MXPA99011344A - Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith - Google Patents

Abstract

Se proporcionan los compuestos que tienen actividad agonista opiode kappa, las composiciones que las contienen y el método de utilizarlos y método de utilizarlos como analgésicos y agentes anti-pruríticos. Los compuestos de las fórmulas (I), (II), (III) y (IV) tienen estructuras en donde X1, X4, X5, X7, Xg;R, R2, R3, R4;Y Y, Z y n son como se describen en la especificación.

Description

KAPPA AGONISTA COMPOUNDS, PHARMACEUTICAL FORMULATIONS AND METHOD OF PREVENTION AND TREATMENT OF PRURITO WITH THE SAME DESCRIPTION OF THE INVENTION This application is a divisional of the application Serial No. 08 / 891,833, filed on July 14, 1997 which in turn is a continuation in part of the application Serial No. 08 / 796,078, filed on 5 February 1997, which in turn is a continuation in part of the application Serial No. 08 / 612,680, filed March 8, 1996. This invention relates to compounds, to processes of their preparation, to pharmaceutical compositions that they already contain their medical use as agonists in kappa opioid receptors. The present invention also relates to compositions and methods for the treatment and / or prevention of itching, also known as pruritus, which has many causes. The compositions that are formulated for topical and systemic administration, contain kappa opiate receptor agonists that are substantially devoid of effects on the central nervous system, and, thus, have a small amount, if no potential to produce side effects associated with kappa receptor agonists. opiate that act centrally. A) Kappa- (K) receptor agonists as analgesics Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high affinity receptors. It has been shown by researchers that there are at least three types of important opioid receptors in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (μ), delta (d) and kappa (K), have distinct, anatomical pharmacological profiles and distributions. [See, for example: Wood, P.L., Neuropharmacology, 21, 487-497, 1982; Simon, E., J. Med Res. Rev., 11, 357-374, 1991; Lutz et al., J. Recept. Res. 12, 267-286; and Mansour et al., Opioid I, ed. Herz., A. (Springer, Berlin) pp. 79-106, 1993.] The d receptors are abundant in the CNS and mediated analgesia, gastrointestinal motility and various hormonal functions. The μ receptors bind drugs similar to morphine and mediate the opiate phenomenon associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and various neuroendocrine effects. The K receptors have a broad distribution in the CNS and mediate a spectrum of functions that include drinking modulation, water balance, food consumption, bowel motility, temperature control and various endocrine functions. They also produce analgesia. [See, for example: Leander et al., J. Pharmacol. Exp. Ther. 234, 463-469, 1985; Morley et al., Peptides 4, 797-800, 1983; Manzanares et al., Neuroendocrinology 52, 200-205, 1990; and Iyengar et al., J. Pharmacol. Exp. Ter. , 238, 429-436, 1986.] The most clinically used opioid analgesics such as morphine and codeine act as μ receptor agonists. These opioids have well-known, undesirable and potentially dangerous side effects that form dependence. Compounds that are K receptor agonists act as analgesics through interaction with opioid K receptors. The advantage of these agonists over classical μ receptor agonists, such as morphine, consists in their ability to cause analgesia while being devoid of situational effects such as morpholine and risk of addiction. A large number of classes of compounds that act as agonists at opioid K-receptors have been described in the art including the following illustrative classes of compounds. U.S. Patent No. 4,065,573 discloses ketal compounds of 4-amino-4-phenylcyclohexane having analgesic activity. U.S. Patent No. 4,212,878 describes phenylacetamide derivatives having analgesic properties and risk properties of reduced physical dependence, relative to morphine and methadone.

U.S. Patent No. 4,145,435 describes N- (2-amino-cycloaliphatic) -phenylacetamide compounds having analgesic activity and narcotic antagonist activity. U.S. Patent No. 4,098,904 discloses N- (2-amino-cycloaliphatic) -benzoamides and naphthamides useful in relieving pain. U.S. Patent No. 4,359,476 describes substituted cycloalkane amides useful as analgesics and which have a low risk of abuse. US Patent No. 4,438,130 describes 1-oxa-, aza- and thia-spirocyclic compounds -which have analgesic activity, low physical dependence and risk properties of abuse and few dysphoric inducing properties. U.S. Patent No. 4,663,343 discloses substituted naphthalenyloxy-1,2-diaminocyclohexylamides as analgesics. U.S. Patent No. 4,906,655 discloses 1,2-cyclohexylaminoarylamides having high kappa-opioid affinity, selectivity and potency, and useful as analgesics, diuretics, anti-inflammatories and psychotherapeutic agents. B) Kappa (K) receptor agonists as Anti-Pruritic Agents The prior art has investigated the physiology and treatment of pruritus as illustrated below.

Pruritus is a well-known sensitive state associated with the desire to scratch. As with pain, pruritus can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. In addition to the difference in the sensitive quality of pruritus and pain, they also differ in that (1) itching, unlike pain can only be evoked from the superficial layers of the skin, mucosa, and conjunctiva, and (2) pruritus and Pain usually does not occur simultaneously from the same dermal region; in fact, moderate painful stimuli, such as scratching, are effective in eliminating pruritus. In addition, the application of histamine to the skin produces itching but not pain. The pruritus and pain are also dissociated pharmacologically: the pruritus seems to be insensitive to opiate and treatment with nonsteroidal anti-inflammatory (NSAID), which are effective in the treatment of pain. Although the pruritus and pain are of a class in which both are modalities of nociception transmitted by small C fibers without myelomas, they show that pruritus is not only a variety of low threshold pain that is overwhelming. Pruritus leads to reflex or urgency of scratching; the pain leads to elimination. Removal of the epidermis eliminates itching but causes pain. Analgesics, particularly opioids, relieve pain but they frequently cause itching (see, for example J. Es.

Acad. Derm. 24: 309-310, 1991). There can be no doubt that pruritus is of primary clinical importance; Most systemic and skin diseases are accompanied by persistent or recurrent pruritus attacks. Current knowledge suggests that pruritus has several characteristics in common with pain but also exhibits disconcerting differences (see, for example, W. Magerl, IASP Newsletter, pp.-4-7, Sept / Oct 1996). McMahon et al (TINS, Vol., 15, No., 12, pp.-497 501, 1992) provides a description of the stimuli (Table a) and a comparison of the established characteristics of pruritus and pain (Table b): Table a Stimuli that can excite or increase the itch Mechanical Physicists. Touch light, pressure, suction. Thermal Heating. Electric . Focal transcutaneous repetitive stimulation, transcutaneous constant current stimulation, intraneural microstimulation. Chemical Non-specific irritants. acids, alkalis. Inflammatory mediators Histamine, kallikrein, bradykinin, prostaglandins.

Substances that release histamine. Compound-48/80, protamine, C3a. Peptidase Mucunain, papain, trypsin, mast cell chymase Neuropeptides. Substance P, vasoactive intestinal polypeptide, neurotensin, secretin. Opioids Morphine (ß-endorphin, encephalitis analogs) Table b Ccxtparation of the established characteristics of pruritus and pain PRURITY PAIN Psycho physiology Tissue Skin Mucosal membranes Most tissues Stimuli See Table a Many stimuli intraneural stimulation Occasionally Yes Sensations Secondary Ochinesis (Skin With Itching) Hyperalges-Psychogenic Modification Pronounced Present Contrast Stress Scratching, pain, cooling Tactile stimuli cooling Neurophysiology Primary afferent neurons C- and Ad-Fiber fibers C- and £ d- Irritation size Large Small Spinal trajectory Anterolateral eunculus Anterolateral funcle Protective reflexes, Scratching, sneezing Flexion, preservation Autonomic reflexes Yes Yes Pharmacology Capsaicin sensitivity Yes Chemogenic pain; NSAID sensitivity Probably not Yes Morphine sensitivity No Yes Abbreviation: NSAIDs, non-steroidal anti-inflammatory drugs.

The experimental focal pruritus stimuli are surrounded by a halo of apparently unaffected tissue where light tactile stimuli are capable of producing similar pruritus sensations. The term irritated skin or alochinesis have been coined for these secondary sensations that are reminiscent of the characteristics of secondary hyperalgesia that evolves around a painful focus. A crucial observation is that itching and pain do not normally coexist in the same region of the skin and a mild noxious stimulus such as scratching is in fact the most effective individual way to eliminate itching. This abolition of pruritus can be prolonged by producing an "antipruritic state." Although moderate scratching is often not painful, microneurographic records of humans have directly determined that such stimuli are among the most common forms. effective to stimulate nociceptive afferents without cutaneous myeloma. (See, for example: Shelly, WB and Arthur, RP (1957) Arch. Derma tol. 76, 296-323; Simone, DA et al. (1987) Soma tosens, Res. 5, 81-92; Graham, DT , Goodell, H. and Wolff, HG (1951) J. Clin.Research 30, 37-49; Simone, DA, Alreja, M., and LaMotte, RH (1991) Soma tosens, Mot. Res. 8, 271 279; Torebjórk, E. (1985) Philos, Trans .. R. Soc. London Ser. B 308, 227-234; and Vallbo, AB, Hagbarth, KE, Torebjork, HE and Wallin, BG (1979) Physiol. 59, 919-957) Physiologically, there is evidence that substance P released from the nociceptive terminals can cause the release of histamine from mast cells. Activation of mast cells, with release of pruritrogen histamine, occurs in immediate-type hypersensitive diseases, such as anaphylactic reactions and urticaria. Urticarial rashes are distinctly pruritic and can involve any portion of the body, and have a variety of causes beyond hypersensitivity, including physical stimuli such as cold, solar radiation, exercise, and mechanical irritation. Other causes of prutitus include: tick, the larval form of which secretes the substance that creates a red papule that causes intense itching; secondary hyperparathyroidism associated with chronic kidney disease; migrans of cutaneous larva, caused by larva excavator of animal hookworms; dermal myiasis, caused by horsefly worms that can affect riders; onchocerciasis ("river blindness") caused by filarial nematodes; pediculosis, caused by infestations of lice; enterobiasis (intestinal worm) infestations that affect approximately 40 million Americans, particularly children of school age; schistosome dermatitis (swimmer's itch); psoriasis; poison ivy and astheatotic eczema ("winter pruritus"). The role of histamine or other endogenous pruritógenes in mediating pruritus associated with these and other pruritus conditions, such as atopic dermatitis, is not yet well established. For atopic dermatitis, in particular, it seems that pruritus not inhibited by antihistamines, but by cyclosporin A, a drug that inhibits the production of cytokines that have been proposed as potential pruritogens. Current therapies for the treatment of pruritus include a variety of topical and systemic agents, such as steroids, antihistamines, and some psychotherapeutic tricyclic compounds, such as Doxepin hydrochloride. Many such agents are listed in PDR Generics (see Second Edition, 1996, p., Cv for a listing of such agents). The limitations of these agents are well known in medical practitioners, and are summarized in the "Warnings" and "Precautions" sections for the individual agents listed in PDR Generics. In particular, the total ineffectiveness of antihistamines is well known, but antihistamines are frequently used in dermatology to treat pruritis due to urticaria, atopic dermatitis, contact dermatitis, psoriasis, and a variety of other conditions. Although sedation has been a common side effect of conventional antihistamines administered systemically, a new generation of antihistamines has been developed to be non-sedating, apparently due to its inability to cross the blood-brain barrier. Intravenous administration of opiate analgesics, such as morphine and hydromorphone, has been associated with prutitus, urticaria, other skin rashes, and hives and inflammation on the vein that is injected. It is believed that these pruritus and pruritus-related reactions are due to a property of histamine release from these opiates, by degranulation of mast cells. It is thought that these opiates act in the mu subtype of the opiate receptor, but the possibility of interactions in the other subtypes of Main opiate receptors (delta and kappa) can not be excluded since these and other pruritogenic analgesics are not purely agonists. Cell sites of the receptor type or types that mediate the effect of pruritus are unknown, although the mast cell is a possible candidate since opiates cause histamine release from these cells. However, some researchers have suggested that the frequent inability of antihistamines to block morphine-induced pruritus suggests a non-histaminergic mediation of the opiate-induced pruritus mechanism - which could involve central opiate receptors. Although intravenous morphine results only occasionally in generalized pruritus (in approximately 1% of patients), pruritus is more prevalent in opiate analgesia with epidural (8.5%) or intraspinal (45.8%) administration. (See, for example: Bernstein et al., "Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochoride," The Journal of Investigative Dermatology, 78: 82-83, 1982; Ballantyne et al., "Itching after epidural and spinal opiates." , Pain, 33: 149-160, 1988.) To date, treatment with opiates has not only proven to be useless in the treatment of pruritus, but it seems to exacerbate pruritus in mammals. The compatible findings from studies in humans indicate that, either by central or peripheral mechanisms, the opiates seem to promote rather than prevent pruritus, and that opiate antagonists have antipruritic activity. Clinical studies in humans have generally shown that opiates cause pruritus and there is evidence that these effects can be reproduced in animal models, where the pruritus sensations themselves can not be reported, but the scratching behavior can be observed. (See, for example: Tomas et al., "Microinjection of morphine into the rat medullary dorsal horn produces a dose dependent increase in facial-scratching", Brain Research, 695: 267 270, 1996; Tomas et al., "Effects of central administration of opioids on facial scratching in monkeys ", Brains Res., 585: 315-317, 1992; and Tomas et al.," The Medullary dorsal horn: A site of action of opioids producing facial scratching in monkeys ", Anesthesiology, 79: 548-554, 1993). It has now surprisingly been discovered that kappa agonist compounds which are substantially devoid of central nervous system effects, in pharmaceutically acceptable vehicles by systemic and topical formulations possessing antipluritic activity in addition to the anti-hyperalgesic activity. Compounds having opioid kappa agonist activity, compositions containing them and method of using them as analgesics. The present invention further provides compositions comprising compounds having kappa opioid agonist activity for the prevention and treatment of pruritus. In its composite aspect, the present invention provides a compound of formula I, II, III and IV, or a pharmaceutically acceptable salt thereof. The compounds of formula (I) have the following structure: where n = l-3, where n = 1 is preferred Ri and R 2 are independently = CH 3; - (CH2) m, where m = 4-8, m = 4 is more preferred; -CH2CH (OH) (CH2) 2-; CH2CH (F) (CH2) 2-; - (CH2) 20 (CH2) 2-; or - (CH2) 2CH = CHCH2-; Ar = unsubstituted or mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of halogen, OCH3, S02CH3, CF3, amino, alkyl, and 3,4-dichlor; benzothiophenyl; benzofuranyl; naphthyl; diphenylmethyl; or 9-fluorene; Z is -P (0) (OBn) 2; -P (0) (0H) 2; - (CH2) PC (0) NHOH; - (CH2) pC02H; -S02CH3; -S02NH2; -CO (CH2) PCH (NH2) (C02H); -C0CH (NH2) (CH2) pC02H; -C02CH3; -C0NH2; - (CH2) p0 (CH2) pC02H; - (CH2) pO (CH2) pCONHOH; - (CH2) pNHS02CH3; - (CH2) PNHC (S) NHCH (C02H) (CH2) pC02H; - (CH2) pS03H; or or Z is where X2 - -COjH; -NHSO2CH ,; NHP (O) (OBn) 2; NHP (O) (OH) 2; -OP (O) (OBn) 2; or OP (O) (OH) 2; X and Y are independently -CH2NHS02CH3, -CH2 HP (O) (OBn) 2, -CH2NHP (O) (OH) 2. -CH2OP (O) (OBn) 2. -CH2OP (O) (OH) 2, - (CH2) qO (CH2) qCO2H, - (CH2) qO (CH2) qSO3H, - (CH2) qO (CH2) qCHNHOH, -CH2NHC (S) NHCH (CO2H) ( CH2) qCO2H or wherein r = 1-20 R4 = -H or -Ac X3 = -CO2H; -NHS02CH3; -NHP (O) (OBn) 2; -NHP (O) (OH) 2; -OP (O) (OBn) 2; or -OP (O) (OH) 2 The compounds of formula II have the following structure where n = l-3, where n = l is preferred Ri and R2 are independently = CH3; - (CH2) m, where m = 4-8, m = 4 are more preferred; -CH2CH (OH) (CH2) 2-; CH2CH (F) (CH2) 2-; - (CH2) 20 (CH2) 2-; or - (CH2) 2CH = CHCH2-; Ar = unsubstituted or mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of halogen, 0CH3, S02CH3, CF3, amino, alkyl, and 3,4-dichlor; benzothiophenyl; benzofuranyl; naphthyl; diphenylmethyl; or 9-fluorene; where t = 1-20 R5 = -H O -Ac Xe s -C02H; -NHSO2CH3; -NHP (0) (OBn) 2; -NHP (0) (OH) 2; -OP (O) (OBn) 2; or -OP (0) (OH) 2.

The compounds of formula III have the following structure: where n = l-3, where n = l is preferred? R? and R2 are independently = CH3; _ (CH2) m, where m = 4-8, m = 4 is more preferred; -CH2CH (0H) (CH2) 2-; CH2CH (F) (CH2) 2-; - (CH2) 20 (CH2) 2-; or - (CH2) 2CH = CHCH2-; Ar = unsubstituted or mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of halogen, 0CH3, S02CH3, CF3, amino, alkyl, and 3,4-dichlor; benzothiophenyl; benzofuranyl; naphthyl; diphenylmethyl; or 9-fluorene; X7 is -NHS02CH3; -NHP (O) (OBn) 2; -NHP (0) (OH) 2; - (CH2) uNHS02CH3; - (CH2) UNHC (S) NHCH (C02H) (CH2) uC02H; -CONHOH; or - (CH2) uCONHOH; where u = 1-5 or X is Rß = Xß = The compounds of formula IV have the following structure: where n = l-3, where n = l is preferred Ri and R 2 are independently = CH 3; - (CH2) m, where m = 4-8, m = 4 is more preferred; -CH2CH (OH) (CH2) 2-; CH2CH (F) (CH2) 2-; - (CH2) 20 (CH2) 2-; or - (CH2) 2CH = CHCH2-; R3 and R4 are independently H; OCH3; I rent; or ? 9 = 1-4 replaced in selected from the groups consisting of -halogen, -CF3; -OCH3; -S02NH (CH2) qC02H; -CONH (CH2) qC02H; -NH2; -NHS02CH3; -NHP (O) (OBn) 2; -NHP (O) (0H) 2; NH (CH2) qC02H; -S02CH3; -OP (O) (OBn) 2; -OP (0) (0H) 2; -C02H; -0 (CH2) qC02H; -0 (CH2) qS03H, -O (CH2) qOP03H2; where q = l-20 or Xg is where t = 1-20 R5 = -H or -Ac X6 = -C02H; -NHS02CH3; -NHP (O) (OBn) 2; -NHP (O) (OH) 2; -OP (O) (OBn) 2; or -OP (O) (OH) 2. The peripherally acting K agonists can be prepared by the adhesion of polar groups to agonists without selective K-peptide opioids, such as the arylacetamides. In design, ligands that act peripherally, the introduction of polar groups can result in either retention or increased antinociceptive potency and selectivity and can also increase the sufficient ligand polarity to reduce or eliminate CNS penetration when crossing the blood-brain barrier (BBB). In this way, the identity and position of the polar group or groups is important. Using the prototypic aryl acetase, U50,488, as an example, the pharmacopoeial arylacetamide can be divided into three regions: the aromatic region, the central region, and the amine region. All three regions represent potential positions for the adherence of the polar groups. central region (-) U50.488 amine region aromatic region The compounds of the formula (I) of the present invention are made as follows. A number of new compounds were made based on the class of arylacetamides reported by Glaxo (J. Med. Chem. 1993, 36, 2075). Specifically, compound 1 can be deproed to produce intermediate 2, which can be derivatized by the adhesion of a variety of polar groups (Scheme 1).

