, dried (MgS0₄) and concentrated under reduced pressure to give a white

solid which was recrystallized from ethyl acetate/hexane. Yield 11.1 g: ^H NMR (400 MHz, CDC1₃) δ 7.63 (brs IH) 7.14-7.06 (m 3H) 4.15 (s 2H) 2.21 (s 6H); LC/MS

(M+H)+ 205. Anal. Calcd for C₁₀Hι₂N₄O: C, 58.81; H, 5.92; N, 27.43. Found: C,

58.81; H, 5.63; N, 27.51.

Example 60 2-Amino-N-(2,6-dimethyl-phenyl)-acetamide

The azide prepared in Example 59 (3.0 g, 14.6 mmol) was dissolved in ethanol

(40 mL) and palladium catalyst (10% Pd/C, 300 mg) suspended in ethanol (10 mL) was added with stirring. The flask was evacuated and rinsed 3 times with hydrogen from the balloon. The reaction mixture was stirred under hydrogen atmosphere overnight and then filtered through a pad of celite. The filtration cake was washed several times with ethanol and combined filtrates were evaporated to yield the crude product which crystallized under diethyl ether. Yield: 1.422 g (54%); 1HNMR (400

MHz, CDCI₃): 8.80 (bs, IH), 7.06 - 7.10 (m, 3H), 3.56 (s, 2H), 2.26 (s, 6H); LC/MS ((MM++HH))⁺⁺ 117799.. AAnnaall.. CCaallccd. for Cι₀Hι₄N₂O C, 67.39; H, 7.92; N, 15.72. Found: C, 67.09; H, 8.13; N, 15.60.

Example 61 N-(2-Diethylamino-ethylV4-tetradecanoylamino-benzamide

Using the procedure in Example 12 and replacing acetyl chloride with myristol chloride (300 mg, 1.2 mmol) gave the title compound after recrystallization

from hot ethyl acetate/hexane. Yield 45 mg. ^!H NMR (400 MHz, CDC1₃) δ 8.82 (brt IH), 8.04 (d 2H), 7.46 (brs IH), 7.65 (d 2H), 3.90-3.86 (brq 2H), 3.27 (m 2H), 3.21-3.15 (q 4H), 2.39 (t 2H), 1.74-1.65 (m 5H), 1.42 (t 6H), 1.36-1.25 (brm 20H),

0.87 (t 3H); LC/MS (M+H) ⁺ 446.

Example 62 N-(3-Bromo-2.6-dimethyl-phenyl)-2-diethylamino-acetamide

Lidocaine dissolved in glacial acetic acid in presence of catalytic amount of acetic anhydride was treated with bromine (dissolved in acetic acid) added dropwise at room temperature. After 1 hour product was precipitated by addition of water. Crude hydrobromide was converted to free base and recrystallized yielding the title compound.

Example 63 2-[l,4']Bipiperidinyl-r-yl-N-(3-bromo-2.6-dimethyl-phenyl -acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-r-yl-N-(2,6- dimethyl-phenyl)-acetamide subjected to identical procedure as in Example 62.

Example 64 2-Diethylamino-N-(3-formyl-2,6-dimethyl-phenyl)-acetamide

N-(3-Bromo-2,6-dimethyl-phenyl)-2-diethylamino-acetamide (compound 62) was treated with 2 equivalents of n-butyl lithium in THF at -78° C, followed by addition of anhydrous N,N-dimethylformamide. After 2 hours, the reaction mixture was quenched with water, extracted with ethyl acetate, which was followed by silica gel chromatography to yield the title compound. Example 65 2-[1.4'lBipiperidinyl-r-yl-N-(3-formyl-2,6-dimethyl-phenyl)-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-r-yl-N-(3-bromo-2,6- dimethyl-phenyl)-acetamide (compound 63) subjected to identical procedure as in Example 64. Example 66 2-Diethylamino-N-(2,6-dimethyl-3-phenylaminomethyl-phenvD-acetamide

Compound 64 (2-diethylamino-N-(3-formyl-2,6-dimethyl-phenyl)-acetamide) dissolved in 1,2-dichloroethane was treated with aniline, followed by sodiumtriacetoxyborohydride. After 24 hours the reaction mixture was washed with dilute NaOH, saturated sodium bicarbonate, brine, dried and crude product was purified by silica gel chromatography to yield the title compound. Example 67

2- l,4'lBipiperidinyl-r-yl-N-(2.6-dimethyl-3-phenylaminomethyl-phenyl)-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-l'-yl-N-(3-formyl-