The 3'-substituted series can be prepared by Scheme 2. The reduction of the intermediate Schiff base formed during the cyclization to 6 is expected to be stereoselective due to the directing effect of the attached hydroxymethyl group. Both intermediates 11 and 12 can be derivatized to confer peripheral selectivity. The 5'-substituted series can be prepared by means of Schemes 3 and 4. Starting from Nt-Boc-O-MEM-D-serine, the 5 '- (S) series can be prepared, and starting from Nt-Boc-O -MEM-L-serine gives the preparation of the series 5'- (R) • Scheme 1 ? - Analogs shown in I formula I where Ar, Ri R2, and n were defined in the formula I. E 9 10 11 Analogs shown in Figure I. where Ar, Ri, R2, and n are as defined in formula I. Scheme 3 19 20 21 Analogs shown in formula I. 22 where Ar, Ri, R2 and n are as defined in formula I Scheme 4 the formula I. where Ar, Ri, R2 and n are as defined in formula I. Using the Schemes 1-4 the following example compounds are made. - Intermediate 3 can be treated with t-butyl bromoacetate and deproed to produce acid. { 4- [1- (3, 4-dichlorophenyl) acetyl-2R- (1-pyrrolidinyl) -methyl] piperazinyl} -acetic (26).

- Intermediate 3 can react with methanesulfonyl chloride to produce [1- (3,4-dichlorophenyl) acetyl-4-methanesulfonyl-2R- (1-pyrrolidinyl) methyl] piperazine (27). - Intermediate 3 can be coupled to N-t-Boc-L-aspartic acid-β-benzyl ester and deproed to produce [4-S-aspartic acid-a-amido-1- (3,4-dichlorophenyl) acetyl-2R- (1-pyrrolidinol) methyl] piperazine (28). - Intermediate 11 can be treated with t-butyl bromoacetate and deproed to produce methyl- [2R- (0-2-acetic acid) hydroxymethyl-4- (3,4-dichlorophenyl) acetyl-3R- (1-pyrrolidinyl) methyl ] -1-piperazinecarboxylate (29). - Intermediate 11 can be coupled to Nt-Boc-L-aspartic acid-β-benzyl ester and deproed to produce methyl- [2R- (0-2-aspartic acid-acetyl) hydroxymethyl-4- (3, 4- dichlorophenyl) acetyl-3R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (30). Intermediate 12 can be treated with methanesulfonyl chloride to produce methyl- [4- (3,4-dichlorophenyl) acetyl-2R- (N-methanesulfonamido) aminomethyl-3R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (31) ). Intermediate 12 can be coupled to 2S-isothiocyanato-succinic acid-dibenzyl ester and deproed to produce methyl-. { 4- [3,4-dichlorophenyl] acetyl-3R- [1- pyrrolidinyl] methyl-2R- [N- (succinic acid-2S-thioureido)] aminomethyl} -l-piperazinecarboxylate (32). Intermediate 21 can be treated with t-butyl bromoacetate and deproed to produce methyl- [2S- (0-2-acetic acid) idroxymethyl-4- (3,4-dichlorophenyl) acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (33). - Intermediate 21 can be coupled to N-t-Boc-L-aspartic acid-β-benzyl ester and deproed to produce methyl- [2S- (O-S-aspartic acid-acetyl) idroxymethyl-4- (3, 4-dichlorophenyl) acetyl-5R- (l-pyrrolidinyl) methyl] -1-piperazinecarboxylate (34). - Intermediary 22 can be treated with methanesulfonyl chloride to produce methyl- [4- (3,4-dichlorophenyl) acetyl-2S- (N-methanesulfonamido) aminomethyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (35) ). - Intermediary 22 can be coupled to 2S-isothiocyanato-succinic acid-dibenzylester and deprotected to produce methyl-. { 4- [3,4-dichlorophenyl] acetyl-5R- [1-pyrrolidinyl] methyl-2S- [N- (succinic acid-2S-thioureido)] -aminomethyl} -1-piperazinecarboxylate (36). The 2R isomers of 33-34 and 35-36 can be prepared from the intermediates 24 and 25, respectively to produce Methyl- [2R- (0-2 -acetic acid) hydroxymethyl-4- (3,4-dichlorophenyl) acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (37). Methyl- [2R- (O-S-aspartic acid-acetyl) hydroxymethyl-4- (3,4-dichlorophenyl) acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (38). Methyl- [4- (3, 4-dichlorophenyl) acetyl-2R- (N-methanesul-fonmido) aminomethyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate (39). Methyl-. { 4- [3,4-dichlorophenyl] acetyl-5R- [1-pyrroli-dinyl] methyl-2R- [N- (succinic acid-2S-thioureido)] amino-methyl} -l-piperazinecarboxylate (40). The corresponding structural formulas are shown in the following.

The compounds of the formula II of the present invention are made by peripheralization by substitutions of the benzo portion of the tetrahydronaphthyl ring of the DuPont series of the compounds with polar groups.

The starting material or precursors of the starting material are commercially available and thus allow for the regiospecific substitutions of the tetrahydronaphthyl ring (Scheme 5). While the derivatives 5-hydroxytetralone, 6-hydroxytetralone, 7-hydroxytetralone, and 7-aminotetralone are readily available, 5-aminotetralone 5-hydroxytetralone (J. Org. Chem. 1972, 37, 3570) could be prepared. The tetralone derivatives can be converted to dihydronaphthyl derivatives and subjected to chemistry similar to that used in the preparation of the U50,488 derivatives. The resulting compounds are racemic mixtures that can be derivatized to confer peripheral selectivity. If necessary, the final compounds or one of the intermediates can be resolved to test both enantiomers. Scheme 5 43 44 Scheme 6 48, X5 = -H, X4 - -OMe (±) -52, X5 -H, X4 = -OMe 49, X5 = -OMe, X4 = -H (±) -53, X5 -OMe, X? = - H 50, X5-NPht, X4 = -H (±) -54, X5 -NPht, X < = -H 51, X5 »-H, X4« -NPht (±) -55, X5 -H, X4 = -NPht (±) -60, X5 = -H, X4 - OMe (±) -56, X < = -H, X4 = -OMe (± hßl.X ^ -OMcX ^ -H (±) -57, X5 = -OMe, X4 = -H (±) -62, X5 = -NPht, X4 - -H ( ±) -58, X5 = -NPht, X4 - -H (±) -63, X5 «-H, X4 = -NPht (±) -59, X5 = -H, X, * -NPht (±) -64, X5 «-H, X --OH (±) -68, X5 - H, X4 - - CO2H (± H» 5, X5 - OH, X4 - H (±) - 69 , X5 - -H, X4 - -SO2C1 (±) -66, X5 «-NH2, X4 - H (±) -70, X5 - -CO2H, X4 = -H (±) -67, X5 - -H , X., - -NH2 (±) -71, X5 - -SO2Cl, X4 = -H Analogs as defined in Formula II Scheme 7 1) NaNOi H2SO4 (aq) ArNH2 ** - ArOH 81 lJNaNO, Kl ROH A? n2 A X ^ R Ni (CO) 4 82 DNaNOz CuCN H3O + AJG G12"** ArCN - ArCOzH 83 84 | H2 ArCI- I2NH2 85 PdCOAcfe ArN7 BF4 '+ CO »- AiCOOH NaOAc 84 CuCl2 AtN2 BF4 '+ S? 3 * - ArSOiCl HC1 86 , 82,84,85,86 le * Analogs shown in formulas II-IV wherein Ri R2, and n are as defined in formula I. Following the procedure shown in Schemes 5-7, the following example compound was prepared. - The intermediate (±) -64 can be treated with t-butyl bromoacetate and deprotected to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4 -tetrahydro-5- (0-2-acetic acid) -hydroxy-2- (1-pyrrolidinyl) naphthyl] acetamide (72) - The intermediate (±) -65 can be treated with t-butyl bromoacetate and deprotected to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4 -tetrahydro-7- (0-2-acetic acid) -hydroxy-2- (1-pyrrolidinyl) naphthyl] acetamide (73) - The intermediate (±) -66 can be treated with ethanesulfonyl chloride to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1,2,3,4-tetrahydro-7 - (N-methansul-fonamido) -amino-2- (1-pyrrolidinyl) naphthyl] acetamide (74). The intermediate (+) - 67 can be treated with methanesulfonyl chloride to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1,2,3,4-tetrahydro-5- (N-methansul-fonamido) -amino-2- (1-pyrrolidinyl) naphthyl] acetamide (75).

- The intermediate (±) -68 can be treated with glycine benzyl ester and deprotected to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4-tetrahydro-5- (N-2-acetic acid) -carboxarnido-2- (1-pyrrolidinyl) naphthyl] ace-tamide (76). - The intermediate (±) -69 can be treated with glycine benzyl ester and deprotected to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4-tetrahydro -5- (N-2-acetic acid) -sulfonamido-2- (1-pyrrolidinyl) naphthyl] acetamide (77). The intermediate (±) -70 can be treated with glycine benzyl ester and deprotected to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4-tetrahydro- 7- (N-2-acetic acid) -carboxamido-2- (1-pyrrolidinyl) naphthyl] acetamide (78). The intermediate (±) -71 can be treated with glycine benzyl ester and deprotected to produce (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4-tetrahydro- 7- (N-2-acetic acid) -sulfonamido-2- (1-pyrrolidinyl) naphthyl] acetamide (79).

The compounds of the formula III of the present invention are prepared by substituting the central phenyl ring with polar groups.

R1, R2, X7 and n are as in Formula lll Compound 80 and the analogs undergo a variety of reactions involving diazonium by the adhesion of the polar groups (Scheme 7).

Using the procedure shown in Scheme 7, the following compounds are made. - Intermediate 81 can be treated with dibenzylphosphoryl chloride followed by deprotection to produce 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1-3- (O-phosphoryl) hydroxypheni1-2- (1-pyrrolidinyl) ethyl} acetamide (87). - Intermediate 85 can be coupled to methanesulfonyl chloride to produce 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1- [3- (N-methanesulfonamido) aminomethyl] phenyl-2- (1-pyrrolidinyl) ethyl} acetamide (88). Intermediate 85 can be coupled to 2'S-isothiocyanate succinic acid and deprotected to produce 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1- [3- (N-succinic acid-2S-thioureido) aminomethyl] phenyl-2- (1-pyrrolidinyl) ethyl} acetamide (89). - Intermediate 80 can be treated with dibenzylphosphoryl chloride followed by deprotection to produce 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1-3- (N-phosphoramido) aminophenyl-2- (1-pyrrolidinyl) ethyl} acetamide (90).

The compounds of the formula IV can be prepared by means of Scheme 8. Scheme 8 91 92, X = 2.3, or 4NO2 93, X = 2.3, or 4 OH 94, X = dihalo and substituted nitro Analogs wherein Ri, R2, R3, and R4 are defined in formulas III and IV. The diamino intermediate 91 (J. Med. Chem. 1990, 33, 286) can be coupled to the different regioisomers of nitrophenylacetic acid which are all commercially available. The reduction of the nitro group provides an amino group for the adhesion of polar groups. Alternatively, the amino intermediates 95-97 readily undergo diazonium chemistry which converts amino groups to carboxyl and sulfonyl chloride groups. This allows the polar groups to be adhered by the different linkers.

Following the procedure in Scheme 8, the following compounds are made. - Intermediary 96 can be treated with methanesulfonyl chloride to produce (-) - (5a, 7a, 8β) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro- [4,5] dec- 8-yl] -3- (N-methanesulfonamido) aminophenylacetamide (104). Intermediate 98 can be coupled to glycine benzyl ester and deprotected to produce (-) - "(5a, 7a, 8β) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro- [4,5] ] dec-8-yl] -3- (N-2-acetic acid) sulfonamidophenylacetamide (105) - Intermediate 99 can be coupled to glycine benzyl ester and deprotected to produce (-) - (5a, 7a, 8ß-N- methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro- [4, 5] dec-8-yl] -3- (N-2-acetic acid) carboxamidophenylacetamide (106).

The compounds of the above formulas may have one or more asymmetric carbon atoms. The stereochemically pure isomeric forms of the above compounds can be obtained, and the diastereomers isolated by physical separation methods, including, but not limited to, crystallization and methods chromatographic Transesteriomeric cis and trans racemates can also be resolved in their isomers. If the separated, active isomers can be identified by their activity. Such purification is not, however, necessary for the preparation of the compositions or practice of the methods herein. As used herein, the compounds provided herein also include pharmaceutically acceptable salts, acids and esters, of the same stereoisomers, and also metabolites or prodrugs thereof which possess analgesic activity but do not cause substantial CNS effects when administered. or applied. The metabolites include any compound that is produced by the administration of the compound and metabolism thereof. Following are the more detailed preparations of the compounds herein. Compounds of Formula I Preparatory for the compounds of formula I, the following intermediates were prepared.