2,6-dimethyl-phenyl)-acetamide (compound 65) subjected to identical procedure as in Example 66. Example 68 2-Diethylamino-N-(3-hydroxy-2.6-dimethyl-phenyl)-acetamide

2-Diethylamino-N-(3-formyl-2,6-dimethyl-phenyl)-acetamide (compound 64) was oxidized using Bayer- Villiger conditions. Starting material, stirred in biphasic mixture (water/dichloromethane) was treated with 30% hydrogen peroxide solution in presence of selenium dioxide catalyst for 24 h at room temperature. Crude formate dissolved in dioxane was hydrolyzed by treating with LiOH and title compound was isolated after extraction and silica gel chromatography.

Example 69 2-[ 1 ,4']Bipiperidinyl- 1 '-yl-N-(3-hydroxy-2,6-dimethyl-phenyl)-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-r-yl-N-(3-formyl-2,6- dimethylphenyl)-acetamide (compound 65) subjected to identical procedure as in Example 68. Example 70 N-(3-Benzyloxy-2,6-dimethyl-phenyl)-2-diethylamino-acetamide

2-Diethylamino-N-(3-hydroxy-2,6-dimethyl-phenyl)-acetamide (compound 68) dissolved in DMF was alkylated with slight excess of benzyl bromide in presence of anhydrous, finely powdered potassium carbonate with heating at 80° C overnight. After cooling down to room temperature reaction mixture was diluted with water and extracted with ethyl acetate. Crude material was purified by silica gel chromatography.

Example 71 N-(3-Benzyloxy-2.6-dimethyl-phenyl)-2-[1.4'1bipiperidinyl- -yl-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-l'-yl-N-(3-hydroxy- 2,6 dimethyl-phenyl)-acetamide (compound 69) by applying the same procedure as for Example 70.

Example 72 2-Diethylamino-N-(2.6-dimethyl-3-styryl-phenyl)-acetamide

N-(3-Bromo-2,6-dimethyl-phenyl)-2-diethylamino-acetamide (compound 62) dissolved in xylene was heated at 130° C for 24 hours with excess of styrene in presence of catalytic palladium(II) acetate and triphenylphosphine (4 equiv. in relation to palladium catalyst). Title compound was obtained after passing the cooled reaction mixture through a pad of celite, followed by silica gel chromatography. Example 73 2-[1.4'lBipiperidinyl- -yl-N-(2.6-dimethyl-3-styryl-phenyl)-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-r-yl-N-(3-bromo-2,6- dimethyl-phenyl)-acetamide (compound 63) applying the Heck conditions and work up as in Example 72.

Example 74 2-Diethylamino-N-(2.6-dimethyl-3-phenethyl-phenyl)-acetamide

2-Diethylamino-N-(2,6-dimethyl-3-styryl-phenyl)-acetamide (compound 72) dissolved in ethanol was hydrogenated in presence of Pd/C catalyst at room temperature for 24 hours. Filtration of reaction mixture through the pad of celite, followed by evaporation of the filtrate and recrystallization of the resulting crude material gave title compound.

Example 75 2-[ 4'1Bipiperidinyl- -yl-N-(2,6-dimethyl-3-phenethyl-phenyl)-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl-r-yl-N-(2,6- dimethyl-3-styryl-phenyl)-acetamide (compound 73) by the same procedure as in Example 74.

Example 76 2-Diethylamino-N-(2,4-dimethyl-biphenyl-3-yl)-acetamide

N-(3-Bromo-2,6-dimethyl-phenyl)-2-diethylamino-acetamide (compound 62) dissolved in toluene was refluxed for 24 hours in the presence of an equivalent of phenylboronic acid, excess of finely powdered anhydrous potassium carbonate and catalytic amount of Pd(PPli₃)₄. After cooling down to room temperature the reaction mixture was passed through a pad of celite, concentrated and purified by silica gel chromatography.

Example 77 2-[l,4']Bipiperidinyl- -yl-N-(2.4-dimethyl-biphenyl-3-yl -acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl- -yl-N-(3-bromo-2,6- dimethyl-phenyl)-acetamide (compound 63) applying the Suzuki conditions and work up as in Example 76. Example 78 2-Diethylamino-N-(2,6-dimethyl-3-phenylethvnyl-phenylVacetamide

N-(3-Bromo-2,6-dimethyl-phenyl)-2-diethylamino-acetamide (compound 62) dissolved in anhydrous THF was stirred at room temperature overnight with an equivalent of phenylacetylene and 1.5 equivalents of triethylamine in the presence of a catalytic amount of cuprous iodide and Cl₂Pd(PPli₃)₂. The reaction mixture was passed through a pad of celite, concentrated and purified by silica gel chromatography.

Example 79 2-f 1 ,4'IBipiperidinyl- 1 '-yl-N-(2.6-dimethyl-3 -phenylethynyl-phenvD-acetamide

Title compound was obtained from 2-[l,4']bipiperidinyl- -yl-N-(3-bromo-2,6- dimethyl-phenyl)-acetamide (compound 63) applying the Sonogashira conditions and worked up as in Example 78.

Example 80 2-(Adamantan- 1 -ylammo)-N-(2.6-dimethyl-phenyl)-acetamide

The title compound was prepared like compound in Example 47 usinj adamantanamine and purified by chromatography using ethyl acetate/hexane (1 :1) LCMS: t_R= 3.656min, (M+H)⁺ 313 (calcd for C₂₀H₂₈N₂O Mol. Wt: 312.45).

Example 81 N-(2,6-Dimethyl-phenyl)-2-(octahydro-quinolin- 1 -yl)-acetamide (cis/trans)

The title compound was prepared like the compound in Example 47 using decahydroquinoline (cis/trans) and purified by cliromatography using 10-30% gradient of ethyl acetate in hexane. Yield: 0.626g (80%);

LCMS: t_R=3.487min and 3.705min (2 diastereoisomers), (M+H)⁺ 301. Anal. Calcd for Cι₉H₂₈N₂0 (Mol. Wt: 300.44): C, 75.96; H, 9.39; N, 9.32. Found: C, 75.67; H, 9.15; N, 9.18.

Example 82 2-(Cyclohexyl-ethyl-amino)-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared like the compound in Example 50 using cyclohexanone in the presence of 1.5 equivalents of acetic acid (due to lower reactivity of the ketone compared to aldehyde). Title compound was obtained after chromatography using 30% ethyl acetate in hexane.

LCMS: t_R= 3.473min, (M+H)⁺ 289. Anal. Calcd for Cι₈H₂₈N₂0 (Mol. Wt.: 288.43) C, 74.96; H, 9.78; N, 9.71. Found: C, 75.26; H, 9.47; N, 9.65.

Example 83 2-Dicvclohexylamino-N-(2,6-dimethyl-phenyl)-acctamide

2-Chloro-2',6'-acetoxylidide (0.395g, 2 mmol) was heated with N,N-dicycyclohcxyl- a ine (5mL of 2M solution, lOmmol) in refluxing toluene overnight. After 24 hours the reaction mixture was allowed to cool down to room temperature, precipitate formed was filtered off and washed with ether. The combined filtrates were evaporated and the residue was purified by recrystallization with diethyl ether/hexane. LCMS: t_R = 4.498min, (M+H)" 343.

Anal. Calcd for C₂₂H₃ N₂0 (Mol. Wt: 342.52) C, 77.14; H, 10.01; N, 8.18. Found: C, 77.37; H, 10.05; N, 8.37.

Example 84 N-(2,6-Dimethyl-phenylV2-(ethyl-phenyl-amino)-acetamide

2-CWoro-2',6'-acetoxylidide, sodium iodide (1.1. equiv), N-ethylaniline (1.5.equiv.) and DIEA (2 equiv) were stirred at room temperature for 5 days in anhydrous acetonitrile. Addition of diethyl ether precipitated starting material and polar impurities. The filtrate was concentrated and residue purified by cliromatography using gradient of 10-30% of ethyl acetate in hexane. LCMS: t_R = 5.415min, (M+H)⁺ 283, (M+Na)⁺ 305.

Anal. Calcd for C₁₈H₂2N₂0 (Mol. Wt.: 282.38) C, 76.56; II, 7.85; N, 9.92. Found: C, 76.33; H, 7.75; N, 10.16.

Example 85 N-(2,6-Dimethyl-phenyl)-2-imidazol- 1 -yl-acetamide

The title compound was prepared as in Example 83. Work-up consisted of diluting the cooled reaction mixture with ethyl acetate, washing 2 times with water, brine and drying over anh. magnesium sulfate. Crude residue obtained after decanting and evaporation was triturated with diethyl ether. Title compound was filtered off and dried. Yield: 0.220g (48%);

LCMS: 1_R = 2.658mm, (M+H)^"* 230. Anal. Calcd for C13H15N3O (Mol. Wt.: 229.28) C, 68.10; H, 6.59; N, 18.33. Found: C, 67.95; H, 6.90; N, 17.94.