-OH, OH MeOH, benzaldehyde -C02H (1) H2N "CO2H NaCNBH3, 24 Hr cr * MeOH, HCl (g) Reflux, 18 Hr i. CHClj, HCl (g) 2. NaHC03, H20 N-Benzyl-D-serine (l) 1: To a mixture of D-serine (25.0 g, 0.237 moles) and 200 L of anhydrous methanol was added sodium cyanoborohydride (11.95 g, 0.190 moles), while maintaining the temperature at 0 ° C with an ice bath. Then, he add benzaldehyde (26.5 mL, 0.261 mol) to the reaction flask, dropwise, at 30 ° C. The mixture was stirred for 60 hr at room temperature. Then, the mixture was filtered and rinsed with methanol (50 L). The white solid was dried in a vacuum oven at 40 ° C and 10 mmHg for 2 nights: 24.5 g. The filtrate was retained and the solvent was evaporated. This oil was passed through a column of silica gel (10% MeOH / CH2Cl2) and 3.4 g of the desired compound was isolated. The total amount of the product was 27.9 g (60.0% yield). 1 R NMR (DMSO-d 6) d 3.25 (m, 1 H, CH), 3.85 (m, 2 H, CH 2), 4.11 (d, 2 H, benzylic CH 2), 7.45-7.53 (m, 5 H, Ar H). Ref. (1) Ohfune, Y .; Kurokawa, N.,; Higuichi, N .; Saito, M .; Hashimoto, M.,; Tanaka, T. An efficient one-step reductive N-monoalkyation of a amino acids. Chemistry Letters, 1984, 441-444. N-Benzyl-D-serine Methylester (2): The hydrogen chloride (gas) was bubbled in anhydrous methanol for 10 min. Then, the solution was allowed to cool to room temperature. Then, N-benzyl-D-serine (24.6 g, 0.126 mol) was added to the reaction flask and refluxed overnight under dry nitrogen. Then, the solvent was evaporated and dissolved in dichloromethane (200 mL), and washed with a saturated solution of sodium bicarbonate. The dichloromethane layer was dried with magnesium sulfate and the solvent evaporated (23 g, 87.2% yield). XH NMR (CDC13) d 3.41 (d, 1H, CH), 3.52-3.80 (dd, 2H, benzyl), 3.69 (s, 3H, OMe), 7.27 (s, 5H, ArH). N- [(1,1-Dimethylethoxy) carbonyl-D-Ser- (O-Bzl) -N-benzyl-D-Ser-OMe (3): To a solution of N-boc-D-serine- (O- bzl) OH (15 g, 50.76 moles) in anhydrous dichloromethane (200 mL) was added HOBt (7.54 g, 55.8 mmol) at 0 ° C under dry nitrogen. Then, DCC (11.5 g, 55.7 mmol) in dichloromethane (100 mL) was added dropwise to the reaction flask. Then, this mixture was stirred for 1 hr. Then, N-benzyl-D-serine-OMe (10 g, 47.8 mmol) in dichloromethane (100 mL) was added dropwise to the reaction flask, then, it was stirred for 4 days, filtered and rinsed with dichloromethane (100 mL). ml). The white precipitate was DCU and HOBt. The filtrate was evaporated and redissolved in ethyl acetate (100 mL). Then, he let himself be precipitated, during the night. It was filtered and rinsed with ethyl acetate. Then, it was isolated on a column of silica gel (20% ethyl acetate / hexanes) to give an oil -17.3 g, 74.3% yield. *? NMR (CDC13) d 1.43 (s, 9H, t-Bu), 3.54 (t, 1H, OH), 3.72 (s, 3H, OMe), 3.75 (dd, 2H, CH2) 3.79 (dd, 2H, CH2) , 4.41 (d, 2H, benzylic CH2), 4.43 (d, 2H, benzylic CH2), 7.27-7.30 (m, 10H, ArH). (2R, 5R) -2- ((Benzyloxy) methyl) -5- (Hydroxymethyl) -4- (eylmethyl) -3,6-piperazinedione (4) 2: Hydrogen chloride (gas) was bubbled into the anhydrous chloroform (300 mL). Then, the dipeptide (3) (13.5 g, 27.7 mmoles) in chloroform (100 ml) was added to the reaction flask. The flask was closed and stirred for 64 hr. Then, a saturated solution (100 ml) of sodium bicarbonate was added and stirred vigorously for 48 hr. The cyclization was completed at this point. The organic layer was separated from the aqueous layer in a 1L separatory funnel. The product was isolated from a column of silica gel, eluting with dichloromethane-methanol-0.88 ammonia (96: 2: 2) to give (4) as an amorphous solid (6.0 g, 61.1% yield). 1H NMR (CDC13) d 3.72-3.96 (m, 7H), 3.97-5.24 (dd, 2H, benzylic CH2), 4.45 (dd, 2H, benzylic CH2), 7.15-7.30 (m, 10H, ArH); MS (FAB) m / e 355 (MH +). Ref. (2) Williams, T., M.; Ciccarone, T. M .; MacToogh, S.C. et al. 2-Substituted piperazines as constrained amino acids. J. Med Chem. 1996, 39.1345-1348. (2S, 5S) -2- ((Benzyloxy) methyl) -4- (phenylmethyl) -5- _ piperazinemethanol (5): A suspension of lithium-aluminum hydride (0.9 g, 23.7 mmol) in anhydrous tetrahydrofuran (40 mL ) was treated with a solution of piperazinedione 4 (2.1 g, 5.92 mmol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated to reflux for 24 hh and then stirred at room temperature for 12 hr. Water was added (10 mL) followed by aqueous sodium hydroxide (1N, 10 mL) and water (10 mL). The mixture was filtered, and the filtrate was evaporated to give 5 (1.67 g, 86.4% yield) as a viscous oil. XH NMR (CDC13) d 2.58 (dd, 2H, CH2), 2.61 (t, 1H, OH), 3.10 (dd, 2H, CH2), 3.25 (dd, 2H, CH2), 3.50 (dd, 2H, CH2) , 3.74 (s, 2H, CH2), 4.41 (dd, 2H, benzylic CH2), 7.20-7.30 (m, 10H, ArH). 2- [(Benzyloxy) methyl] -5 (hydroxymethyl) -4- (phenylmethyl) -1-piperazinecarboxylate of (2S, 5S) -Methyl (6) 3: _ A solution of 5 (1.67 g, 5.11 mmol) in acetonitrile (20 mL) was treated with a methyl chloroformate solution (0.532 g, 5.63 mmol) in acetonitrile (10 mL) at 0 ° C. The mixture was stirred at room temperature for 30 min and then the aqueous sodium carbonate solution (15 L) was added. The organic solvent was removed, and the aqueous residue was extracted with chloroform (3x10 mL). The combined organic extracts were washed with aqueous sodium carbonate solution (10 mL), dried, and evaporated to give 6 (1.52 g, 77.3% yield) as an oil. XH NMR (CDC13) d 2.54 (dd, 2H, CH2), 2.45 (t, 1H, OH), 2.72 (dd, 2H, CH2), 3.51 (dd, 2H, CH2), 3.67 (dd, 2H, CH2) , 3.69 (s, 3H, OMe), 3.81 (dd, 2H, CH2), 4.44 (dd, 2H, benzylic CH2), 7.17-7.31 (10H, ArH). 2- [(Benzyloxy) methyl] -5- [(1-pyrrolidinyl) methyl] -4- (phenylmethyl) -1-piperazinecarboxylate of (2S, 5S) -Methyl (7) 3: A solution of oxalyl chloride (0.545) mL, 6.24 mmol) in dichloromethane (10 mL) at -65 ° C was treated with a solution of dimethyl sulfoxide (1.14 mL, 16.0 mmol) in dichloromethane (5 mL) keeping the reaction temperature below -65 ° C. The mixture was stirred at -70 ° C for 10 min, and then a solution of piperazinemethanol (6: 2 g, 5.19 mmol) in dichloromethane (20 mL) was added in such proportion that the reaction temperature remained below -65. ° C. The reaction mixture was stirred at -65 ° C for 3 hr, and a solution of N-methylmorpholine (1.42 mL, 12.91 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at -20 ° C for 45 min and then washed with ice-cold hydrochloric acid (0.01 N, 100 mL and 50 mL), dried, evaporated, and placed in a high vacuum pump during the night. The residue was dissolved in methanol (10 L) and added to a solution of pyrrolidine (0.91 mL, 10.94 mmol) in methanol (10 L) at -10 ° C which was adjusted to pH 6.0 by the addition of methanolic hydrogen chloride . Sodium cyanoborohydride (0.67 g, 10.66 mmol) and 4-A molecular sieves (0.66 g) were added, and the mixture was stirred at room temperature for 18 hr. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in aqueous sodium carbonate (1M, 25 mL) and extracted with dichloromethane (2x50 mL). The product was isolated from a column of silica gel and eluted with dichloromethane-methanol (98: 2) to give 71.0 g, 23.0% yield). 1 H NMR (CDC13) 8 1.75 (m, 4 H, CH 2 CH 2), 2.46 (m, 3 H), 2.48 (m, 4 H, CH 2 CH 2), 2.55 (dd, 2H, CH2), 2.70-2.85 (m, 3H), 3.41 (dd, 2H, CH2), 3.69 (s, 3H, OMe) ', 4.10 (m, 1H), 4.20 (m, 1H), 4.41 (dd) , 2H, benzylic CH2), 7.10-7.31 (m, 10H, ArH); MS (FAB) m / e 438 (MH +). (3) Naylor, A .; Judd, D. B .; Lloyd, J. E .; Scopes, D. I. C; Hayes, A. G .; Birch, P. J. A potent new class of K- Receptor agonist: 4-substituted 1- (arylacetyl) -2- [(dialkylamino) methyl] piperazines. J. Med. Chem. 1993, 36, 2075-2083. 2- (Hydroxymethyl) -5 - [(1-pyrrolidinyl) methyl] -1-piperazinecarboxylate of (2S, 5S) -Methyl (8): A solution of (0.25 g, 0.571 mmol) in ethanol (200 mL) was hydrogenated over 10% palladium on carbon (Degussa type E101 NE / W) at 50 psi for 7 days, then filtered through celite and the filtrate was evaporated. (0.13 g, 0.5 mmol: 87% yield). 4- [(3,4-Dichlorophenyl) acetyl] -2- (hydroxy) methyl-5- [(1-pyrrolidinyl) -methyl] -1-piperazinecarboxylate of (2S, 5S) -Methyl (9): To one solution of 1, 1 '-carbonyldiimiazole (0.20 g, 1.26 mmol) in dichloromethane (10 mL) was added portionwise 3,4-dichlorophenylacetic acid (0.25 g, 1.26 mmol) and the resulting solution was stirred under nitrogen for 1 hr, room temperature. A solution of 8 (0.13 g, 0.5 mmol) in dichloromethane (10 mL) was added and the mixture was allowed to stand at room temperature for 18 hr. The reaction mixture was washed with sodium carbonate solution (2 N, 2 x mL), dried, and evaporated to give a viscous oil. This material was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) and treated with lithium hydroxide (42 mg, 1.0 mmol). The reaction mixture was removed, and the aqueous residue was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried and evaporated to give a colorless gum which was purified by flash column chromatography on silica gel, eluting with ethyl acetate-methanol (40: 1) to give 9 (155 mg, 70%) as a colorless foam. Using the intermediates denoted in the foregoing, the following compounds are prepared. Quiral compounds Example: 1 Hydrochloride [(R) -1 HCl] of (R) -4- (Phenylmethyl) -1 - [(3, 4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine ADL-01-0143-6 The compound (R) -1 HCl was prepared following the procedure of the literature3 in 54% yield; p.f. 168-170 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 1.95-3.00 (6H, m), 3.10-3.80 (9H, m), 4.35 (1H, m), 4.70 (1H,), 7.00 (1H, m), 7.30 (7H, m); MS (FAB) 448 (M + H) +; Anal. Cale, for C24H29C12N30.2HC1.H20: C, 53.64; H, 6.19; N, 7.82. Found: C, 53.69; H, 5.88; N, 7.49. Example 2 Hydrochloride [(R) -2HC1] of (R) -1-1 (3,4-dichlorophenyl) cetyl] -2- [(1-pyrrolidinyl) methyl] piperazine ADL-01-0047-9 The compound was prepared by the catalytic hydrogenation of (R) -1 HCl following the procedure described in the previous reference. The product was isolated as a clear base as a clear oil in 81% yield and the dihydrochloride salt was prepared from 1M ethereal HCl; ~? NMR (free base, 200 MHz, CDC13) d 1.67 (4H, m), 1.95-3.10 (6H, m), 3.10-3.80 (7H, m), 4.30 (1H, m), 4.65 (1H, m), 7.05 (1H, m), 7.35 (3H, m); MS (FAB) 356 (M + H) +. Example 3 Hydrochloride [(R) -3aHCl] of (R) 4-ethanesulfonyl-1- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine AD -01-0039-6 To the solution of (R) -2 (712 mg, 2 mmol in 10 ml of CH2C12), methanesulfonyl chloride (573 mg, 5 mmol) and pyridine (1 ml) were added at 0 ° C, stirring overnight at that temperature, the solution was washed with 5% aqueous K2C03 solution, extracted with dichloromethane, dried and the solvent was evaporated to give an unpurified oil. This material was purified by flash column chromatography on silica gel, eluting with dichloromethane-methanol-ammonia (100: 5: 1), to give the free base which was dissolved in 2 ml of dichloromethane and HCl (3 ml, 1 M in Et20) was added to provide a white salt (R) -3a HCl (600 mg, 69%): mp 130-132 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.61-1.85 (4H, m), 2.38-2.65 (6H, m), 2.72 (3H, s), 2.80-3.06 (2H, m), 3.15-3.36 ( 1H,), 3.50-3.96 (4H, m), 4.48-4.93 (1H, m), 7.00-7.10 (1H, m), 7.25-7.40 (2H, m); MS (FAB) 434 (M + H) +; Anal. Cale, for Ci8H25Cl2N3? 3S. HCl.0.5 CH3OH: C, 45.64; H, 5.59; N, 8.63. Found: C, 45.69; H, 5.58; N, 8.73. EXAMPLE 4 [(R) -3b] of (R) -4-t-Butyl-acetyl-l- [3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine. AD -01-0040-4 To the solution of (R) -2 (356 mg, 1 mmol in 10 ml of acetone), t-butyl bromoacetate (234 mg, 1.2 mmol) and K2C03 (207 mg, 1.5 mg) were added. mmoles) at 0 ° C, stirred overnight at that temperature, the solution was washed with solution K2C03 5% aqueous, extracted with dichloromethane, dried and the solvent evaporated to give an oil without purification. This material was purified by flash column chromatography on silica gel, diluting with dichloromethane-methanol-ammonia (100: 5: 1), to give (R) -3b (329 mg, 70%): 1H NMR (free base, 200 MHz, CDC13) d 1.36 (9H, s), 1.91-2.37 (7H, m), 2.65-3.13 (7H, m), 3.58-4.20 (6H, m), 5.00 (1H, m) , 7.12- 7.21 (2H, m), 7.40 (1H, m). The compound was used directly in the next reaction. Example 5 [(R) -3c 2HC1] Dihydrochloride] of (R) -4 - [(3,4-dichloro-enyl) -acetyl] -3- [(1-pyrrolidinyl) methyl] -1- piperazine acetic acid ADL-01-0042 -0 The compound (R) -3b (329 mg, 0.7 mmol) was dissolved in 5 ml of THF / Et20 (1: 1), and HCl (5 ml, 1 M in Et20) was added, maintained 12 hrs for provide a white salt (R) -3c HCl (275 mg, 61%): mp 190 ° C (d). XH NMR (free base, 200 MHz, CDC13) d 1.85-2.20 (4H, m), 2.95-4.41 (17H, m), 5.18-5.35 (1H, m), 7.30-7.45 (1H, m), 7.56- 7.72 (2H, m); MS (FAB) 414 (M + H) +; Anal. Cale, for C? 9H25Cl2N303. 2 HCl .0.5 H20 .: C, 45.16; H, 5.78; N, 8.32. Found: C, 44.91; H, 5.88; N, 8.56. Example 6 [(R) -3d] (R) -4-Nt-Boc-D-aspartic acid-β-benzyl ester-1- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine AD -01-0048-7 To the solution of Nt-Boc-D-aspic acid-β-benzyl ester (646 mg, 2 mmol) and HOBt (270 mg, 2 mmol in 10 ml of CH2C12), DCC (413 mg, mmoles) was added at 0 ° C, stirred 1 hr at that temperature, (R) -2 (356 mg, 1 mmol in 10 ml of CH2C12) was added, stirred 24 hrs at room temperature, the solution was washed with 5% aqueous K2C03 solution, extracted with dichloromethane, dried and the solvent evaporated to give an unpurified oil. This material was purified by flash column chromatography on silica gel, eluting with dichloromethane-methanol-ammonia (100: 1: 1), to give (R) -3d (628 mg, 95%), "NMR (free base). , 200 MHz, CDC13) d 1.35 (9H, s), 1.70-1.87 (4H, m), 2.32-3.16 (6H, m), 3.35-4.46 (6H, m), 4.80-5.68 (6H, m), 7.07-7.45 (8H, m) The compound was used directly in the following reaction Example 7 Dihydrochloride [(R) -3e 2HC1] (R) -4-Aspartic acid-1- [(3,4-dichlorophenyl) acetyl ] -2- [(1-pyrrolidinyl) methyl] -piperazine ADL-01-0041-2 Compound (R) -3d was dissolved in 1 ml of HOAc, and HCl (1 ml, 2N) was added and resting for 20 min , then hydrogenated at 1 atm., 10% Pd on carbon at temperature ambient for 1 h to provide a white salt (R) -3e (430 mg, 91.5%): m.p. 168 ° C (d). 1H NMR (DMSO-d6) d 1.92-2.16 (4H, m), 2.75-5.28 (18H, m), 2.72 (3H, s), 7.31-7.52 (3H, m), 8.45-8.80 (3H, m); MS (FAB) 471 (M + H); Anal. Cale, for C2? H28Cl2N404. 2 HCl: C, 46.34; H, 5.18; N, 10.29. Found: C, 45.52; H, 6.02; N, 9.73. Example 8 Hydrochloride [(R) -3 £ HC1] of (R) -4-acetyl-l- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine AD -01- 0148-5 The compound was prepared as reported in the literature (J. Med. Chem. 1993, 36, 2075 2083) of (R) -2. The hydrochloride salt was prepared from 1M etheral HCl to provide (R) -3f HCl in 88% yield; p.f. 153-155 ° C; MS (FAB) 398 (M + H) +. Anal. Cale. for C? gH25Cl2N302.HCl.H20: C, 52.49; H, 6.03; N, 9.66. Found: C, 50.40; H, 6.23; N, 9.28. Example 9 Hydrochloride [(R) -3g HCl] of (R) -4- (Diethoxyphosphonate) -1 - [(3, 4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine ADL-01 -0149-3 To a solution of (R) -2 (0.178 g, 0.5 mmol) in 10 mL of CH2C12 was added Et3N (0.101 g, 1.0 mmol) and diethylchlorophosphonate (0.174 g, 1.0 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at temperature environment for 13 hr and then it was emptied over 10% aqueous K2C03. The organic layer was separated, dried over anhydrous Na 2 SO, and evaporated to dryness under reduced pressure to give the compound as a yellow oil. The oil was purified on a column of silica gel (solvent system: CH2C12: CH30H: 28% NH40H, 95: 5: 2) and converted to the hydrochloride salt by the usual method to give (R) -3g HCl, 0.10 g (38%); p.f. 168-170 ° C; "? NMR (free base, 200 MHz, CDCI3) d 1.20 (6H, t, J = 7.0 Hz), 1.64 (4H, m), 2.30-2.70 (6H, m), 2.85-3.15 (1H, m), 3.45-3.80 (4H, m), 3.60 (2H, broad s), 3.98 (4H, m), 4.35 (1H, m), 4.70 (1H, m), 7.00 (1H, m), 7.30 (2H, m ); MS (FAB) 492, 494 (M + H) + Anal Cale for C 21 H 32 Cl 2 N 3 O 4 P HCl O 5 H 2 O: C, 46.90; H, 6.37; N, 7.81 Found: C, 46.66; H, 5.90; N, 8.16 EXAMPLE 10 Hydrochloride [(R) -3h HCl] of (R) -4-Trifluoroacetyl-1- [(3, 4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine ADL-01-0150-1 To a solution of (R) -2 (0.356 g, 1.0 mmol) in 10 mL of CH2C12 was added Et3N (0.202 g, 2.0 mmol) and trifluoroacetic anhydride (0.42 g, 2.0 mmol) in a Nitrogen atmosphere The reaction mixture was stirred at room temperature for 12 hr and the initial material shown TLC was still present, another equivalent of trifluoroacetic anhydride was added and it was continued stirring for 12 hr additional The reaction was worked up as above and the hydrochloride salt was prepared as usual to give (R) -3h HCl, 0.25 g (50%); p.f. 145-147 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.60 (4H, m), 2.20-2.75 (6H, m), 3.10 (1H, m), 3.45-3.80 (4H, m), 4.00 (1H, J = 14.0 Hz, d), 4.25 (1H, m), 4.45 (1H, J = 14.0 Hz, d), 4.70 (1H, m), 7.00 (1H, m), 7.28 (2H, irt); MS (FAB) 452, 454 (M + H) +. Anal. Cale. for C19H22Cl2F3N3O2.HC1.0.5H2O: C, 45.85; H, 4.86; N, 8.44. Found: C, 46.26; H, 4.82; N, 8.33. EXAMPLE 11 Hydrochloride [(R) -3IHC1] (R) -4- [(3,4-Dichloroph nyl) acetyl] -3 - [(1-pyrrolidinyl) methyl] -1-piperazinecarboxamide ADL-01-0151-9 A a solution of (R) -2 (0.356 g, 1.0 mmol) in acetic acid (0.186 g, 3.0 mmol) and water was added KOCN (0.244 g, 3.0 mmol) and the reaction mixture was stirred at room temperature for 72 h. 10% aqueous K2C03 was added to the reaction mixture to bring the pH close to 12.0 and the product was extracted with CH2C12, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the unpurified product which was purified on a column of silica gel (solvent system: CH2C12: CH30H: 28% NH0H, 95: 5: 1) to give the desired product as a white solid. The hydrochloride salt was prepared from 1M ethanol HCl to give (R) -3i HCl as a white solid, 0.15 g (31%); 1ñ NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 2.10-3.20 (6H, m), 3.40-3.70 (4H, m), 3.95 (2H, m), 4.20 (2H, J = 14.0 Hz, d, m), 4.70 (1H, m), 5.35 (2H, broad s), 7.00 (1H, m), 7.25 (2H, m); MS (FAB) 399, 401 (M + H) +. Anal. Cale, for C? 8H24Cl2N402.HCl .H20.0.125 CH2C12: C, 46.88; H, 5.91; N, 12.06. Found: C, 46.66; H, 5.50; N, 11.97. Example 12 Hydrochloride [(R) -3j HCl] of (R) -4-1 (3,4-Dichlorophenyl) acetyl] -3 - [(1-pyrrolidinyl) methyl] -1-piperazinecarboxaldehyde ADL-01-0156-8 To a solution of (R) -2 (0.356 g, 1.0 mmol) in 10 mL of CH2C12 was added 1.0 mL of ethyl formate (excess) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred for 24 h and the solvent was removed under reduced pressure to give the product without purification. The compound was purified on silica gel column (solvent system: CH2C12: CH30H: 28% NH4OH, 95: 5: 1) and converted to the hydrochloride salt, (R) -3j HCl, 0.10 g (23% ); p.f. 126 ° C (d); XH NMR (free base, 200 MHz, CDC13) d 1.62 (4H, m), 2.10-3.20 (6H, m), 3.35-3.85 (5H, m), 4.25 (3H, m), 4.60 (1H, m) , 7.00 (1H, m), 7.26 (2H, m), 7.90 (1H, s); MS (FAB) 384, 386 (M + H) +. Example 13 Hydrochloride [(R) -3k HCl] (R) -4- [(3,4-Dichloro-enyl) -acetyl] -3- [(1-pyrrolidinyl) methyl] -1-piperazine-sulfonamide ADL-01-0164-2 To a solution of (R) -2 (0.356 g, 1.0 mmol) in 5 mL of p-dioxane was added sulfamide4 (NH2S02NH2, 0.96 g, 10 mmol) under a nitrogen atmosphere and the mixture of reaction was heated to reflux for 2 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was redissolved in CH2C12 and washed with 10% K2CO3 aqueous saturated salt solution, and dried over anhydrous Na2SO4. Removal of the solvent resulted in the free base of the product which was purified on a column of silica gel (solvent system: CH2C12: CH30H: 28% NH4OH, 98: 2: 1). The hydrochloride salt was prepared from 1M etheral HCl to give (R) -3k HCl, 0.10 g (21%); p.f. 183-185 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.68 (4H, m), 2.30-3.00 (6H, m), 3.15-4.00 (5H, m), 4.15-4.65 (3H, m), 4.85 (1H, m), 7.00 (1H, m), 7.31 (4H, m); MS (FAB) 435 (M + H) +. Anal. Cale. for C17H24C12N403S.HC1: C, 43.28; H, 5.34; N, 11.87. Found: C, 42.90; H, 5.35; N, 11.43. Ref. (4) Alker, D. et al J. Med. Chem. 1990, 33, 585. EXAMPLE 14 Hydrochloride [(R) -31 HCl] of (R) -4- (4-methylphenylsulfonyl) -1- [3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] - piperazine? D -01-0165-9 To a solution of (R) -2 (0.356 g, 1.0 mmol) in 5 mL of CH2C12 was added p-toluenesulfonyl chloride (0.38 g, 2 mmol) followed by 0.5 mL of pyridine under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h and then poured into 10% aqueous K2C03. The organic layer was separated and dried over anhydrous Na2SO4. Removal of the solvent gave the product which was purified on a silica gel column (solvent system: CH2C12: CH3OH: 28% NH4OH, 98: 2: 1). The hydrochloride salt was prepared to give (R) -31 HCl, 0.15 g (27%); p.f. 240 ° C (d); XH NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 1.95-3.00 (6H,), 2.38 (3H, s), 3.15-3.85 (5H.m), 4.45 (1H, m), 4.75 (1H, m) , 6.95 (1H, m), 7.25 (4H, m), 7.50 (2H, J = 8.0 Hz, d); EM (FAB) 510 (M + H) +. Anal. Cale, for C24H29C12N303S. HCl .0.25H20: C, 52.32; H, 5.35; N, 7.63. Found: C, 52.23; H, 5.50; N, 7.51. Racemic Compounds Racemic compounds were prepared as illustrated by the following steps Hydrochloride E (R, S) -4 HCl] of (R, S) -2 - [(l-Pyrrolidinyl) ethyl] piperazine The compound was prepared following the procedure of the literature and isolated as the hydrochloride salt. Hydrochloride [(R, S) -5, 6,7] of (R, S) -4- (R = SQ7CH3, CQ2CH3, COCH3) -2- [(1-pyrrolidinyl) methyl] piperazine These compounds were also prepared from according to the procedures described in the literature1 and each of the products was purified as a free base before being used in the following. Example 15 Hydrochloride [(R, S) -8a HCl) of (R, S) -4-Methanesulfonyl-1 - [(3, 4-dichloro-enyl) -acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine (General Procedure) ADL-01-0135-2 1, 1'-Carbonyldiimidazole (0.324 g, 2.0 mmol) was added to a stirring solution of 3,4-dichlorophenylacetic acid (0.41 g, 2.0 mmol) in 10 mL of CH2C12. at room temperature under a nitrogen atmosphere, and the resulting solution was stirred further for 1 hr. The resulting solution was then added to a stirred solution of (R, S) -5 (0.247 g, 1.0 mmol) in 10 mL of CH2C12 at 0 ° C and the reaction mixture was stirred for an additional 20 h. The reaction mixture was diluted with CH2C12 and washed with 2M aqueous Na2CO3. The organic layer was dried and evaporated to dryness and the product was purified on a column of silica gel (solvent system: CH2C12: CH30H: 28% NH4OH, 98: 2: 1). The hydrochloride salt was prepared by redissolving the compound in CH2C12 and treating the solution with 1M ethereal HCl to give (R, S) -8a HCl as a white solid, 0.20 g (32%); NMR (see R-3a); MS (FAB) 434 (M + H) +; Anal. Cale, for C, i8H25Cl2 3? 3S. HC1.0.5H2O: C, 45.13; H, 5.51; N, 8.77. Found: C, 45.46; H, 5.36; N, 8.71. The following compounds were similarly prepared from (R, S) -5, 6, and 7,: EXAMPLE 16 Hydrochloride [(R, S) -8b HCl] of (R, S) -4-methanesulfonyl-1 - [(4 - mathylsulfonylphenyl) cetyl] -2- [(1-pyrrolidinyl) -methyl] piperazine ADL-01-0117-0 The compound was prepared from 4-methylsulfonylphenylacetic acid and the hydrochloride salt was recrystallized from CH 3 OH to give ( R, S) -8b HCl in 60% yield; p.f. 185-188 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 2.30-2.70 (6H, m), 2.80 (3H, s), 2.85- 3.10 (3H, m), 3.00 (2H, m) , 3.25 (1H, m), 3.50-3.95 (4H, m), 4. 50 (1H, m), 4.80 (1H, m)), 7.40 (2H, J = 7.5 Hz, d), 7.80 (2H, J = 7.5 Hz, d); MS (FAB) 444 (M + H) +; Anal. Cale, for Ci9H29N3? 5S2. HCl: C, 47.54; H, 6.30; N, 8.75. Found: C, 46.03; H, 6.24; N, 8.80.

Example 17 Hydrochloride [(R, S) -8c HCl] of (R, S) -4-methanesulfonyl-l- [(2-nitrophenyl) acetyl] -2- [(1-pyrrolidinyl) -methyl] piperazine ADL-01 -0119-6 The compound was prepared from 2-nitrophenylacetic acid in 65% yield as the hydrochloride salt; p.f. 253-255 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.70 (4H, m), 2.40-3.10 (6H, m), 2.75 (3H, s), 3.45 (1H, m), 3.70-4.00 (4H, m) , 4.05-4.30 (2H, m), 4.50 (1H, m), 4.72 (1H, m), 7.45 (3H, m), 8.05 (1H, J = 8.0 Hz, d); MS (FAB) 411 (M + H) +; Anal. Cale, for C18H26N405S. HCl: C, 48.37; H, 6.09; N, 12.54. Found: C, 48.36; H, 5.66; N, 12.29. Example 18 Hydrochloride [(R, S) -8d HCl] of (R, S) -4-Methanesulfonyl-l- [(4-trifluoromethylphenyl) acetyl] -2- [(1-pyrrolidinyl) -methyl] piperazine ADL-01 -0120-4 The compound was prepared as a hydrochloride salt from 4-trifluoromethylphenylacetic acid in 82% yield; 182-185 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 2.35-3.05 (6H, m), 2.71 (3H, s), 3.25 (1H, m), 3.50-3.95 (5H, m) , 4.55 (1H, m), 4.85 (1H, m), 7.30 (2H, m), 7.50 (2H, J = 7.8 Hz, d); MS (FAB) 434 (M + H) +; Anal. Cale, for C19H26F3N303S. HCl .0.5H20: C, 47.65; H, 5.89; N, 8.77. Found: C, 48.36; H, 5.80; N, 8.51.

EXAMPLE 19 Hydrochloride [(R, S) -8e HCl] of (R, S) -4-Methanesulfonyl-l- [(3-indolyl acetyl) -2- [(1-pyrrolidinyl) -methyl] piperazine AD -01-0134 -5 The compound was prepared from 3-indoleacetic acid and isolated as free base in 40% yield and converted to hydrochloride salt; p.f. 219-221 ° C; 1ñ NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 2.10-3.00 (6H, m), 2.55 (3H, S), 3.10-3.45 (2H, m), 3.45-3.90 (4H, m), 4.05 (1H, m), 4.55 (1H, m), 4.90 (1H, m), 7.05 (3H, m), 7.25 (1H, m), 7.50 (1H, m), 8.95 (1H, s) large); MS (FAB) 405 (M + H) +; Anal. Caled, for C20H28N4O3S .HCl .0.5H20: C, 58.09; H, 7.07; N, 13.55. Found: C, 58.37; H, 6.68; N, 13.30. Example 20 Hydrochloride [(R, S) -9a Hcl] of (R, S) -Methyl 4 - [(4-methylsulfonylphenyl) acetyl] -3 - [(1-pyrrolidinyl) -methyl] -1- piperazinecarboxylate ADL-01 -0092-5 The compound was prepared from 4-methylsulfonylphenylactatic acid and the hydrochloride was prepared from 1M etheral HCl to give (R, S) -9a HCl in 46% yield, mp 225 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.6U (4H, m), 2.15-2.95 (6H, m), 2.98 (3H, s), 3.15 (2H, m), 3.35 (3H, m) , 3.60 (3H, s), 3.95 (2H, m), 4.30 (1H, m), 4.72 (1H, m), 7.45 (2H, m), 7.75 (2H, J = 7.5 Hz, d); FAB) 424 (M + H) +; Anal. Cale, for C20H29N3O5S. HCl .0.25H20: C, 51.72; H, 6.62; N, 9.05 Found: C, 51.93; H, 6.47; N, 8.44. Example 21 Hydrochloride [(R, S) -9b HCl] (R, S) -Methyl 4 - [(4-trifluoromethylphenyl) acetyl] -3 - [(1-pyrrolidinyl) -methyl] -1- piperazinecarboxylate AD -01- 0094-1 The compound was prepared as a hydrochloride salt from 4-trifluoromethylphenylacetic acid to give (R, S) -9b HCl in 48% yield; p.f. 210 ° C; XH NMR (200 MHz, CDC13) d 1.50 (4H, m), 1.95-2.30 (6H, m), 2.35-3.50 (4H, m), 3.65 (3H, S), 3.70-4.50 (5H, m), 7.45 (4H, m); MS (FAB) 414 (M + H) +; Anal. Cale. for C2oH26F3N303.HC1.0.25H20: C, 52.86; H, 6.10; N, 9.25. Found: C, 53.03; H, 5.94; N, 8.94.

Another minor product (R, S) -11 (ADL-01-0093-3) was isolated as a hydrochloride salt of this reaction in 10% yield; p.f. 190 ° C; MS (FAB) 446 (M + H) +.

Example 22 Hydrochloride [(R, S) -9c HCl of (R, S) -methyl 4 - [(3-indolyl) acetyl] -3- (1-pyrrolidinyl) -methyl] -1-piperazinecarboxylate? DL- 01-0095-8 The compound was prepared from 3-indoleacetic acid and the hydrochloride salt was prepared to give (R, S) -9c HCl in 75% yield; p.f. 143 ° C; X NMR (200 MHz, CDC13) d 1.55 (4H, m), 1.90-2.52 (6H, m), 2.70-3.75 (9H, m), 3.35 (3H, S), 6.60 (2H, m), 6.85 (2H, m) 7.20 (1H, s), 7. 65 (1H, broad); MS (FAB) 385 (M + H) +. EXAMPLE 23 Hydrochloride [(R, S) -9d HCl] (R, S) -Methyl-4- t (2-nitrofyl) acetyl] -3 - [(1-pyrrolidinyl) -methyl] -1-piperazinecarboxylate ADL -Ol-0096-6 The compound was prepared from 2-nitrophenylacetic acid and the hydrochloride was prepared from 1M etheral HCl to give (R, 5) -9d HCl in 42% yield; p.f. 228 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.60 (4H, broad s), 1.80-2.30 (4H, m), 2.70 (2H, m), 3.05 (2H, m), 3.60 (3H, s), 3.55-4.10 (4H, m), 4.35 (2H, J = 14.0 Hz, dd), 5.10 (1H, m), 7.50 (3H, m), 8.05 (1H, J = 7.5 Hz, d); EM (FAB) 391 (M + H) +; Anal. Cale, for C? 9H26N405.HCl: C, 53.46; H, 6.37; N, 13.12. Found: C, 54.29; H, 6.38; N, 12.58.

Example 24 Hydrochloride [(R, S) -9e HCl] of (R, S) -methyl 4 - [(2-methoxyphenyl) acetyl] -3 - [(1-pyrrolidinyl) -methyl) -methyl] -1- piperazinecarboxylate ADL-01-0097-4 The compound was prepared as above from 2-methoxyphenylacetic acid to give (R, S) -9e HCl in 12% yield; p.f. 120 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 2.25-2.95 (6H,), 3.10 (1H, m), 3.30-4.10 (5H, m), 3.60 (3H, s), 3.70 (3H, s), 4.40 (1H, m), 4.70 (1H, m), 6.84 (2H, m), 7.15 (3H, m); MS (FAB) 376 (M + H) +; Anal. Cale. for C20H29N3O4. HCl. H20: C, 55.87; H, 7.50; N, 9.77. Found: C, 55.78; H, 6.97; N, 9.42. EXAMPLE 25 Hydrochloride [(R, S) -9f 2HC1] of (R, S) -Methyl 4 - [(2-aminophenyl) acetyl] -3 - [(1-pyrrolidinyl) -methyl] -1- piperazinecarboxylate? DL- 01-0098-2 The compound was prepared by the hydrogenation of (R, S) -9e HCl in 10% ~ Pd / C following the procedure described in the literature. The compound, (R, S) -9f 2HC1, was isolated as dihydrochloride in 84% yield; p.f. 195 ° C (d); * H NMR (200 MHz, DMSO-d6) d 2.00 (4H, m), 3.05-4.45 (16H, m), 3.75 (3H, s), 5.00 (1H, m), 7.45 (4H, brs); EM (FAB) 361 (M + H) +; Anal. Cale, for C? 9H28, N403.2HC1. H20: C, 50.56; H, 7.15; N, 12.41. Found: C, 50.36; H, 7.26; N, 12.05. EXAMPLE 26 Hydrochloride [(R, S) -10a HCl] (R, S) -4-acetyl-l- [(4-methylsulfonylphenyl) acetyl] -3- [(1-pyrrolidinyl) -methyl] -piperazine ADL-01 -0144-4 The compound was prepared as above from 4-methylsulfonylphenylacetic acid and the hydrochloride salt was prepared in a usual manner to give (R, S) -10a HCl in 45% yield; p.f. 145-147 ° C; XH NMR (200 MHz, DMS0-d6) d 1.90 (4H, m), 2.17 (3H, s), 2.65-3.80 (6H, m). 3.32 (3H, s), 3.85-4.45 (8H, m), 5.05 (1H, m), 7.65 (2H, J = 8.0 Hz, d), 7.95 (2H, J = 8.0 Hz, d); MS (FAB) 408 (M + H) +. Example 27 Hydrochloride [(R, S) -10b HC1] of (R, S) -4-Acetyl-1- (4-trifluoromethyl-enyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] -piperazinecarboxylate ADL-01 -0145-1 The compound was prepared from 4-trifluoromethylphenylacetic acid and was isolated as the hydrochloride salt, (R, S) -10b HCl, in 30% yield; p.f. 110 ° C; -? NMR (200 MHz, DMS0-d6) d 2.00 (4H, m), 2.15 (3H, s), 2.70-3.25 (6H, m), 3.50-4.45 (8H, m), 5.05 (1H, m), 7.70 (4H, m); MS (FAB) 398 (M + H) +.

Example 28 [(R, S) -10c HCl] Hydrochloride of (R, S) -4-Acetyl-l- [(2-trifluoromethyl-enyl) -acetyl] -3- [(-pyrrolidinyl) -methyl] piperazinecarboxylate ADL-01 -0157-6 The compound was prepared from 2-trifluoromethylphenylacetic acid and the hydrochloride salt was made from 1M etheral HCl to give (R, S) -10c HCl in 57%; 220 ° C (d); XH NMR (free base, 200 MHz, CDC13) d 1.65 (4H, m), 2.05 (3H, s), 2.25-3.25 (6H, m), 3.40-4.10 (6H, m), 4.50 (2H, m) , 4.70 (1H, m), 7.30 (2H, m), 7.60 (2H, m); MS (FAB) 398 (M + H) +. Example 29 Hydrochloride [(R, S) -lOd HCl] of (R, S) -4-Acetyl-l- [(3-nitrophenyl) cetyl] -3 - [(1-pyrrolidinyl) -methyl] piperazinecarboxylate ADL -01-0158-4 The compound was prepared from 3-nitxophenylacetic acid and the hydrochloride salt, (R, S) lOd HCl was isolated as a white solid in 69% yield; p.f. 143-145 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.63 (4H, broad s), 2.05 (3H, s), 2.20-2.80 (6H, m), 2.90-3.25 (2H, m), 3.50-3.90 (3H , m), 4.00 (1H, J = 14.0 Hz, d), 4.45 (2H, m), 4.65 (1H, m), 7.45 (2H, m), 8.00 (2H, m); EM (FAB) 375 (M + H) +; Anal. Cale, for C19H26N4? 4.HCl .H20: C, 53.21; H, 6.81; N, 13.06. Found: C, 53.51; H, 6.13; N, 12.91. Example 30 Hydrochloride [(R, S) -lOe HCU of (R, S) -4-Acetyl-l- [(2-nitro-enyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] -piperazine-carboxylate ADL -01-0163-4 The compound was prepared as above from 2-nitrophenylacetic acid to give (R, S) -10e HCl as a white solid in 50% yield; p.f. 180 ° C (d); XH NMR (free base, 200 MHz, CDC13) d 1.63 (4H, m), 2.04 (3H, s), 2.20-2.85 (6H, m), 2.98-3.35 (3H, m), 3.60-4.25 (4H, m), 4.60 (2H, m), 7.35 (3H, m), 8.00 (1H, J = 7.0 Hz, d); MS (FAB) 375 (M + H) +; Anal. Cale, for C? 9H26N404. HCl .0.5H20: C, 55.54; H, 6.62; N, 13.64. Found: C, 54.38; H, 6.35; N, 13.58. Example 31 Hydrochloride [(R, S) -lOf HCl] of (R, S) -4-Acetyl-l- [(4-nitro-enyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] -piperazinecarboxylate AD -01-0159-2 The compound was prepared from 2-nitrophenylacetic acid as above to give (R, S) -10f HCl in 52% yield; 146-148 ° C; XH NMR (free base, 200 MHz, CDC13) d 1.68 (4H, m), 2.07 (3H, s), 2.20-2.75 (6H, m), 3.40-3.90 (3H, m), 4.05 (1H, J = 13.5 Hz, d), 4.50 (2H , m), 7.35 (2H, J = 8.0 Hz, d), 8.10 (2H, J = 8.0 Hz, d); MS (FAB) 375 (M + H) +; Anal. Cale, for C? 9H26N404. HCl .0.5H20.0.125CH2C12: C, 53.36; 6.61; 13.01. Found: C, 53.16; H, 6.27; N, 13.36. EXAMPLE 32 Dihydrochloride [(R, S) -12 2HC1] of (R, S) -4- (phenylmethyl) -1- [(, 5-dichloro-2-nitrophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine ADL-01-0166-7 The compound was prepared from 4-phenylmethyl-2 [(1-pyrrolidinyl) methyl] piperazine (Ref. 1) and 4,5-dichloro-2-nitrophenylacetic acid following the method described in the above to give (R, S) -12 2HC1 in 63% yield; p.f. 235 ° C (d); XH NMR (free base, 200 MHz, CDC13) d 1.66 (4H, m), 2.05-3.00 (8H, m), 3.45 (4H, m), 4.00 (5H, m), 4.60 (1H, m), 7.35 (6H, m), 8.15 (1H, s); MS (FAB) 493 (M + H); Anal. Cale. for C24H29C12N403.2HC1: C, 50.99; 5.53; 9.91. Found: C, 50.55; H, 5.16; N, 9.44. Compounds of the formula II General procedure for coupling DCC / pyr. With stirring at 25 ° C under N2, DCC (2.06 eq) and CH2C12 were added to a mixture of the acid (2 eq) and pyridine (2.06 eq) in CH2C12. After 1-2 minutes, a solution of amine (1 eq) in CH2C12 was added, and the mixture was stirred at 25 ° C under N2 overnight. The final concentration of the mixture is around 0.1-0.3 mM with respect to the amine. NaHC03 Satur. (2 mL) added to destroy excess active esters before the mixture was filtered through celite, and the DCU was washed with CH2C12. The filtrate was then partitioned between NaHCO 3 satur. and CH2C12 which was dried (Na2SO4), filtered through celite, and evaporated. Toluene was added to the quenched azeotrope of the pyridine before the product without purification, chromatography and conversion to HCl salt. Compounds having the following structures were prepared: The intermediaries (±) -1 and (±) -2 were prepared by the methods reported from the materials appropriate initials.5 Compounds (±) -3 and (±) -4 are known compounds prepared by reported methods.5 Compounds (±) -5 a (±) -16 were prepared by DCC coupling of either (± ) -1 as (±) -2 to an arylacetic acid followed by demethylation or reduction to allow for peripheralization. Ref ~ (5) Rajagopalan, P., et al Bioorg. Med. Chem. Letters 1992, 2, 721 -726, Intermediates 17 and 18 were prepared by known methods from 6-methoxy-1-tetraione and 1-tetralone, respectively. Intermediates 17 and 18 were coupled to 3,4-dichlorophenylacetic acid to produce (±) -19 and (±) -20. (±) -21 (±) -22, ADL-01-0051-1 The Intermediates (±) -21 and (±) -23 were prepared by the similar chemistry from 1-benzosuberone and (±) -trans-2-bromo-1-indanol. 1 Compounds (±) -22, (±) -25 (Niravoline), 6 and (±) -27 are known compounds prepared by reported chemistry. Compounds (±) -24 a (+) - 29 were prepared by coupling DCC to the appropriate arylacetic acid. Ref. (6) Bellissant, E. et al .. J. Pharmacol. Exp. Ther. 1996, 278, 232-242. They follow representative examples.