Example 86 N-(2.6-Dimethyl-phenyl)-2-(3,4 ,8-tetrahydro-2H,6H-pyrimido[ 1 ,2-a]pyrimidin-l - yl)-acetamide

The title compound was prepared like in Example 83. After 1 hour of refluxing the reaction mixture in toluene a precipitate started to form. After cooling down ethyl acetate was added and organic phase was extracted 2 times with water (organic layer contained mostly 2,6-dimethylaniline). The aqueous phase was then saturated with sodium chloride and extracted with chloroform 3 times. After drying, decanting and evaporation of the organic extract yellowish residue was obtained. After washing with diethyl ether and recrystallizing from 2-propanol/diethyl ether the tile compound was obtained as hydrochloride. Yield: 0.215g (32%); LCMS: t_R = 2.840min, (M+H)⁺ 301.Anal. Calcd for Cι₇H₂₄N₄0 x HCl (Mol. Wt: 300.40) C, 60.61; H, 7.48; N, 16.63. Found: C, 60.29; H, 7.25; N, 16.76.

Example 87 2-(4-Benzyl-piρerazin-l-yl)-N-f2,6-dimethyl-phenyl)-acetamide

The title compound was prepared like in Example 51 using N-benzylpiperazine as a starting material. Crude material was purified using gradient of l%-5% of methanol in dichloromethane. LCMS: t_R = 3.707min, (M+H)⁺ 337 (calcd for C₂₁H₂₇N₃O Mol. Wt.: 337.46).

Example 88 N-(2,6-Dimethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-l-yl)-acetaιιιide

The title compound was prepared as in Example 51 using l-(2-pyridyl)piperazine. LCMS: t_R = 2.533min, (M+H)⁺ 339 (calcd for C2oH₂₆N₄0 Mol. Wt.: 338.45) Example 89 N-(2₁6-Dimethyl-phenyl)-2-(4-pyridin-3-ylmethyl-pipcrazin-l-yl)-acctamide

The title compound was prepared as in Example 51 using l-(3-pyridyl)piperazine

LCMS: t_R = 2.332min, (M+H)⁺ 339 (calcd for C₂₀H₂₆N₄O Mol. Wt.: 338.45)

Example 90 N-(2,6-Dimethyl-phenyl)-2-(4-pyridin-4-ylmetlιyl-piperazin-l-yl)-acetamide

The title compound was prepared like in Example 51 using l-(4-pyridyl)piperazme. Crude material was crystallized from ether and then purified by chromatography using 5% methanol in dichloromethanc.Yield: 0.328g (48%); LCMS: t_R = 2.195min,

(M+H)⁺ 339, (M+Na)⁺ 361. Anal. Calcd for C₂₀H₂₆N₄O (Mol. Wt.: 338.45) C, 70.98; H, 7.74; N, 16.55. Found: C, 70.91; H, 8.02; N, 16.37.

Example 91 2-(4-Benzoyl-piperazin-l-yl)-N-(2.6-dimethyl-phenyl -acetamide

The title compound was prepared like in Example 51 using 1-benzoylpiperazine. Crude material was purified by chromatography using gradient of 50%-67% of ethyl acetate in hexane. Yield: 0.422g (60%); LCMS: t_R = 3.440min, (M+H)⁺ 352, (M+Na)⁺ 374. Anal. Calcd for C_2tH₂5N₃0₂ (Mol. Wt: 351.44) C, 71.77; H, 7.17; N, 11.96. Found: C, 71.42; H, 7.03; N, 11.78. Example 92 2-(4-Acetyl-piperazin- 1 -yl)-N-(2,6-dimethyl-phenyl Vaeetamide

The title compound was prepared like in Example 51 using 1-acetylpiperazine. Crude material was crystallized from dichloromethane/hexane and then purified by chromatography using gradient of 50%- 100% of ethyl acetate in hexane. Yield: 0.266g (46%); LCMS: t_R = 3.513min, (M+H)⁺ 290, (M+Na)⁺ 312. Anal. Calcd for C₁₆H2₃N₃O2 (Mol. Wt: 289.37) C, 66.41; H, 8.01; N, 14.52. Found: C, 66.64; H, 7.78; N, 14.40. Example 93 2-(4-Benzhydi_Υl-piperazm-l-yl)-N-(2.6-dimethyl-phenyl)-acctamide

The title compound was prepared like in Example 51 using 1- diphenylmethylpiperazine. Crude material was purified by chiOmatography using gradient of 10%-30% of ethyl acetate in hexane. Yield: 0.142g (17%); LCMS: t_R = 3.324min, (M+H)⁺ 414, (M+Na)⁺ 436. Anal. Calcd for C2₇H_3.N₃O (Mol. Wt.: 413.55)

C, 78.42; H, 7.56; N, 10.16. Found: C, 78.21; H, 7.71; N, 10.01.