Example 33 Acid ((±) -5, ADL-01-0019-8) of 2-. { 7- [(±) -trans-1- (N-3, 4- dichlorophenylacetamido-N-methylamino) -2- (1-pyrrolidinyl) -1,2,3,4-tetrahydronaphthoxy} acetic With stirring at 25 ° C under N2, t-butyl bromoacetate (0.35 mL, 2.38 mmol) was added to a mixture of (±) -4 (0.688 g, 1.59 mmole) and K2C03 (0.5 g, 3.6 mmole) in DMF (8 mL), and the mixture was stirred at 25 ° C under N2 overnight then the mixture was evaporated under high vacuum. The residue was partitioned between saturated NaHCO 3. and CH2C12 (2 X 100 mL), which was dried (Na2SO4), filtered through celite, and evaporated. The t-butyl ester intermediate was flash column chromatographed eluting twice with CH2C12: 2% NH3: 2% MeOH and CH2C12: 2% NH3: 1% MeOH, respectively. The t-butyl ester was then deprotected in a mixture of THF (4 ml) and concentrated HCl (2 ml) with stirring at 25 ° C overnight and at 50 ° C for 1 hr then the mixture was evaporated. The residue was then dissolved in a mixture of trifluoroacetic acid (2 mL), 4 N HCl (2 mL), and anisole (1 drop), and stirred at 25 ° C for 2.5 days after the mixture was evaporated. The oily residue was triturated with Et20 and sonicated to yield (±) 5HC1 (0.259 g, 31%): m.p. (HCl salt) 138 ° C (dec); * H NMR (HCl salt, DMSO-d6) d 1.7-2.1 (s broad, 4H, -CH2CH2-), 2.2-4.8 (complex, 13H, 6 -CH2- and 1 -CH-), 2.79 (s, 3H, -NCH3), 5.98 (d, J = 10.3 Hz, 1H , -CH-), 6. 40 (s, 1H, aromatic), 6.82 (m, 1H, aromatic), 7.12 (d, J = 8.2 Hz, 1H, aromatic) 7.39 (d, J = 8.3 Hz, 1H, aromatic), 7.63 (m, 2H , aromatic). MS (FAB) m / z 491. Anal. (C, H, N) C25H28N204C12HC1. Example 34 2, 2-Diphenyl-N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7-methoxy-1,2,3,4-tetrahydrone tl-yl] acetamide ((± ) -6, ADL-01-0020-6) The ADL-01-0020-6 was prepared by the general coupling method DCC / pyr from (±) -1 (1.453 g, 5.58 mmol), diphenylacetic acid ( 2.369 g, 11.16 mmoles), DCC (2.373 g, 11.50 mmoles), and pyridine (0.93 mL, 11.5 mmoles). The product was flash column chromatographed eluting with CH2C12: 2% NH3: 1% MeOH then covered in the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH-Et20 to produce (±) -6HC1 (1.7 g, 63%): pf (HCl salt) > 250 ° C; XH NMR (HCl salt, DMSO-d6) d 1.8-2.0 (broad s, 4H, -CH2CH2-), 2.2-3.9 (complex, 9H, 4 -CH2- and 1 -CH-), 2.79 (s, 3H , -NCH3), 3.48 (s, 3H, -OCH3), 5.66 (s, 1H, -CH-), 6.1 (d, J = 9.4 Hz, 1H, -CH-), 6.23 (s, 1H, aromatic) , 6.77 (d of d, J = 2.4 Hz and 8.4 Hz, 1H, aromatic), 7.09 (d, J = 8.5 Hz, 1H, aromatic), 7.2-7.5 (complex, 10H, aromatic). MS (FAB) n / z 455. Anal. (C, H, N) C 30 H 34 N 2 O 2 HCl.

Example 35 2, 2-Diphenyl-N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7-hydroxy-1, 2,3, 4-tetrahydronaphth-l-yl] acetamide ((±) -7, ADL-01-0021-4) With stirring in dry frozen acetone under N2, 1.0 M Br3 in CH2C12 (19.7 mL) was added to a fast drip rate to a solution of (±) -6 (1491 g, 3.28 mmol) in CH2C1 (20 mL), and the mixture was allowed to slowly warm to 25 ° C under N2 when the dry ice sublimed. After 6.5 h, the mixture was quenched with MeOH with H20 frozen by cooling and diluting with CH2C12 (50 mL). The mixture was partitioned between NaHCO 3 satur. and CH2C12. Some yellowish precipitate was extracted in CH2C12 by adding some MeOH. The organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was flash column chromatographed eluting with CHC13: 2% NH3: 2% MeOH to yield (±) -7 (0.426 g, 30%). Part of the free base was converted to the HCl salt with 1.0 M HCl in Et20: 1h NMR (free base, CDC13) d 1.5-1.8 (broad s, 4H, -CH2CH2-), 1.8-2.9 (complex, 9H, 4-CH2- and 1-CH-), 2.55 (s, 3H, -NCH3), 5.21 (s, 1H, -CH-), 5.83 (d, J = 8.6 Hz, 1H, -CH-), 6.22 ( s, 1H, aromatic), 6.46 (m, 1H, aromatic), 6.78 (d, J = 8.1 Hz, 1H, aromatic), 7-7.4 (complex, 10H, aromatic). MS (FAB) m / z 441. Anal. (C, H, N) C29H32N202HC1H20.

Example 36 2- (2-Nitro-4,5-dichlorophenyl) -N-methyl-N- [(+) - trans-2- (1-pyrrolidinyl) -7-nitro-l, 2,3,4-tetrahydronaft -l-il] acetamide ((±) -8; ADL-01-0029-7) ADL-01-0029-7 was prepared by the general coupling method DCC / pyr from (±) -2 (0.5790) g, 2. 103 mmoles), 2-nitro-4,5-dichlorophenylacetic acid (1.0512 g, 4.204 mmoles), DCC (0.8948 g, 4.34 immoles), and pyr (0.35 mL, 4.3 mmol). After stirring at 25 ° C overnight, more 2-nitro-4,5-dichlorophenylacetic acid is added (1.0510 g, 4.203 mmole), DCC (0.8946 g, 4.34 mmole), and CH2C12 (10 mL), and after 5 h, the reaction was worked up according to the general procedure. The unpurified product was purified by gravity column eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and washed with hot MeOH to yield (±) -8 HCl (0.4948 g, 43% yield): p.f. (HCl salt) > 250 ° C; XH NMR (salt of HCl, DMSO-de) d 1.8-2. (s broad, 4H, -CH2CH2-), 2.2-4.6 (complex, 11H, 5 -CH2- and 1 -CH-), 2.9 (s, 3H, -NCH3), 6.1 (d, J = 10.2 Hz, 1H, -CH-), 7.53 (d, J = 8.5 Hz , 1H, aromatic), 7.89 (s, 1H, aromatic), 7.91 (s, 1H, aromatic), 8.12 (d of d, J = 2.2 Hz and 8.5 Hz, 1H, aromatic), 8.4 (s, 1H, aromatic). EM (FAB) m / z 507 Anal. (C, H, N) C 23 H 24 N 4 O Cl 2 HCl.

EXAMPLE 37 2- (3 ^ 4-Dichlorophenyl) -N-metul-N- [(±) -trans-2- (1-pyrrolidinyl) -7-nitro-1,2,3-tetrahydrone-1-yl] acetamide ((±) -9, ADL-01-0031-3) ADL-01-0031-3 was prepared by the general coupling procedure DCC / pyr of (±) -2 (1.8173 g, 6,600 mmoles), 3,4-dichlorophenylacetic acid (2.7066 g, 13.20 mmoles), DCC (2.8057 g, 13.60 mmoles), and pyr (1.10 mL, 13.6 mmol). The product was purified by flash column eluting with CH2C12: 2% H3: 1% MeOH then converted to the HCl salt with Et20-HCl and washed with hot MeOH to yield (+) - 9HC1 (2.49 g, 76%): pf (Get ouf of HCl) 255-257 ° C; 1R NMR (HCl salt, DMSO-d6) d 1.8-2 (broad s, 4H, -CH2CH2-), 2-4.2 (complex, 11H, of 5 -CH2- and 1 -CH-), 2.83 (s, 3H, -NCH3), 6.1 (d, J = 9.8 Hz, 1H, -CH-), 7.3-7.7 (complex, 5H, aromatic), 8.06 (d of d, J = 2.4 Hz and 8.6 Hz, 1H, aromatic). MS (FAB) m / z 462. Anal. (C, H, N) C23H25N3? 3Cl2 HCl. EXAMPLE 38 2- (3,4-Dichlorophenyl) -N-methyl-N- [(+) - trans-2- (1-pyrrolidinyl) - 7-amino-1, 2, 3, 4-tetrahydronaphth-1- il] acetamide ((±) -1Q, ADL-01-0032-1) With stirring at 55 ° C, Raney nickel (50% suspension in H20) is added in small portions to a mixture of (±) -9 ( 2.10 g, 4.54 mmol) and hydrazine hydrate (4 mL) in EtOH (60 mL) until all the hydrazine decomposes in 30 minutes. The mixture was filtered through celite, and the Raney nickel was washed with hot MeOH (120 mL). The filtrate was evaporated and dried in vacuo, then the residue was partitioned between saturated NaHC03. and CH2C12 which was dried (Na2SO4), filtered through celite, and evaporated. The product was purified by gravity column eluting with CHC13: 2% NH3: 0.5% MeOH then converted to HCl salt with Et20-HCl to yield (±) -10HCl (0.3 g, 14%, non-optimized): m.p. (HCl salt) > 250 ° C; * H NMR (free base, CDC13) d 1.64 (broad s, 4H, -CH2CH2-), 1.9-3.8 (complex, 11H, 5 -CH2- and 1 -CH-), 2.59 (s, 3H, -NCH3) , 5.8 (d, J = 9.7 Hz, 1H, -CH-), 6.29 (s, 1H, aromatic), 6.43 (d, J = 8 Hz, 1H, aromatic), 6.8 (d, J = 8 Hz, 1H , aromatic), 7.17 (d, J = 8 Hz, 1H, aromatic), 7.3 (m, 2H, aromatic). MS (FAB) m / z 432. Anal. (C, H, N) C23H27N30C122HC1. Example 39 2- (4-Methylsulfonylphenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7-nitro-l, 2,3,4-tetrahydronaphth-l-yl] acetamide ((+) -ll, ADL-01-0034-7) The ADL-01-0034-7 was prepared by the DCC / pyr general coupling procedure from (+) -2 (0.3414 g, 1240 mmole), 4-methylsulfonylphenylacetic acid (0.5309 g, 2.478 mmole), DCC (0.5288 g, 2563 mmoles), and pyr (0.21 mL, 2.55 mmoles). After stirring at 25 ° C overnight, more were added of 4-methylsulfonylphenylacetic acid (0.5307 g, 2.477 mmol), DCC (1.1356 g, 5.504, mmol), and CH2C12 (13 mL), and the mixture was worked up according to the general procedure after another night of stirring. The product was purified by gravity column eluting with CHC13: 2% NH3: 1% MeOH then converted to the HCl salt with Et2-0-HCl and washed with hot MeOH to yield (±) -11 HCl (0.4455 g , 76%): pf (HCl salt) 284-285 ° C; NMR (HCl salt, DMSO-de) d 1.96 (broad s, 4H, -CH2CH2-), 2.1-4.3 (complex 11H, 5, -CH2- and 1 -CH-), 2.88 (s, 3H, -NCH3), 3.24 (s, 3H, -S02CH3), 6.13 (d, J = 10 Hz, 1H, -CH-), 7.51 (d, J = 8.8 Hz, 1H, aromatic), 7.68 (m, 3H, aromatic), 7.9 (d, J = 8.7 Hz, 2H, aromatic), 8.08 (d of d, J = 2.6 Hz and 8.5 Hz, 1H, aromatic). MS (FAB) m / z 472. Anal. (C, H, N) C24H29N305SHC1 0.25CH2C12. Example 40 2- (3,4-Dichlorophenyl) -N-RETHYL-N-. { [±] -trans-2- [1-pyrrolidinyl] -7- [N, N-bis- (t-butoxycarbonylmethyl) -amino] -1,2,3,4-tetrahydronaphth-1-yl} ketamide ((+) - 12, ADL-01-0037-0) With stirring in H20 frozen under N2, t-butyl bromoacetate (0.34 mL, 2.32 mmol) was added dropwise to a mixture of (±) -10 ( 0.4014 g, 0.928 mmol) and NEt (iPr) 2 (0.81 mL, 4.64 mmol) in dry THF (10 mL). After 10 minutes, the mixture was stirred at 25 ° C under N2 overnight then more t-butyl bromoacetate (0.30 mL) was added at 25 ° C. After stirring overnight, added more NEt (iPr) 2 (0.40 mL) and t-butyl bromoacetate (0.30 mL), and after one more night of stirring, the mixture was partitioned between NaHCO 3 satur. and CH2C12. The aqueous fraction was extracted with more CH2C12, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The crude product was purified by gravity column eluting with CH2C12: 2% NH3: 1% MeOH then part of the free base was converted to the HCl salt with 1.0 M HCl in Et20 with stirring in frozen H20. The residue was sonicated in hexane to yield (±) -12 2HC1 (0.1610 g, 25%, non-optimized): m.p. (HCl salt) 143 ° C (dec); 1H NMR (free base, CDC13) d 1.39 (s, 9H, t -butyl), 1.43 (s, 9H, t -butyl), 1.65 (broad s, 4H, -CH2CH2-), 1.9-4.1 (complex, 15H , 7-CH2- and 1-CH-), 2.58 (s, 3H, -NCH3), 5.8 (m, 1H, -CH-), 6.2-7.4 (complex, 6H, aromatic). MS (FAB) 660. Anal. (C, H, N) C35H47N3? 5Cl2 2HC1 0.5CH3CN. Example 41 2- (3,4-Dichloroenyl) -N-methyl-N-. { [±] -trans-2- [1-pyrrolidinyl] -7-N, N-bis- (carboxymethyl) amino] -1,2,3,4-tetrahydronaphth-1-yl} acetamide ((±) -13, ADL-01-0044-6) A solution of (+) - 12 (0.35 g, 0.5 mmol) in 1: 1 AcOH and 3 N of HCl (8 mL) with some anisole (2 drops) was stirred at 25 ° C overnight after conc. HCl was added. (0.5 mL), and the mixture was heated at 40 ° C for 1 h. Then some anisole (4 drops) was added, and the mixture was stirred at 25 ° C for 5 h then it was evaporated. The residue was sequentially evaporated from iPrOH and PhCH3 then sonicated with Et20 to yield (±) -13HC1 (0.2360 g, 81%): m.p. (HCl salt) 160 ° C (dec); XH NMR (HCl salt, DMSO-d6) d 1.93 (broad s, 4H, -CH2CH2-), 2.2-4.3 (complex, 15H, 7 -CH2- and 1 -CH-), 2.79 (s, 3H, - NCH3-), 5.93 (d, J = 10.7 Hz, 1H, -CH-), 6.37 (s, 1H, aromatic), 6.68 (d, J = 8.8 Hz, 1H, aromatic), 7.00 (d, J = 8.1 Hz, 1H, aromatic), 7.40 (d, J = 8.1 Hz, 1H, aromatic), 7.63 (m, 2H, aromatic). MS (FAB) m / z 490 (M + 1-CH 2 CO 2 H). Anal. (C, H, N) C27H3? N305Cl2lHCl. Example 42 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [±] -trans-2 [1-pyrrolidinyl] -7- [N, N-bis- (ethoxycarbonylmethyl) -amino] -1,2,3,4-tetrahydronaf-l-yl} actamidide ((±) -14, ADL-01-0Q52-9) With stirring H20 frozen under N2, ethyl bromoacetate (0.47 mL, 4.21 mmol) was added dropwise to a mixture of (+) - 10 (0.3640 g, 0.842 mmoles) and NEt (iPr) 2 (0.88 mL, 5.05 mmol) in dry THF (6 mL). After minutes, the mixture was stirred at 25 ° C under N2 overnight then it was partitioned between NaHC03 satur. and CH2C12. The aqueous fraction was extracted with more CH2C12, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was purified by gravity column eluting with CH2C12: 2% NH3: 1% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and washed with Et20 to produce (±) -14HC1 (0.27 g, 47%): m.p. (HCl salt) 128 ° C (dec); XH NMR (HCl salt, DMSO-d6) d 1.2 (m, 6H, 2 -CH3), 1.9 (broad s, 4H, -CH2CH2-), 2.2-4.4 (complex, 19H, 9 -. 9-CH2 and 1 -CH-), 2.78 (s, 3H, -NCH3), 5.9 (d, J = 10.3 Hz, 1H, -CH-), 6.14 (s, 1H, aromatic), 6.49 (d, J = 8.2 Hz, 1H, aromatic), 6.91 (d, J = 8.3 Hz, 1H, aromatic), 7.39 (d, J = 8.3 Hz, 1H, aromatic), 7.6 (m, 2H, aromatic). MS (FAB) m / z 605. Anal. (C, H, N) C3iH39N3? 5Cl2 1.25HC1 0.3CH3CN. EXAMPLE 43 2- (3,4-Dichlorophenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7- (N-diethylphos oramidato-amino) -1,2,3, 4-tetrahydrona tl-yl] acetamide ((±) -15 ADL-01-0053-7) With stirring in H0 frozen under N2, diethyl chlorophosphate (0.57 mL, 3.92 mmol) was added dropwise to a mixture of (± ) -10 (0.3393 g, 0.785 mmoles) and NEt (iPr) 2 (0.82 mL, 4.71 mmoles) in dry THF (6 mL). After minutes, the mixture was stirred at 25 ° C under N2 overnight after the mixture was evaporated and dried in vacuo. The residue was partitioned between saturated NaHCO 3. and CH2C12. The aqueous fraction was extracted with more CHC12, and the combined organic fraction was dried (a2SO4), filtered through celite, and evaporated. The product was purified by gravity column eluting with CH2C12: 2% NH3: 1.5% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and sonicated in Et20 to yield (±) -15 HCl (0.4205 g , 89%): pf (HCl salt) 247- 249 ° C; XH NMR (HCl salt, DMSO-d6) d 1.2 (m, 6H, 2 -CH3), 1.95 (broad s, 4H, -CH2CH2-), 2.2-4.1 (complex, 15H, 7 -CH2- and 1- CH-), 2.75 (s, 3H, -NCH3), 5.98 (d, J = 10.3 Hz, 1H, -CH-), 6.7 (s, 1H, aromatic), 6.9 (m, 1H, aromatic), 7.03 ( d, J = 8.4 Hz, 1H, aromatic), 7.3 (d of d, J = 2 Hz and 8.2 Hz, 1H, aromatic), 7.6 (m, 2H, aromatic), 7.92 (d, J = 9.7 Hz, - NHP). MS (FAB) m / z 568. Anal. (C, H, N) C ^ HseN ^ PCl;, HCl 0.25H2O. Example 44 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [±] -trans-2- [1-pyrrolidinyl] -7- [N-2- (diethylphosphoryl) ethyl-amino] -1,2,3,4-tetrahydronaphth-l- yl] acetamide ((±) - 16, ADL-01-0070-l) With stirring in H20 frozen under N2, diethyl 2-bromoethylphosphonate (0.8601 g, 3.52 mmol) was added to a mixture of (±) -10 (0.3042 g, 0.704 mmole) and NEt (iPr) 2 (0.74 mL, 4.2 mmol) in dry THF (4 mL). After 10 minutes, the mixture was stirred at 25 ° C under N2 for 2.5 days then more diethyl 2-bromoethylphosphonate (0.8546 g) and NEt (iPr) 2 (0.74 mL, 4.2 mmol) was added. After stirring for a further 14 days, the mixture was evaporated to dryness and dried in vacuo then the residue was partitioned between saturated NaHC03. and CH2C12. The aqueous fraction was extracted with more CH2C12, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was purified by gravity column eluting with CH2C12: 2% NH3: 1% MeOH and then by radial chromatography eluting with CH2C12: 2% NH3. The product was converted to the HCl salt with 1.0 M HCl in Et20 and solidified by evaporation of CH2C12 and sonication with Et20 to yield (±) -16HCl (0.2466 g, 52%): m.p. (HCl salt) 151 ° C (dec); 2H NMR (HCl salt, DMS0-d6) d 1.24 (t, J = 7 Hz, 6H, 2 -CH3), 1.93 (broad s, 4H, -CH2CH2-), 2-4.3 (complex, 19H, 9- CH2- and 1 -CH-), 2.8 (s, 3H, NCH3), 5.96 (d, J = 10.2 Hz, 1H, -CH-), 6.69 (broad s, 1H, aromatic), 6.87 (d, J = 7.5 Hz, 1H, aromatic), 7.11 (d, J = 8.1 Hz, 1H, aromatic), 7.43 (d, J = 8.3 Hz, 1H, aromatic), 7.64 (m, 2H, aromatic). MS (FAB) m / z 596. Anal. (C, H, N) C29H40N3O4PCl2 2HC1. Example 45 2- (3,4-dichlorophenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -6-methoxy-7- (N-benzyl-N-methylaminosulfonyl) -1 , 2,3,4-tetrahydronaphth-l-yl] acetamide ((+) - 19, ADL-01-0090-9). The ADL-01-0090-9 was prepared by the general coupling procedure DCC / pyr from (±) -17 (0.6213 g, 1.40 mmoles), 3,4-dichlorophenylacetic acid (0.5764 g, 2.81 mmoles), DCC (0.5951 g, 2.88 mmoles), and pyr (0.23 mL, 2.88 mmoles). The product was chromatographed by gravity column eluting with CH2C12: 2% NH3: 1% MeOH and further purified by radial chromatography eluting with CH2C12: 2% NH3. The product was converted to the HCl salt with 1.0 M HCl in Et20 to yield (±) -19HC1 (0.3 g, 32%): m.p.

(HCl salt) 150 ° C (dec); 1H NMR (HCl salt, DMSO-d6) d 1.91 (broad s, 4H, -CH2CH2-), 2.2-4.1 (complex, 11H, 5 -CH2- and 1 -CH-), 2.55 (s, 3H, - NCH3), 2.77 (s, 3H, -NCH3), 3.88 (s, 3H, -OCH3), 4.2 (s, 2H, -CH2pH), 6.0 (d, J = 9.7 Hz, 1H, -CH-), 7.10 (s, 1H, aromatic), 7.2-7.4 (complex, 7H, aromatic), 7.55 (m, 2H, aromatic). MS (FAB) m / z 630. Anal. (C, H, N) C 32 H 37, 304 Cl 2 S HCl 0.5H 2 O. Example 46 2- (3,4-Dichlorophenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7- (N-benzyl-N-methylaminosulfonyl) -1,2,3 , 4-tetrahydronaphth-l-yl] acetamide ((±) -20, ADL-01-0099-0) ADL-01-0099-0 was prepared by the general coupling procedure DCC / pyr from (±) -18 (0.4530 g, 1.095 mmoles), 3,4-dichlorophenylacetic acid (0.4485 g, 2.19 mmoles), DCC (0.4677 g, 2.27 mmoles), and pyr (0.18 mL, 2.26 mmoles). The product was purified by flash column eluting with CH2C12: 2% NH3 and then by radial chromatography eluting with CH2C12: 2% NH3. The product was converted to the HCl salt with 1.0 M HCl in Et20 and then washed with hot MeOH to yield (±) - 20HC1 (0.33 g, 47%): m.p. (HCl salt) 251-254 ° C; 1H NMR (HCl salt, from DMS0-d6) d 1.97 (broad s, 4H, -CH2CH2-), 2.3-4.2 (complex, 13H, 6 -CH2- and 1 -CH-), 2.49 (s, 3H, NCH3), 2.90 (s, 3H, NCH3), 6.17 (d, J = 10.4 Hz, 1H, -CH-), 7.2-7.8 (complex, 11H, aromatic). MS (FAB) m / z 600. Anal. (C, H, N) C31H35N3S03C12 HCl.

EXAMPLE 47 2- (2-Nitro-4,5-dichloro-enyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -indan-1-yl] acetamide ((±) - 24, ADL-01-0104-8) The ADL-01-0104-8 was prepared by the DCC / pyr general coupling procedure from (±) -23 (0.4265 g, 1971 mmoles), 2-nitro-4,5-dichlorophenylacetic acid (0.9859 g, 3,943 mmol), DCC (0.8350 g, 4. 047 mmole), and pyr (0.33 mL, 4.06 mmole). The unpurified product was purified by column on silica gel eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH to yield (+) - 24HC1 (0.3630 g, 38%, first harvest): m.p.

(HCl salt) 284-287 ° C; XH NMR (HCl salt, DMSO-d6) d 1.8- 2.1"(broad s, 4H, -CH2CH2-), 2.84 (s, 3H, NCH3), 3-4.4 (complex, 9H, 4 -CH2- and 1 -CH-), 6.37 (d, J = 8 Hz, 1H, -CH-), 7. 08 (broad s, 1H, aromatic), 7.3 (m, 3H, aromatic), 7.92 (s, 1H, aromatic), 8.41 (s, 1H, aromatic). EM (FAB) m / z 448. Anal (C, H, N) C22H23N303C12HC1. Example 48 2- (2-Nitro-4-trifluoromethylphenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -indan-1-yl] acetamide ((±) -26, ADL -01-0106-3) The ADL-01-0106-3 was prepared by the general coupling procedure DCC / pyr from (±) -23 (0.3229 g, 1492 mmol), 2-nitro-4-trifluoromethylphenylacetic acid (0.5579 g, 2.24 mmol), DCC (0.5512 g, 2.67 mmol), and pyr (0.19 mL, 2.31 mmol). The crude product was chromatographed by gravity column eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH Et20 to yield (±) -26HC1 (0.3643 g , 50%): pf (HCl salt) 249-250 ° C; XH NMR (HCl salt, DMSO-d6) d 1.8- 2.1 (broad s, 4H, -CH2CH2-), 2.89 (s, 3H, -NCH3), 3-4.6 (complex, 9H, 4 -CH2- and 1 -CH-), 6.40 (d, J = 8.1 Hz, 1H, -CH-), 7.1 (broad s, 1H, aromatic), 7.3 (m, 3H, aromatic), 7. 83 (d, J = 8.1 Hz, 1H, aromatic), 8.17 (d, J = 7.8 Hz, 1H, aromatic), 8. 41 (s, 1H, aromatic). MS (FAB) m / z 448. Anal (C, H, N) C23H24N3? 3F3 HCl. Example 49 2, 2-Diphenyl-N-methyl-N- [(±) -tran3-2- (1-pyrrolidinyl) -indan-1-yl] acetamide ((±) -28, ADL-01-0108-9 ) ADL-01-108-9 was prepared by the general DCC / pyr coupling procedure from (±) -23 (0.2615 g, 1,209 mmoles), diphenylacetic acid (0.5123 g, 2.41 mmoles), DCC (0.5138 g, 2.49 mmoles), and pyr (0.20 mL, 2.5 mmol). The crude product was purified by gravity column eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH to yield (±) -28HC1 (0.3815 g, 71%): m.p. (HCl salt) > 300 ° C; XH NMR (HCl salt, DMSO-de; cis-trans rotamers were observed at a ratio of approximately 3.6 to 1. Only peaks were reported for the major rotamer.) D 1.88 (broad s, 4H, -CH2CH2-) , 2.75 (s, 3H, NCH3), 3-4.2 (complex, 7H, 3 -CH2- and 1 -CH-), 5.61 (s, 1H, -CH-), 6.5 (d, J = 8 Hz, 1H , -CH-), 6.88 (d, J = 6.5 Hz, 1H, aromatic), 7.1-7.4 (complex, 13 H, aromatic). MS (FAB) m / z 411. Anal. (C, H, N) C28H30N2O HCl 0.75 H2O. Example 50 2- (4-Methylsulfonylphenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -indan-1-yl] acetamide ((+) - 29, ADL-01-0109 -7) The ADL-01-0109-7 was prepared by the general coupling procedure DCC / pyr from (±) -23 (0.3271 g, 1.51 mmoles), 4-methylsulfonyl-phenylacetic acid (0.6464 g, 3.017 mmoles), DCC (0.6438, 3.12 mmoles), and pyr (0.25 mL, 3.1 mmoles). The product was purified by gravity column eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH Et20 to yield (±) -29HC1 (0.5295 g, 78 %): pf (HCl salt) 246-248 ° C; 1R NMR (HCl salt, DMSO-de) d 1.8-2 (broad s, 4H, -CH2C12-), 2.81 (s, 3H, -NCH3), 2.9-4.2 (complex, 9H, 4 -CH2- and 1-CH-), 3.21 (s, 3H, -S02CH3), 6.4 (d, J = 8.1 Hz, 1H, aromatic), 7 (m, 1H, aromatic), 7.3 (m, 3H, aromatic), 7.58 (d, J = 8.1 Hz, 2H, aromatic), 7.9 (d, J = 7.8 Hz, 2H, aromatic). MS (FAB) m / z 413. Anal. (C, H, N) C23H28N2S03 HCl 0.25H2O Compounds of formula III Compounds having the following structures were prepared The compounds 1-5 were prepared by the method described in Chang, A.-C. Ph.D. Thesis, University of Minnesota Twin Cities, 1995. 9, ADL-01-0113-9, X «-N? |, Z-2-NH2 10, ADL-01) 115-4, X = -NQ, Z-2-NOi 11, ADL-01-0124- 6, X "= - NHPQEt2, Z-2-HP? 3Et2 12, ADL-01-012« S-1, X «-N (SQMe) 2, Z« 2-N (S02Me) 2 13, ADL-01 -0128-7, X- < -NQ, Z = 2-N? 2-4.5-Cl2 14, ADL-01-0129-5, X-NQ, Z-4-m lsúlfonil 15, ADL- 01 -0132-9, X-NQ, Z-4-NH2 16, ADL-01-0133-7, X = -NQ, Z ^ -N'SOiMek 17, AD -01-0136-0, X «- Nr * ¡, Z = 4-N {S? 2Mc) 2 18, ADL-01-0138-t, X = -NQ, Z = 4-NHBoc 19, ADL-01-0139-4, X «- NHPQEt2, Z = 4-N (SO, Me) 2 Compounds 9-19 were prepared from the appropriate arylacetic acids by DCC / pyr coupling, followed by reduction, deprotection, and / or derivatization by known chemistry. Intermediary 8 was prepared by the method described in Chang, A.-C. Ph.D. Thesis, University of Minnesota-Twin Cities, 1995.

Intermediate 20 was prepared by minor modifications of known methods.7'8 Compounds 23 (EMD 60400) and 24 (EMD 61753) are known compounds that were synthesized at home by minor modifications of reported methods.9 Compounds 21, 22 and 25-27 were prepared by DDC coupling, followed by reduction where applicable. Ref / (7) Costello, G. F. et al. J. Med. Chem. 1991, 34, 181-189. (8) Naylor, A., et al., J. Med. Chem. 1994, 37, 2138-2144. (9) Gottschlich, R., et al .. Bioorg. Med. Chem. Letters 1994, 4, 677-682. Example 51 2- (3,4-dichloro-enyl) -N-methyl-N-. { [ÍS] -1- [N- (S-aspartic acid-a-amide-S-aspar-ico-a-amido) -3-amino-enyl] -2- [1- pyrrolidinyl] ethyl} acetamide (6, ADL-01-0010-7) With stirring in H20 frozen under N2, 1,3-dicyclohexylcarbodiimide (DCC, 0.353 g, 1711 mmol) and dry CH2C12 (2 L) were added to a mixture of 5 t- butylester (0.311 g, 0.538 mmol), N-Boc-L-aspartic acid-β-t-butylester (0.495 g, 1.711 mmol), and 1-hydroxybenzotriazole (HOBT, 0.232 g, 1.717 mmol) in dry CH2C12 (8 mL ). After 5 minutes, the mixture was stirred at 25 ° C under N2 overnight then H20 (1 mL) was added, and the mixture was filtered through celite. The 1,3-dicyclohexylurea (DCU) was washed with CH2C12 (18 mL). The filtrate was partitioned between NaHCO 3 satur. and CH2C12 which was dried (Na2SO4), filtered through celite, and evaporated. After flash column chromatography eluting with CH2C12: 2% NH3: 2% MeOH, the protected intermediate (0.411 g, 90%) was dissolved in 3N HCl (4 mL), AcOH (4 mL) with anisole (2 drops) ), and stirred at 25 ° C overnight. The mixture was then evaporated to dryness, and evaporation from iPrOH then produced ADL-01-0010-7: XH NMR (HCl salt, DMSO-de) d 2.0 (broad s, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 6.1 (broad m, 1H, -CH-). MS (FAB) m / z 636. Anal. (C, H, N) C29H35N507C12 1.5 HCl 0.25iPrOH. Example 52 2- (3,4-dichlorophenyl) -N-methyl-N-. { [SS] -1- [N- (bis-methyl-3-phonamido) -3-aminophenyl] -2- [1-pyrrolidinyl] ethyl} acetamide (7, ADL-01-0011-5) With stirring at 25 ° C, a solution of methanesulfonyl chloride (MsCl, 0.25 mL, 3.2 mmol) in dry CH2C12 (0.75 mL) was added to a mixture of ADL-01 -0007-3 (0.225 g, 0.554 mol) and Et3N (1 mL, 7 mmol) dry CH2C12 (4 mL), and the mixture was stirred at 25 ° C adapted with a dried tube. After 5 h, more CH2C12 (6 L), MsCl (0.5 mL), and Et3N (2 mL) were added, and the mixture was stirred at 25 ° C overnight then split between CH2C12 (50 L) and NaHC03 satur. The aqueous fraction was extracted with more CH2C12 (25 mL), and the combined organic fraction was dried (Na2S0), filtered through celite, and evaporated. Acetonitrile was used for azeotrope outside Et3N after the product was chromatographed by gravity column eluting twice with CH2C12: 2% NH3: 2% MeOH. The pure product was then treated with 1.0 M HCl in Et20 to produce 7HC1 (0.131 g, 39%, not optimized): m.p. (HCl salt) 145 ° C (dec.); NMR (free base, CDC13) d 1.7 (broad s, 4H, -CH2CH2-), 2.4-3.8 (8H complex, 4 -CH2-), 2.7 (s, 3H, -NCH3), 3.37 (s, 6H, 2 -S02CH3), 6.1 (m, 1H, -CH-), 7.1-7.4 (complex, 7H, aromatic). MS (FAB) m / z 562. Anal. (C, H, N) C23H29N305S2C12HC1 0.75H2O. Example 53 2- (2-Nitrophenyl) -N-methyl-N- [(SS) -1- (3-nitro-enyl) -2- (1-pyrrolidinyl) ethyl] acetamide (10, ADL-01-0115-4 ) The ADL-01-0115-4 was prepared by the DCC / pyr general coupling procedure from 8 (1.4886 g, 5.97 mmol), 2-nitrophenylacetic acid (2.1619 g, 11.93 mmoles), DCC (2.5402 g, 12.31 mmoles), and pyridine (1.00 mL, 12.36 mmoles). The crude product was converted to the HCl salt with Et20-HCl without chromatography and crystallized from MeOH-Et20. The first crop was recrystallized again from MeOH-Et20 to yield 10HC1 (1.3663 g, 51%): m.p. (HCl salt) 258-259 ° C; XH NMR (HCl salt, DMSO-d6) d 1.97 (broad s, 4H, -CH2CH2-), 2.91 (s, 3H, -NCH3), 3.11-4.45 (complex, 8H, 4 -CH2-), 6.17 ( m, 1H, -CH-), 7.51-8.25 (complex, 8H, aromatic). MS (FAB) m / z 413. Anal. (C, H, N) C2? H24N405HCl 0.25H2O. Example 54 2- (2-aminophenyl) -N-methyl-N- [(SS) -1- (3-aminophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide (9, ADL-01-0113-9) With stirring at 55 ° C, Raney nickel in small amounts was added to a mixture of 10 (0.9857 g, 2. 3899 mmoles) and hydrazine hydrate (55%, 2 mL) in EtOH (30 mL) until the evolution of gas stopped in approximately 10 min. The mixture was then filtered through celite, and the Raney nickel was washed with hot MeOH (100 mL). The filtrate was evaporated and dried in vacuo then the residue was partitioned between saturated NaHC03. and CH2C12, which was dried (Na2SO4), filtered through celite, and evaporated. The product was chromatographed by gravity column eluting with CHC13: 2% NH3: 2% MeOH was then converted to the HCl salt with Et20-HCl to yield 93HC1 (0.3159 g, 29%, not optimized): m.p. (HCl salt) 219-222 ° C; 1H NMR (HCl salt, DMSO-d6) d 1.98 (broad s, 4H, -CH2CH2-), 2.87 (s, 3H, -NCH3), 3.2-4.3 (complex, 8H, 4 -CH2-), 6.1 ( m, 1H, -CH-), 7.11-7.45 (complex, 8H, aromatic). MS (FAB) m / z 353. Anal (C, H, N) C2? H28N40 3HCl0. 25H2O. Example 55 2- (N-diethylphosphoramidate-2-aminophenyl) -N-methyl-N- [(SS) -1- (N-diethylphosphoramidate-3-aminophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide (11 ADL-01 -0124-6) With stirring in H20 frozen under N2, diethyl chlorophosphate (0.53 mL, 3.67 mmol) was added to a mixture of 9 (0.2394 g, 0.6792 mmoles) and NEt (iPr) 2 (0.77 mL, 4.40 mmoles) in dry THF (5 mL). After 10 minutes, the mixture was stirred at 25 ° C under N2 for 3.5 days then diluted with CH2C12, evaporated, and dried in vacuo. The residue was partitioned between saturated NaHCO 3. and CH2C12. The aqueous fraction was extracted with more CH2C12, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was chromatographed eluting with CH2C12: 2% NH3: 2% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from iPrOH Et20 to produce 11 HCl (0.2364 g, 53%): p.f. (HCl salt) 184-186 ° C; XH NMR (salt of HCl, DMSO-d6) d 1.2 (m, 12H, 4-CH3), 1.96 (broad s, 4H, -CH2CH2-), 2.81 (s, 3H, -NCH3), 3-4 (complex, 16H, 8 -CH2-), 6. 05 (m, 1H, -CH-), 6.7-7.3 (complex, 9H, aromatic and 1 NH), 8.08 (d, J = 9.4 Hz, 1H, NHP). MS (FAB) m / z 625. Anal. (C, H, N) C29H46N407P2 HCl. Example 56 2- (M-Bis-sulphonamido-2-aminofenyl) -N-methyl-N- [(SS) -1- (N-bis-sulphonamido-3-aminophenyl) -2- (1-pyrrolidinyl ) ethyl] acetamide (12, ADL-01-0126-1) With stirring at 0 ° C under N2, MsCl (0.61 mL, 7. 87 mmole) was added to a mixture of 9 (0.2774 g, 0. 787 mmol) and Et3N (2.2 mL, 15.7 mmol) in CH2C12 (8 mL).