Example 94 2-(5-Benzyl-2,5-diaza-bicyclor2.2.11hept-2-yl)-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared like in Example 51 using (IS, 4S)-(+)-2-benzyl-2,5- diazabicyclo[2,2,l Jheptane dihydrobromide (1 equiv.). Crude material was purified by preparative HPLC yielding title compound as bis-TFA salt. Yield: 0.184g;

LCMS: t_R = 3.615min, (M+H)⁺ 350. Anal. Calcd for C₂₂H₂₇N₃0 x 2CF₃COOH (Mol. Wt: 349.47) C, 54.07; H, 5.06; N, 7.28. Found: C, 53.63; H, 5.00; N, 6.83.

Example 95 2-r5-(4-ChloiO-phenyl)-2.5-diaza-bicyclor2.2.nhept-2-vη-N-(2,6-dimethyl-phenyl)- acetamide

The title compound was prepared like in Example 51 using (IS, 4S)-(-)-4- chlorophenyl-2,5-diazabicyclo[2,2,l]heptane hydrobromide (1.2 equiv.). Crude material was crystallized from diethyl ether and then purified by chromatography using 50% ethyl acetate in hexane. Yield: 0.289g (39%); LCMS: t_R = 4.337mm,

(M+H)⁺ 370, (M+Na)⁺ 392. Anal. Calcd for C₂ιH₂ ClN₃0 (Mol. Wt: 369.89) C, 68.19; H, 6.54; N, 11.36. Found: C, 68.43; H, 6.48; N, 11.45.

Example 96 2-(l-Aza-bicvclo[2.2.2]oct-3-ylamino)-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared like in Example 51 using racemic 3- aminoquinuclidine dihydrochloride in presence of N,N-dimethylformamide to help solubility. Product was present in the precipitate from diethyl ether. Crude material was purified by preparative HPLC yielding title compound as bis-TFA salt.

LCMS: t_R = 2.142min, (M+H)⁺ 288. (calcd for Cι₇H₂₅N₃0 Mol. Wt: 287.40). Example 97 N-(2,6-Dimethyl-phenyl)-2-(3,5-dimetlιyl-piperazin-l-yl)-acetamide

The title compound was prepared analogously as described in Example 51 , using 2,6- dimethylpiperazine (cis) and purified by precipitation with diethyl ether. Yield: 0.512g (92%), LCMS: t_R = 2.372min (M+H)⁺ 276. (calcd. for C₁₆H₂₅N₃O Mol.

Wt: 275.39).

Example 98 N-(2,6-Dimethyl-phenyl)-2-(2,5-dimethyl-piperazin-l-yl -acetamide

The title compound was prepared analogously as described in Example 51 , using 2,5- dimethylpiperazine (trans) Example 99 2-(4-Allyl-2,5-dimethyl-piperazin-l-yl)-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared analogously as described in Example 51, using N- allyl-2,5-dimethylpiperazine (trans) Example 100 N-(2,6-Dimethyl-phenyl)-2-[4-(2-metlιoxy-phenyl)-piperazin-l-yll-acetamide

The title compound was prepared analogously as described in Example 51, using 1- (2-methoxyphenyl)piperazine.

Example 101 N-(2.6-Dimethyl-phenyl)-2-r4-(3-methoxy-phenyl)-piperazin-l-yl1-acetamide

The title compound was prepared analogously as described in Example 51, using 1- (3-methoxyphenyl)piperazine.

Example 102 N-(2,6-Dimethyl-phenyl)-2-[4-(4-methoxy-phenyl)-piperazin-l-yl1-acetamide

The title compound was prepared analogously as described in Example 51, using 1- (4-methoxyphenyl)piperazme. Example 103 N-(2,6-Dimethyl-phenyl)-2- 4-(2-oxo-2,3-dihydro-benzoimidazol-l-yl)-piperidin-l- yl^"|-acetamide

The title compound was prepared analogously as described in Example 51, using (2-oxo-2,3-dihydro-benzoimidazol-l-yl)-piperidine.

Example 104 N-(2,6-Dimethyl-phenyl)-2-(1.4-dioxa-8-aza-spiro[4.51dec-8-yl)-acetamide

The title compound was prepared analogously as described in Example 51, using 1,4- dioxa-8-azaspirodecane.

Example 105 4- ([(2,6-Dimethyl-phenylcarbamoyl)-methyl1-aminol-piperidine- 1-carboxylic acid ethyl ester

The title compound was prepared analogously as described in Example 51, using 4- aminopiperidine- 1-carboxylic acid ethyl ester. Example 106 N-(2,6-Dimethyl-phenyl)-2-(4-phenyl-3.6-dihvdro-2H-pyridm- 1 -yl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4- phenyl-3 ,6-dihydro-2H-pyridine.

Example 107

The title compound was prepared analogously as described in Example 51, using octamethyleneimine.

Example 108 N-(2,6-Dimethyl-phenyl)-2-(4-hvdroxy-4-phenyl-piρeridin-l-yl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4- hydroxy-4-phenylpiperidine. Example 109 2-(4-Bromo-piperidin- 1 -yl)-N-(2,6-dimethyl-phenyl )-acetamide

The title compound was prepared analogously as described in Example 51, using 4- bromopiperidine.

Example 110 N-(2.6-Dimethyl-phenyl)-2-(4-oxo-piperidm- 1 -yl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4- oxo-piperidine.

Example 1 11 2-(3-Acetylamino-pyrrolidin-l-yl)-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared analogously as described in Example 51, using 2- (3 -acetylamino-pyrrolidine.

Example 112 2- (l-Benzyl-ρvιτolidin-3-yl)-ethyl-aminol-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared analogously as described in Example 51, using 1- benzyl-3-(2-ethylamino)pyrrolidine. Example 113 N-(2,6-Dimethyl-phenyl -2-(4-phenoxy-piperidm-l-yl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4- phenoxypiperidine.

Example 114 2-[4-(2-Chloro-phenoxy)-piperidin-l-yll-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4-

(2-chloro-phenoxy)-piperidine.

Example 115 N-(2.6-Dimethyl-phenyl)-2-(4-p-tolyloxy-piperidin-l-yl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4-p- tolyloxy-piperidine. Example 116 2- 4-(2-Benzenesulfonyl-ethyl)-piperazm-l-yl1-N-(2,6-dimethyl-phenyl)-acetamide

The title compound was prepared analogously as described in Example 51, using 4- (2-benzenesulfonyl-ethyl)-piperazine. .

Example 117 Eosinophil Survival Assay Eosinophil Purification Eosinophils were isolated from Pall blood processing filters (Pall Filters; Pall Biomedical, East Hills, NY) which were used to separate red blood cells (RBC) from peripheral blood mononuclear (PBMC) cells (eosinophils, monocytes, macrophages, natural killer, T & B lymphocytes, platelets, and basophils). The used filters were obtained from the Puget Sound Blood Center and were back- flushed with 100 mL of Dulbecco's Phosphate Buffered Saline (DPBS) supplemented with 50 mM NaCl, 2% DMSO and 10,000 units/L heparin. The cell suspension was layered over histopaque (1.077 g/ml, Sigma-Aldrich) and centrifuged at 1,400 rpm, room temperature, for 15 min in a Beckman Coulter Allegra 6R centrifuge. Contaminating RBCs were lysed by osmotic shock in distilled water. The remaining eosinophils and neutrophils were incubated on ice for 30 min with a CD 16 antibody conjugated to magnetic particles (Miltenyi Biotec). The CD 16 antigen is expressed on neutrophils but not eosinophils. Antibody bound neutrophils were removed by passing the cell suspension over a magnetic column. Unbound eosinophils were collected in the eluent and adjusted to 2 x 10⁶ cells/ml in RPMI 1640 supplemented with 10% fetal bovine serum, 446 mg/L L-alanyl-L-glutamine, 50 μg/mL gentamicin, 100 units/mL penicillin, 100 μg/mL streptomycin, 200 pg/mL IL-5. Cell viability was determined by trypan blue exclusion and cells counted with a hemocytometer. Test compounds were suspended in 100% DMSO. Two fold serial dilutions (50 μl) of test articles were made in RPMI 1640 containing 10% heat-inactivated FBS, 446 mg/L L-alanyl-L-glutamine, 50 μg/mL gentamicin, 100 units/mL penicillin, 100 μg/mL streptomycin in 96 well tissue culture plates. An equal volume of purified eosinophils were added to the drug dilutions and incubated at 37°C, 5% C0₂ for 96 hours. The final number of eosinphils was 1 x 10⁵ cells in a volume of 100 μl. Compounds were tested in duplicate and each experiment repeated at least three times. Eosinophil survival was determined by a colorimetric method (Promega; CellTiter 96 Aqueous One Solution Cell Proliferation Assay) utilizing a MTS tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2- (4-sulfophenyl)-2H-tetrazolium. The MTS tetrazolium compound is reduced by live cells into a forazan product. The amount of absorbance at 490 nm is directly proportional to the number of viable cells. CellTiter 96 Aqueous One Solution was added directly to eosinophil/drug dilutions, incubated at 37°C, 5% CO₂ for 2 hours and the absorbance read at 490 nm with a 96-well spectrophotometer. Fifty percent half maximal inhibition (IC5₀) of eosinophil survival was calculated for each test compound. Example 118 IC™ Values for Compounds of the Invention that Inhibit Eosinophil Survival Example # Mean ICsn(μM) SEM(uM Lidot :aine 1441 128 60 1446 375 7 1450 240 4 862 404 3 503 122 58B 1821 99 5 705 279 2 1748 138 1 1940 173 53 37 1 6 65 61 54 46 4 48 915 376 49 1624 194 55A 65 28 55B 111 1 52 140 15 11 26 9 15 1022 332 17 1141 126 18 1149 220