After 10-15 minutes, the mixture was stirred at 25 ° C under N2 overnight after the mixture was partitioned between NaHCO 3 satur. and CH2C12. The aqueous fraction was extracted with more CH2C12, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. Acetonitrile was added to the quenched Et3N azeotrope. The product was chromatographed with flash column eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 to produce 12HC1 (0.3564 g, 65%): m.p. (HCl salt) 180 ° C; 1 HOUR NMR (HCl salt, DMSO-d6) d 2.0 (broad s, 4H, -CH2CH2-), 2.76 (s, 3H, -NCH3), 3-4.3 (complex, 8H, 4 -CH2-), 3.53 (s, 12H, 4 -S02CH3), 6.25 (m, 1H, -CH-), 7.3-7.6 (complex , 8H, aromatic). MS (FAB) m / z 665. Anal. (C, H, N) C25H36N409S4HC1 MeOH. Example 57 2- (2-Nitro-4,5-dichloro-enyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (1-pyrrolidinyl) ethyl] -cetamide (13, ADL -01- 0128-7) The ADL-01-0128-7 was prepared by the general coupling procedure DCC / pyr from 8 (0.3690 g, 1.4801 mmol), 2-nitro-4,5-dichlorophenyl-acetic acid (0.7301 g, 2920 mmol), DCC (0.6213 g, 3. 01 mmoles), and pyridine (0.24 mL, 3.01 mmol). The unpurified product was converted to the HCl salt with Et20 HCl without chromatography and crystallized from MeOH to yield 13HC1 (0.3232 g, 42%): m.p. (HCl salt) 165 ° C (dec); XH NMR (HCl salt, DMSO-de) d 2.0 (broad s, 4H, -CH2CH2-), 2.93 (s, 3H, -NCH3), 3.1-4.3 (complex, 6H, 3 -CH2-) 4.4 (s , 2H, benzylic methylene), 6.2 (m, 1H, -CH-), 7.7-7.8 (m, 2H, aromatic), 7.9 (s, 1H, aromatic), 8.14 (s, 1H, aromatic), 8.27 (d , J = 7.7 Hz, 1H, aromatic), 8.43 (s, 1H, aromatic). MS (FAB) m / z 481. Anal. (C, H, N) C21H22N405C12 HCl 0.5MeOH. Example 58 2- (4-Methylsul onyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide (14, ADL-01-0129- 5) The ADL-01-0129-5 was prepared by the DCC / pyr general coupling procedure from 8 (0.5138 g, 2061 mmol), 4-methylsulfonylphenylacetic acid (0.8825 g, 4.119 mmoles), DCC (0.8771 g, 4.251 mmoles), and pyridine (0.34 mL, 4.245 immoles). The crude product was chromatographed by gravity column eluting with CHCl3: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH to yield 14HC1 (0.4695 g, 47%): pf (HCl salt) 276-277 ° C; NMR (HCl salt, DMS0-d6) d 2.0 (broad s, 4H, -CH2CH2-), 2.92 (s, 3H -NCH3), 3.2 (s, 3H, -S02CH3), 3.2-4.3 (complex, 8H, 4 -CH2-), 6.25 (m, 1H, -CH-), 7.61 (d, J = 7.2 Hz, 2H, aromatic), 7.75 (m, 2H, aromatic), 7.89 (d, J = 7 Hz, 2H, aromatic), 8.12 (s, 1H, aromatic), 8.25 (m, 1H, aromatic). MS (FAB) m / z 446. Anal. (C, H, N) C22H27N305SHC1. Example 59 2- (N-Butyloxycarbonyl-4-aminophenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide (18, ADL-01- 0138- The ADL-01-0138-6 was prepared by the general coupling method DCC / pyr from 8 (1.9948 g, 8,001 mol), N-Boc-4-aminophenylacetic acid (3.0589 g, 12. 173 mmole), DCC (2.6602 g, 12.89 mmole), and pyridine (1.04 mL, 12.9 mmol). The crude product was chromatographed on a gravity column eluting with CH2C12,: 2% NH3: 1% MeOH was then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH to yield 18HC1 (0.4891 g, 12%, first harvest): m.p. (HCl salt) 170 ° C (dec); XH NMR (HCl salt, DMSO-d6) d 1.49 (s, 9H.t-butyl), 2.01 (broad s, 4H, -CH2CH2-), 2.83 (s, 3H, -NCH3), 3.1-4.15 (complex , 8H, 4 -CH2-), 6.27 (m, 1H, -CH-), 7.17 (d, J = 8 Hz, 2H, aromatic), 7.39 (d, J = 8 Hz, 2H, aromatic), 7.7 ( m, 2H, aromatic), 8.09 (s, 1H, aromatic), 8.23 (d, J = 6 Hz, 1H, aromatic), 9".3 (s, 1H, -NHBoc) EM (FAB) 483. Anal (C, H, N) C26H34N405 HCl 0.25 H20, Example 60 2- (4-Aminophenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide (15, ADL-01-0132-9) The ADL -01-0138-6 (2.9211 g, 6.053 mmol) and anisole (2 drops) were mixed in AcOH (10 mL) and 4N HCl (10 mL) and stirred at 25 ° C overnight, adapted with a drying tube. . The mixture was adjusted to pH 13 with 1N NaOH with stirring in frozen H20 and then extracted with CH2C12 (2 X 70 mL). The combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was chromatographed by gravity column eluting with CHCl3: 2% NH3 then converted to the HCl salt with Et20 HCl to produce 15HC1 (0.5531 g, 22%, not optimized): m.p. (HCl salt) 200 ° C (dec); XH NMR (HCl salt, DMSO-d6) d 1.98 (broad s, 4H, -CH2CH2-), 2.87 (s, 3H, -NCH3), 3.2-4.3 (complex, 8H, 4 -CH2-), 6.25 ( m, 1H, -CH-), 7.16 (d, J = 7.4 Hz, aromatic 2H), 7.33 (d, J = 7.5 Hz, aromatic 2H), 7.7 (m, 2H, aromatic), 8.08 (s, 1H, aromatic), 8.23 (m, 1H, aromatic) MS (FAB) m / z 383. Anal. (C, H, N) C2? H26N4032HCl 0.75 H20. Example 61 2- (N-Bis-sulfonamido-4-aminophenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide (16, ADL- 01-0133- 21 With stirring in H20 frozen under N2, a solution of MsCl (1.56 mL, 20.17 mmol) in CH2C1, (6 mL) was added dropwise over 2-3 minutes to a mixture of 15 (1.5430 g, 4.0344 immoles) and Et3N (5.6 mL, 40 mmol) in CH2C12 (24 mL). After 10 minutes, the mixture was stirred at 25 ° C under N2 overnight then the mixture was partitioned between CH2C12 and NaHC03 satur. The aqueous fraction was extracted with more CH2C12, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. Acetonitrile was added to the quenched azeotrope of Et3N then the crude product was chromatographed by flash column eluting with CH2C12: 2% NH3. The product was converted to the HCl salt with 1.0 M HCl in Et20 and washed with hot MeOH to yield 16HC1 (1.3091 g, 56%, first harvest): m.p. (HCl salt) 257-259 ° C; XH NMR (HCl salt, DMSO-d6) d 1.99 (broad s, 4H, -CH2CH2-), 2.87 (s, 3H, -NCH3), 3.15-4.3 (complex, 8H, 4 -CH2-), 3.51 ( s, 6H, 2 -S02CH3), 6.25 (m, 1H, -CH-), 7.4 (m, 4H, aromatic), 7.7 (m, 2H, aromatic), 8.1 (s, 1H, aromatic), 8.21 (m , 1H, aromatic). MS (FAB) m / z 539. Anal. (C, H, N) C23H3oN4? 7S2 HCl 0.5CH2C12. Example 62 2- (N-bis-sulfonamido-4-aminophenyl) -N-methyl-N- [(SS) -1- (3-aminophenyl) -2- (1-pyrrolidinyl) ethyl] cetamide (17, ADL- 01-0136- The ADL-01-0136-0 was prepared from 16 (1.0729 g, 1992 mmoles), Raney nickel, and hydrazine hydrate (2 mL) in EtOH (30 mL). The conditions were similar to those used for the preparation of 9. The product was chromatographed by gravity column eluting with CH2C12: 2% NH3, and the pure fractions were converted to the HCl salt with 1.0 M HCl in Et20 to produce 17HC1 (0.1194 g, 11%, not optimized): m.p. (HCl salt) 252-255 ° C; XH NMR (HCl salt, DMSO-d6) d 2.0 (broad s, 4H, -CH2CH2-), 2.86 (s, 3H, -NCH3), 3.1-4.2 (complex, 8H, 4 -CH2-), 3.54 ( s, 6H, 2 -S02CH3), 6.1 (m, 1H, -CH-), 6.8-7.5 (complex, 8H, aromatic). MS (FAB) m / z 509. Anal. (C, H, N) C23H32N4? 5S2 1.75HC1. Example 63 2- (N-Bis-sulfonamido-4-aminophenyl) -N-methyl-N- [(SS) -1- (N-diethylphosphoramide-3-aminophenyl) -2- (1-pyrrolidinyl) ethyl] acetamide ( 19, ADL-01-0139-4) With stirring in H20 frozen under N2, diethyl chlorophosphate (0.84 mL, 5.81 mmol) was added to a mixture of 17 (0.7383 g, 1.4514 mmol) and NEt (iPr) 2 (1.5 mL, 8.7 mmol) in dry THF (15 mL). After 10 minutes, the mixture was stirred at 25 ° C under N2 overnight, then THF (15 mL), NEt (iPr) 2 (0.76 mL), and diethyl chlorophosphate (0.42 mL) were added sequentially. After 3 h, the mixture was quenched with H20, diluted with CH2C12, evaporated, and dried in vacuo. The residue was divided between CH2C12 and NaHC? 3 satur. The aqueous fraction was extracted with more CH2CI2, and the combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product without purify was chromatographed by flash column eluting with CH2C12: 2% NH3: 1.5% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH to produce 19HC1 (0.3274 g, 33%): pf (HCl salt) 245-247 ° C; XH NMR (HCl salt, DMSO-d6) d 1.193 (t, J = 7 Hz, 6H, 2 -CH3), 1.95 (broad s, 4H, -CH2CH2-), 2.81 (s, 3H, -NCH3), 3.1-4.1 (complex, 12H, 6 -CH2-), 3.52 (s, 6H, 2 -S02CH3), 6.1 (m, 1H, -CH-), 6.79 (d, J = 7.3 Hz, 1H, aromatic), 6.91 (s, 1H, aromatic), 6.99 (d, J = 7.7 Hz, 1H, aromatic), 7.23 (t, J = 7.8 Hz, 1H, aromatic), 7.36 (d, J = 8.3 Hz, 2H, aromatic) , 7.44 (d, J = 8.6 Hz, 2H, aromatic), 8.09 (d, J = 9.4 Hz, 1H, -NHP). MS (FAB) m / z 645. Anal. (C, H, N) C27H4? N408S2P HCl. Example 64 2- (2-nitrophenyl) -N-methyl-N-. { [SS] -l-phenyl-2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl} acetamide (21, ADL-01-0055-2) With stirring at 25 ° C under N2, DCC (0.160 g, 0.79 mmol) was added to a mixture of 2-nitrophenylacetic acid (0.140 g, 0.79 mmol) and pyridine (0.064). mL, 0.79 mmol) in CH2C12 (1.5 mL). After 3 minutes, a solution of 20 (0.160 g, 0.72 mmol) in CH2C12 (1.5 mL) was added, followed by NEt (iPr) 2 (0.375 mL, 2.15 mmol). The mixture was stirred at 25 ° C under N2 overnight, then saturated NaHC03 was added, and the mixture was filtered through celite. The DCU was washed with a little CH2C12, and the filtrate was partitioned between saturated NaHC03. Y CH2C12 which was dried (MgSO4), filtered through celite, and evaporated. Toluene was added to the quenched azeotrope of pyridine. The product was chromatographed by flash column eluting with CHC13: 2% NH3: 2% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from MeOH to yield 21 HCl (0.14 g, 47%) : pf (HCl salt) 226-227 ° C; XH NMR (HCl salt, DMSO-de) d 1.8-2.4 (m, 2H, -CH2-), 2.86 (s, 3H, -NCH3), 3-4.5 (complex, 8H, 4 -CH2-), 5.5 (m, 1H, -CHOH), 6.1 (m, 1H, -CH-), 73-7.8 (complex, 8H, aromatic), 8.11 (d, J = 8 Hz, 1H, aromatic). MS (FAB) m / z 384. Anal. (C, H, N) C2? H25N304HCl 0.5H2O. Example 65 2- (2-Nitro-4,5-dichlorophenyl) -N-methyl-N-. { [SS] -l-phenyl-2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl} acetamide (22, ADL-01-0056- £ 1 ADL-01-0056-0 was prepared from 20 (0.2 g, 0.91 mmol), 2-nitro-4,5-dichlorophenylacetic acid (0.45 g, 1.8 mmol) ), DCC (0.37 g, 1.8 mmol), NEt (iPr) 2 (0.48 mL, 2.7 mmol), and pyridine (0.15 mL, 1.8 mmol) Conditions are similar to those for the preparation of 21. The product was chromatographed per column eluting with CH2C12: 2% NH3: 1% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and crystallized from iPrOH to produce 22HC1 (0.060 g, 14%): pf (HCl salt 231-233 ° C (desc); * H NMR (HCl salt, DMSO-d6) d 1.8-2.4 (m, 2H, -CH2-), 2.85 (s, 3H, -NCH3), 3.1-4.5 (complex, 8H, 4 -CH2-), 5.5 (m, 1H, -CHOH), 6.1 (m, 1H, -CH-),, 7.2-7.5 (m, 5H, aromatic), 7.88 (s, 1H, aromatic), 8.42 (s, 1H, aromatic) . MS (FAB) m / z 452. Anal. (C, H, N) C2? H23N304Cl2 HCl. EXAMPLE 66 2- (Methyl-sulfonyl-enyl) -N-methyl-N-. { [SS] -l-phenyl-2- [1- (3S) - (3-hydroxypyrrolidinyl) ethyl} acetamide (25, ADL-01-064-4) ADL-01-0064-4 was prepared from 20 (0.2 g, 0.91 mmol), 4-methylsulfonylphenylacetic acid (0.41 g, 1.8 mmol), DCC (0.37 g) , 1.8 mmoles), pyridine (0.15 mL, 1.8 mmol), and NEt (iPr) 2 (0.48 mL, 2.7 mmol). The conditions are similar to those for the preparation of 21. After stirring at 25 ° C overnight, more pyridine (0.075 mL, 0.9 mmol) and DCC (0.18 g, 0.9 mmol) was added, and the reaction was worked on. next day. The product was purified by radial chromatography eluting with CH2C12: 2% NH3: 1% MeOH then converted to the HCl salt with 1.0 M HCl in Et20 and washed with hot iPrOH to produce 25HC1 (0.15 g, 36%): pf (HCl salt) 240-241 ° C; NMR (HCl salt, DMS0-d6) d 1.8-2.4 (m, 2H, -CH2-), 2.8 (d, 3H, cis -NCH3 and trans amide rotamers), 3.23 (s, 3H, - S02CH3). 3.1-4.5 (m, 8H, 4-CH2-), 5.5 (m, 1H, -CHOH), 6.15 (m, 1H, -CH-), 7.2-7.5 (m, 5H, aromatic), 7.55 (m, 2H, aromatic), 7. 85 (m, 2H, aromatic). MS (FAB) m / z 417. Anal. (C, H, N) C22H28N204SHC1. Example 67 2- (2-Nitro-4-tri luoromethyl enyl) -N-methyl-N-. { [SS] -l-enyl-2- [1- (3S) ~ (3-hydroxypyrrolidinyl)] ethyl} acetamide (26, ADL-01-0067-7) With shaking at 25 ° C under N2, DCC (0.39 g, 1.9 mmol) was added to a mixture of 2-nitro-4-trifluoromethylphenylacetic acid (0.47 g, 1.9 mmol) and pyridine (0.15 mL, 1.9 mmol) in CH2C12 (10 mL). After 5 minutes, a solution of 20 (0.4 g, 1.8 mmol) in CH2C12 (5 mL) was added. After 2 h, more DCC (0.1 g, 0.5 mmol) was added, and the mixture was stirred at 25 ° C overnight then more 2-nitro-4-trifluoromethylphenylacetic acid (0.045 g, 0.18 mmol) and DCC were added. (0.1 g, 0.5 immoles). After 2 h, the reaction was worked up as in the preparation of 21. The product was purified by radial chromatography eluting with CH2C12: 2% NH3 then converted to the HCl salt with 1.0 M HCl in Et20 and precipitated from of CH2C12 to produce 26HC1 (0.050 g, 5.4%): XH NMR (HCl salt, DMSO-d6) d 1.8-2.4 (m, 2H, -CH2-), 2.87 (s, 3H, -NCH3), 3.1- 4.5 (complex, 8H, 4-CH2-), 5.5 (m, 1H, -CHOH), 6.1 (m, 1H, -CH-), 7.2-7.5 (m, 5H, aromatic), 7.82 (d, J = 7.7 Hz, 1H, aromatic), 8.16 (d, J = 8 Hz, 1H, aromatic), 8.42 (s, 1H, aromatic). MS (FAB) m / z 452. Anal. (C, H, N) C22H24F3N3? 4 HCl O. 5H20 EXAMPLE 68 2- (2-Amino-4-trifluoromethyl-enyl) -N-methyl-N-. { [SS] -l-phenyl-2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl} acetamide (27, ADL-01- 0076-8) ADL-01-0076-8 was prepared from 26 (0.14 g, 0. 31 mmol), Raney nickel, and hydrazine hydrate (0.2 mL) in EtOH (14 mL). The conditions were similar to those used for the preparation of 9. The product was purified by radial chromatography eluting with CHC13: 2% NH3: 2% MeOH then converted to the HCl salt with Et20-HCl to produce 27HC1 (0.11 g, 77%): XH NMR (DMSO-d6) d 1.8-2.2 (m, 2H, -CH2-), 2.88 (s, 3H, -NCH3), 3.1-4.5 (complex, 9H, 4 -CH2- and 1- CHOH), 6.2 (m, 1H, -CH-), 6.8-7.5 (complex, 8 H, aromatic). MS (FAB) m / z 423. Anal. (C, H, N) C22H26N302F3 HCl 2.5H20. The compounds of Examples 69-91 were prepared from the appropriate acid / arylacetic acid chlorides by EDCI / DIPEA or DCC / pyridine couplings, followed by reduction, deprotection, and / or derivatization by known chemistry. Intermediary A was prepared by the method reported in J. Med. Chem., 34, 1991 pp. 181 189, Costello, G.F. the al ..