10 19 1711 74 20 346 75 28 350 13

15 29 515 37 30 474 61

20 31 131 35 32 376 114 33 111 88

25 34 66 12

35A 89 7

30 45 1961 280

61 10 3

12 606 252 35 13 359 51

14 73 10

40 16 65 10

21 196 40

22 50 11 45 23 21 3

24 8 0

50 25 107 55

26 8 1

38 555 48 61 10 3 46 9 -

10 37 5 1 39 83 13 43 7 1

15 10 ill 20 27 49

20 35B 517 36 27 0 40 359

25 47 1450 241 50 45

30 51 11 2 56 216 42 80 103

35 81 49 17 82 49

40 83 106 14 85 57 57 62 20

45 9 1940

Example 119

50 Sodium Channel Blockade Assay Local anesthetics cause numbing by blocking sodium channel activity.

Xenopus oocytes were used as an expression system to study the effect of test articles on the alpha subunit of the NAV 1.4 sodium channel derived from human skeletal muscle. Oocytes were harvested from female Xenopus laevis (Xenopus I, Dexter, MI), previously injected with human chorionic gonadotropin. Frogs were anesthetized by immersion in 0.2% 3-aminobenzoic acid ethyl ester and the ovarian tubes surgically removed. Oocytes were dissociated by gentle agitation for 1 hour in 1 mg/ml collagenase D (Boehringer-Mannheim), and then washed extensively in Ca²⁺ free OR- 2 solution (96 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 5 mM HEPES, pH 7.4). Stage V and VI oocytes were collected with the aid of a dissecting microscope. Plasmid containing cDNA for the NAV 1.4 alpha subunit of the human skeletal muscle Na channel was linearized, and capped cRNAs synthesized in vitro (Message Machine RNA polymerase kit; A bio, Austin TX). RNA was purified with an RNAid kit (BiolOl, Vista, CA). Individual oocytes were injected with cRNA (50 nl) and maintained at 18°C in frog saline solution (96 mM NaCl, 1 mM KCl, 1 mM

CaCl₂, mM MgCl₂, 10 mM Hepes, ImM theophylline, 2 mM Na pyruvate, pH 7.4, 50U/ml penicillin G, and 50 ug/ml streptomycin.

Electrophysiological recordings were performed at 2 days post- cRNA injection. Sodium channel currents were recorded from oocytes with a two-electrode voltage clamp using a Geneclamp 500B amplifier (Axon Instruments, Foster City,

CA). Voltage-measuring and current passing electrodes were filled with 3 M KCl and adjusted to resistance of 0.3 to 1 M. Currents were sampled at 5 kHz and filtered at 1-

2 kHz. Oocytes were perfused continuously with an external solution containing 96 mM NaCl, 2 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, pH 7.4. Oocytes were clamped at -70 mV and step depolarized to -20mV to activated the channels. Compounds were tested with five (5) replicates, and each experiment was repeated in triplicate.

Example 120 Percent Inhibition of Substituted Anilides and Benzamides at 1 mM concentration in the Sodium Channel Blockade Assay

Example ICsn (uM) % Inhibition (1 mM) SEM(%) Lidocaine 290 98 9 60 2 2 47 308 86 7 11 10 8 15 3 2 7 7 3 18 8 8 19 4 4 20 44 10 61 0 0 12 0 0 13 15 14 79 10 16 261 88 4

Claims

CLAIMS The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 1. A compound of the formula 1

wherein: X and Y are independently selected from the group consisting of NH, O, S0₂, and CO; n is 1-5; W and Z are independently selected from the group consisting of H, NH, NR where R is alkyl or alkenyl, alkenyl, substituted alkenyl, O, and CH₂; provided that when Z is H, Rj-W is absent and when W is absent, RI is bonded directly to Z; A and B are independently selected from the group consisting of H, NH, CH₂ and CO provided that when A is H, R₆-B is absent and when B is absent, R₆ is bonded directly to A; Ri and Re are independently selected from the group consisting of hydrogen, alkylheterocycle, alkylaryl, substituted alkylaryl, biaryl, arylalkyl, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkoxyaryl, substituted arylalkyl and substituted alkyl; R₂ and R3 are independently H or CH₃; R₄ and R₅ are hydrogen or loweralkyl or R and R₅ can be linked such that a nonaromatic cyclic ring is formed having 2-10 atoms selected from C, O, S and N where the ring can be optionally substituted with alkyl, heterocycle, or aryl groups; and the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein: A and Z are H; R₂ and R are methyl; X is NH; Y is CO; n is 1 and * and R₅ are taken together to form 4-phenylpiperazine.

3. The compound of claim 1 wherein: A and Z are H; R₂ and R3 are methyl; X is NH; Y is CO; n is 1 and R4 and R5 are taken together to form 4-(2-pyridinyl)piperazine.

4. The compound of claim 1 wherein: A and Z are H; R₂ and R₃ are methyl; X is NH; Y is CO; n is 1 and R* and R5 are taken together to form 4-piperidinopiperadine.

5. The compound of claim 1 wherein: A is H; Z is NH; W is CH₂; Ri is PhCH₂CH₂CH₂; R₂ and R₃ are methyl; X is NH; Y is CO; n is 1 and R₄ and R₅ are ethyl.

6. The compound of claim 1 wherein: A is H; Z is H; W is CO; Ri is CH₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH2CH₂; R₂ and R₃ are methyl; X is NH; Y is CO; n is 1 and _t and R₅ are taken together to form N- methylhomopiperazine.

7. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

8. An aerosol formulation for the prevention and treatment of pulmonary inflammation in asthma patients, said formulation comprising from about 10 mg to about 500 mg of at least one compound of claim 1 prepared as aqueous solution liposomes or microscopic particles or other suitable carrier suspended in about 5 ml of solution containing about 0.225% (w/v) of sodium chloride; said formulation having a pH between about 5.0 and 7.0; wherein said formulation is to be administered by aerosolization using a jet, ultrasonic, pressurized, or vibrating porous plate nebulizer able to produce predominantly aerosol particles between 1 and 5 μ .

9. An aerosol formulation for the prevention and treatment of pulmonary inflammation in asthma patients, said formulation comprising from about 10 mg to about 500 mg of at least one compound of claim 1 prepared as a dry powder for aerosol delivery in a physiologically compatible and tolerable matrix; wherein said formulation is to be administered by aerosolization using a dry powder inhaler able to produce predominantly aerosol particles between 1 and 5 μ .

10. An aerosol formulation for the prevention and treatment of pulmonary inflammation in asthma patients, said formulation comprising from about 10 mg to about 500 mg of at least one compound of claim 1 as a lyophihzed powder for reconstitution as a 5 ml solution containing about 0.225%) (w/v) of sodium chloride; said formulation having pH between about 5.0 and 7.0; wherein said formulation is to be administered by aerosolization using a jet, ultrasonic, or vibrating porous plate nebulizer able to produce predominantly aerosol particles between 1 and 5 μ .

11. A method for the prevention and treatment of pulmonary inflammation comprising administering to a patient in need of such treatment an effective amount of an aerosol formulation comprising about 10-500 mg of at least a compound of claim 1.

12. A method for the prevention and treatment of pulmonary inflammation comprising administering to a patient in need of such treatment an effective amount of an aerosol formulation comprising about 10-500 mg of at least one compound of claim 1 in combination with a β-agonist to be delivered as a mixture or sequentially by aerosol.