Compounds of Examples 69-91 General procedure for EDCI / D PEA coupling. To a solution of acid (1.1 eq.) And 1-hydroxybenzotriazole hydrate (HOBT; 1.1 eq.) In a shallow ice bath N2 1- (3-Dimethylamino? Ropil) -3-ethylcarbodiimide hydrochloride (EDCI; 1.1 eq.) Was added. The mixture was stirred during minutes. A solution of the amine (1.0 eq.) In dry methylene chloride was added dropwise followed by N, N-Diisopropylethylamine (DIPEA, 1.5 eq.). The solution was allowed to stir at room temperature overnight. The reaction was quenched with sat. Sodium bicarbonate. and separated from methylene chloride. The organic layer was dried (Na2SO), filtered through Celite, and evaporated. The crude product was chromatographed and converted to the HCl salt. Example 69 2, 2-Diphenyl-N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] -acetamide; ADL-01-0023-0 To a solution of diphenylacetic acid (1.5 g, 7.3 mmoles) and pyridine (1.0 mL, 12.2 mmoles) in 20 mL of Methylene chloride dried at 25 degrees under N2 was added 1,3-dicyclohexylcarbodiimide, DCC (2.0 g, 9.8 mmol). After 5 minutes, 28 (1.0 g, 4.9 mmol) in 20 mL of dry methylene chloride were added and the mixture was stirred overnight. TLC (95: 5 methylene chloride-methanol with 2% ammonia) indicated that all of the starting materials were consumed. The reaction was quenched with sat. Sodium bicarbonate. and filtered through a plug of Celite. The plug was rinsed with methylene chloride and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried (Na 2 S 4), filtered and concentrated in vacuo to give 2.2 g of a light brown solid. The unpurified product was purified by flash chromatography using a step gradient of 2% to 8% MeOH: methylene chloride with 2% ammonia to provide 1.7 g (88%) of the pure product which was treated with 1.0 M of HCl in diethyl ether to give 29 as the HCl salt. ~ H NMR (HCl salt, DMSO-d6) d 2.0 (broad s, 4H, -CH2CH2-), 2.7 (s, 3H, -NCH3), 6.2 (broad m, 1H, -CH-), 7.1-7.5 (complex, 15H, aromatic). MS (FAB) m / z 398. Anal. (C, H, N) C27H30N2O. HCl .0.75H20. Example 70 N ', N' -Diphenyl-N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] urea; ADL-01-0027-1 To a solution at 0 degrees of 28 (500 mg, 2.4 mmol) and triethylamine (731 L, 5.2 mmol) in 10 mL of dry methylene chloride under N2 was added a solution of diphenylcarbamyl chloride (629 mg, 2.7 mmol) in 5 mL of dry methylene chloride. The solution was warmed to room temperature and stirred overnight. TLC (95: 5 methylene chloride: methanol with 2% ammonia) indicated that the initial material was consumed. The reaction solution was concentrated to a residue, which was pre-adsorbed to silica and purified using a step gradient of 2% to 7% MeOH: methylene chloride with 2% ammonia to provide 350 mg (36%) ) of the pure product which was treated with 1.0M of HCl in diethylether to give 30 as the HCl salt, LH NMR (HCl salt, DMSO-d6) d 2.0 (broad s, 4H, -CH2CH2-), 2.5 (s, 3H, -NCH3), 5.8 (m, broad, 1H, -CH-), 7.1-7.5 (complex , 15H, aromatic). MS (FAB) m / z 399. Anal. (C, H, N) C26H29N30. HCl .0.5H20 EXAMPLE 71 2- (2-Nitrophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0030-5 The ADL-01-0030-5 was prepared by the procedure described in the preparation of 29 from 28 (0.6 g, 2.9 mmol), 2-nitrophenylacetic acid (0.8 g; Four . 4 mmoles), DCC (1.2 g, 5.8 mmoles), and pyridine (0.1 mL; 1. 4 mmoles). The unpurified product was purified by instant chromatography using a step gradient of 2% to 7% MeOH: methylene chloride with 2% ammonia to provide 0.2 g (20%) of the pure product which was treated with 1. OM of HCl in diethyl ether to give 31 as the HCl salt. 1H NMR (HCl salt, DMSO-d6) d 2.0 (broad s, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 6.1 (m, broad, 1H, -CH-) 7.3-8.1 ( complex, 9H, aromatic). MS (FAB) m / z 367. Anal. (C, H, N) C2? H25N303.HCl. Example 72 2- (2-Nitro-4,5-dichlorophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0033-9 The ADL-01-0033-9 was prepared by the general coupling procedure EDCI / DIPEA from 28 (1.4 g, 6.9 mmoles), 2-nitro-4,5-dichlorophenylacetic acid (1.9 g, 7.6 immoles), HOBT (1.0 g, 7.6 mmoles), EDCI (1.4 g, 7.6 mmoles), and pyridine (0.8 mL, 10.3 mmoles). The unpurified product was purified by flash chromatography using a step gradient of 2% to 5% MeOH: methylene chloride with 2% ammonia to provide 2.0 g (60%) of the pure product which was treated with 1.0M of HCl in diethyl ether to give 32 as the HCl salt. 1H NMR (HCl salt, DMSO-de) d 2.0 (s, broad, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 6.1 (m, broad, 1H, -CH-), 7.2 7.6 (complex, 5H, aromatic), 7.9 (s, 1H, aromatic), 8.4 (s, 1H, aromatic). MS (FAB) m / z 436. Anal. (C, H, N) C2? H23 303 Cl2. HCl .0.25 H20 Example 73 2- (4-methylsulfonyl enyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0036-2 The ADL-01-0036-2 was prepared by the general coupling procedure EDCI / DIPEA from 28 (432 mg, 2 mmol), 4-methylsulfonylphenylacetic acid (500 mg, 2.3 mmol), HOBT (341 mg, 2.5 mmol), EDCI (483 mg, 2.5 mmol), and DIPEA (550 mL, 3.1 mmol). The unpurified product was purified by flash chromatography using a step gradient of 2% to 4% MeOH: methylene chloride with 2% ammonia to provide 160 mg (19%) of the pure product which was treated with 1.0M HCl in diethyl ether to give 33 as the HCl salt, 1 H NMR (HCl salt, DMSO-de) d 2.0 (s, broad, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 3.2- (s, -S02CH3), 6.1 (m, broad, 1H, -CH-), 7.3-7.5 (complex, 5H, aromatic), 7.6 (d, broad, 2H, aromatic), 7. 9 (d, broad, 2H, aromatic). MS (FAB) m / z 400. Anal.

(C, H, N) C22H28N2O3S.HC1.0.5 H20. Example 74 2- (2-methoxyphenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0049-5 The ADL-01-0049-5 was prepared by the general coupling procedure EDCI / DIPEA from 28 (500 mg, 2.4 mmol), 2-methoxyphenylacetic acid (610 mg, 3.6 mmoles), HOBT (495 mg, 3.6 mmol), EDCI (700 mg; 3. 6 mmoles), and DIPEA (850 mL, 4.8 mmoles). The unpurified product was purified by flash chromatography using a step gradient of 1% to 7% MeOH: methylene chloride with 2% ammonia to provide 822 mg (96%) of the pure product which was treated with l.OM HCl in diethyl ether to give 34 as the HCl salt. 1H NMR (free base, CDC13) d 1.8 (s, broad, 4H, -CH2CH2-), 2.8 (s, 3H, -NCH3), 3.8 (s, 3H, OCH3), 6.1 (, broad, 1H, -CH -), 6.8-7.4 (complex, 9H, aromatic). MS (FAB) m / z 352. Anal. (C, H, N) C22H28N20.HC1 Example 75 2- (3-Indolyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] -ethamide; ADL-01-0054-5 ADL-01-0054-5 was prepared by the general coupling procedure EDCI / DIPEA a patir 28 (500 mg; 2.4 mmol), indole-3-acetic acid (641 mg, 3.6 mmol), HOBT (494 mg, 3.6 mmol), EDCI (700 mg, 3.6 mmol), and DIPEA (637 mL, 3.6 mmol). The unpurified product was purified by flash chromatography using a step gradient of 1% to 7% MeOH: methylene chloride to provide 761 mg (88%) of the pure product which was treated with 1 μM HCl in diethyl ether give 35 as the HCl salt. XH NMR (HCl salt, CD3OD) d 2.1 (s, broad, 4H, -CH2CH2-), 2.8 (s, 3H, -NCH3), 6.3 (m, broad, 1H, -CH-), 7.1 7.7 (complex, 9H, aromatic). MS (FAB) m / z 361. Anal. (C, H, N) C23H27N30. HCl 1.0 H20. Example 76 2- (, a, -trifluoro-p-tolyl) -N-methyl-N- [(SS) -l- enyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0058-6 ADL-01-0058-6 was prepared by the general coupling procedure EDCI / DIPEA from 28 (200 mg, 0.9 mmol), acid (a, a, a-Trifluoro-p- tolyl) acetic (239 mg, 1.1 mmol), HOBT (157 mg, 1.1 mmol), EDCI (223 mg, 1.1 mmol), and DIPEA (203 mL, 1.1 mmol). The unpurified product was purified by flash chromatography using a step gradient of 1% to 2% MeOH: methylene chloride to provide 354 mg (93%) of the pure product which was treated with 1 .OM HCl in diethyl ether to give 36 as the HCl salt. JH NMR (HCl salt, CDC13) d 1.8 (s, broad, 4H, -CH2CH2-), 3.0 (s, 3H, -NCH3), 6.4 (m, broad, 1H, -CH-), 7.2-7.6 ( complex, 9H, aromatic). MS (FAB) m / z 390. Anal. (C, H, N) C22H25N2OF3. HCl. Example 77 2- (2-Nitro-a, a, a-Trifluoro-4-tolyl) -N-methyl-N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0062-8 The ADL-01-0062-8 was prepared by the general coupling procedure EDCI / DIPEA from 28 (500 mg, 2.4 mmol), acid (2-Nitro-a, α, α-trifluoro-4-tolyl) acetic acid (728 mg, 2.9 mmol), HOBT (395 mg, 2.9 Immoles), EDCI (559 mg, 2.9 mmol), and DIPEA (510 mL, 2.9 mmol). The unpurified product was purified by flash chromatography using a step gradient of 2% to 10% MeOH chloride: methylene chloride to provide 786 mg (74%) of the pure product which was treated with 1 .OM HCl in diethylether. to give 37 as the HCl salt. H NMR (HCl salt, CDC13) d 2.0 (s, broad, 4H, -CH2CH2), 2.9 (s, 3H, -NCH3), 6.3 (m, broad, 1H, CH), 7.1 7.5 (complex, 4H, aromatic), 7.8-7.9 (m, broad, 2H, aromatic), 8.3-8.4 (s, broad, 2H, aromatic). MS (FAB) m / z 435. Anal. (C, H, N) C22H24N3? 3F3.HCl. EXAMPLE 78 2- (1- [4-chlorobenzoyl) -5-methoxy-2-methylindol) -N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0078-4 ADL 01-0078-4 was prepared by the general coupling procedure EDCI / DIPEA from 28 (100 mg, 0.4 mmol), (1- [p-chlorobenzoyl] -5-methoxy) -2-Indole-3-acetic (189 mg, 0.5 mmol), HOBT (73 mg, 0.5 mmol), EDCI (101 mg, 0.5 mmol), and DIPEA (128 mL, 0.7 mmol). The unpurified product was purified by flash chromatography using a step gradient of 2% to 5% MeOH: methylene chloride to provide 200 mg (79%) of the pure product which was treated with l.OM HCl in diethyl ether to give 38 as the 1N NMR salt (HCl salt, CDC13) d 1.6-1.8 (m, broad, 4H, -CH2CH2-), 2.3 (s, broad, 3H, -CH3), 2.9 (s, broad, -NCH3), 3.8 (s, broad, 3H, -OCH3), 6.7 (m, broad, 1H, -CH), 7.1-7.6 (complex, 12H, aromatic) . MS (FAB) m / z 509. Anal. (C, H, N) C 32 H 35 N 3 3 3 Cl. HCl. Example 79 2- (4-Nitrophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0079-2 The ADL-01-0079-2 was prepared * by the general coupling procedure EDCI / DIPEA from 28 (1.5 g, 7.3 mmol), 4-Nitrophenylacetic acid (2.0 g, 11.0 mmol), HOBT 1.4 g; 11.0 mmol), EDCI (2.1 g; 11. 0 mmol), and DIPEA (2.5 mL, 1 4.6 immoles). The unpurified product was purified by flash chromatography using a stepwise gradient of 1% to 5% MeOH: methylene chloride to provide 2.5 g (93%) of the pure product which was treated with 1 μM of HCl in diethyl ether. give 39 as the HCl salt. XH NMR (HCl salt, CDC13) d 1.6 (m, broad, 4H, -CH2CH2-), 2.8 (s, broad, 3H, -NCH3), 6.4 (m, broad, 1H, -CH-), 7.1- 7.5 (complex, 7H, aromatic), 8.0 (d, broad, 2h, aromatic). MS (FAB) m / z 367. Anal. (C, H, N) C2? H25N303 HCl. Example 80 2- (3-Nitrophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0084-2 The ADL-01-0084-2 was prepared by the general coupling procedure EDCI / DIPEA from 28 (1.5 g, 7.3 mmol), 3-Nitrophenylacetic acid (2.0 g; 11.0 mmol), HOBT (1.4 g, 11.0 mmol), EDCI (2.1 g, 11.0 mmol), and DIPEA (2.5 mL, 14.6 mmol). The unpurified product was purified by flash chromatography using a step gradient of 1% to 5% MeOH: methylene chloride with 2% ammonia to provide 2.6 g (100%) of the pure product which was treated with l.OM of HCl in diethyl ether to give 40 as the HCl salt. 1H NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, 3H, -NCH3), 6.3 (m, broad, 1H, -CH-), 7.2- 7.6 (complex, 6H, aromatic), 7.8 (d, broad, 1H, aromatic), 8.1-8.2 (complex, 2H, aromatic). MS (FAB) m / z 367. Anal. (C, H, N) C2? H25N303 HCl. 0.5H2O. EXAMPLE 81 2- (2-Pyridyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0085-9 ADL-01-0085-9 was prepared by the general coupling procedure EDCI / DIPEA from 28 (350 mg, 1.7 mmol), 2-pyridylacetic acid hydrochloride (326 mg, 1.8 mmoles), HOBT (253 mg, 1.8 mmol), EDCI (360 mg, 1.8 mmol) and DIPEA (644 mL, 3.7 mmol). The unpurified product was purified by flash chromatography using a step gradient of 2% to 5% MeOH: methylene chloride with 2% ammonia to provide 400 mg (72%) of the pure product which was treated with l.OM HCl in diethyl ether to give 41 as the HCl salt. 1H NMR (free base, CDC13) d 1.7-1.9 (m, broad, 4H, -CH2CH2-), 2.8 (s, broad, 3H, -NCH3), 6.0-6.2 (m, broad, 1H, -CH), 7.1-7.8 (complex, 8H, aromatic), 8.5 (d, broad, 1H, aromatic). MS (FAB) m / z 323. Anal. (C, H, N) C20H25N30. 2 HCl. 0.5H2O. Example 82 2- (3-pyridyl) -N-methyl-N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0100-6 The ADL-01-0100-6 was prepared by the general coupling procedure EDCI / DIPEA from 28 (120 mg, 0.5 mmol), 3-pyridylacetic acid hydrochloride (110 mg, 0.6 mmol), HOBT (85 mg; 0. 6 mmol), EDCI (120 mg, 0.6 mmol), and DIPEA (280 mL; 1. 5 immoral). The unpurified product was purified by flash chromatography using a stepwise gradient of 1% to 6% MeOH: methylene chloride with 2% ammonia to provide 142 mg (76%) of the pure product that was treated with l.OM HCl in diethyl ether to give 42 as the salt of '? Cl. H NMR (HCl salt, CDC13) d 2.1 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, 3H, -NCH3), 6.2-6.3 (m, broad, 1H, -CH), 7.2-7.3 (complex, 5H, aromatic), 7.8-7.9 (t, broad, 1H, aromatic), 8.6-8.9 (complex, 3H, aromatic). MS (FAB) m / z 323. Anal. (C, H, N) C20H25N3O.2 HCl.1.25 H20.

Example 83 2- ((+) - 6-Methoxy-a-methyl-2-naphthalene) -N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0110-5 ADL-01-0110-5 was prepared by the general coupling procedure EDCI / DIPEA from 28 (200 m, 0.9 mmoles), (+) - 6-methoxy-a- methyl-2-naphthalene acetic (217 mg, 1.0 mmol), HOBT (142 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), and DIPEA (256 mL, 1.4 mmol). The unpurified product was purified by. instant chromatography using a step gradient of 1% to 2% MeOH: methylene chloride with 2% ammonia to provide 130 mg (33%) of the pure product which was treated with l.OM HCl in diethyl ether to give 43 as the HCl salt. 1H NMR (HCl salt, CDC13) d 1.4 (d, 3H, -CH3), 2.9 (s, broad, -NCH3), 3.9 (s, -0CH3), 5.5 (m, broad, 1H, -CH), 7.0-7.7 (complex, 11H, aromatic). MS (FAB) m / z 416. Anal. (C, H, N) C27H32N202.HC1 0.25 H20. Example 84 2- (a, a, -trifluoro-3-tolyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0111-3 The ADL-01-0111-3 was prepared by the general coupling procedure EDCI / DIPEA from 28 (200 mg, 0.9 mmol), acid (a, a, a-Trifluoro-m-tolyl) acetic (214 mg, 1.0 mmol), HOBT (142 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), and DIPEA (256 mL; 1. 4 mmoles). The unpurified product was purified by flash chromatography using a stepwise gradient of 2% to 6% MeOH: methylene chloride to provide 250 mg (67%) of the pure product which was treated with 1 μM of HCl in diethyl ether. give 44 as the HCl salt. 1H NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, 3H, -NCH3), 6.4 (m, broad, 1H), 7.1-7.7 (complex, 9H, aromatic). MS (FAB) m / z 390. Anal. (C, H, N) C22H25N2OF3. HCl. Example 85 2- (4-pyridyl) -N-methyl-N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0122-0 The ADL-01-0122-0 was prepared by the general coupling procedure EDCI / DIPEA from 28 (120 mg, 0.5 mmol), 4-pyridylacetic acid hydrochloride (150 mg, 0.8 mmol), HOBT (117 mg; 0. 8 mmol), EDCI (166 mg, 0.8 mmol), and DIPEA (202 mL; 1. 1 mmol). The unpurified product was purified by flash chromatography using a step gradient of 2% to 5% MeOH: methylene chloride to provide 172 mg (92%) of the pure product which was treated with 1 μM of HCl in diethyl ether give 45 as the HCl salt. 1H NMR (HCl salt, CDC13) d 2.1 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, -NCH3), 6.3 (m, broad, -CH), 7.2-7.3 (complex, 5H, aromatic), 7.8 (s, broad, 2H, aromatic), 8.6 (s, broad, 2H, aromatic). MS (FAB) m / z 323. Anal. (C, H, N) C20H25N30.1.5. HCl. 0.5 H20. Example 86 2- (a, a, a-Trifluoro-2-tolyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0123-8 The ADL-01-0123-8 was prepared by the general coupling procedure EDCI / DIPEA from 28 (200 mg, 0.9 mmol), acid (α, α, α-trifluoro-o-tolyl) acetic acid (239 mg, 1.1 mmol), HOBT (157 mg, 1.1 mmol), EDCI (223 mg, 1.1 mmol), and DIPEA (203 mL; 1. 1 mmol). The unpurified product was purified by flash chromatography using a stepwise gradient of 1% to 4% MeOH: methylene chloride with 2% ammonia to provide 339 mg (82%) of the pure product which was treated with l.OM HCl in diethyl ether to give 46 as the HCl salt. XH NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, -NCH3), 6.3 (m, broad, -CH), 7.1-7.7 (complex, 9H, aromatic). MS (FAB) m / z 390. Anal. (C, H, N) C22H25N2OF3.

HCl. Example 87 2- ((S) - (+) -4-Isobutyl-a-methylphenyl) -N-methyl-N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0125-3 The ADL-01-0125-3 was prepared by the general coupling procedure EDCI / DIPEA from 28 (200 mg, 0.9 mmol), acid (S) - (+) -4-Isobutyl -to- Methylphenylacetic acid (217 mg, 1.0 mmol), HOBT (142 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), and DIPEA (256 mL, 1.4 mmol). The unpurified product was purified by flash chromatography using a step gradient of 1% to 2% MeOH: methylene chloride with 2% ammonia to provide 240 mg (66%) of the pure product which was treated with l.OM HCl in diethyl ether to give 47 as the HCl salt. 1H NMR (HCl salt, CDC13) d 0.8 (d, 6H, - (CH3) 2), 1.4 (d, 2H, -CH3), 2.0 (m, broad, -CH2CH2-), 2.3-2.4 (d, 2H, -CH2-), 2.9 (s, 3H, -NCH3), 5.6 (m, broad, 1H, -CH), 7.0 (c, broad, 4H, aromatic), 7.3 (s, broad, 5H, aromatic) . MS (FAB) m / z 392. Anal. (C, H, N) C 26 H 36 N 20. HCl. 0.25 H20. EXAMPLE 88 2- (3, 4, 5-Trimethoxy enyl) -N-methyl-N- [(SS) -1- enyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0146-9 The ADL 01-0146-9 was prepared by the general coupling procedure EDCI / DIPEA from 28 (250 mg, 1.2 mmol), 3, 4, 5-trimethoxyphenylacetic acid (304 mg, 1.3 mmol), HOBT (181 mg, 1.3 mmol), EDCI (256 mg, 1.3 mmol), and DIPEA (318 mL, 1.8 mmol). The unpurified product was purified by flash chromatography using a step gradient of 2% to 5% MeOH: methylene chloride with 2% ammonia to provide 500 mg (100%) of the pure product which was treated with 1 .OM HCl in diethyl ether to give 48 as the HCl salt. 1H NMR (free base, CDC13) d 1. 7 (m, broad, 4H, -CH2CH2-), 2.7 (s, 3H, -NCH3), 3.8 (d, 9H, -OCH3), 6.0-6.2 (m, broad, 1H, -CH), 6.4 (s) , 2H, aromatic), 7.1-7.3 (complex, 5H, aromatic). MS (FAB) m / z 412. Anal. (C, H, N) C24H32N204 HCl. Example 89 2- (2-aminophenyl) -N-methyl-N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide ADL-01-0024-8 Raney Nickel (50%) suspension in water) to a mixture of 31 (2.30 g, 6.1 mmol), 2.2 mL (61.9 mmol) of hydrazine hydrate and 45 mL of EtOH abs. to 55 degrees to maintain a regular gas evolution. After 45 minutes, TLC (95: 5 methylene chloride: methanol p / 2% ammonia) indicated that all the starting material was consumed. The mixture was filtered through a plug of Celite and rinsed with copious amounts of hot methanol. The filtrates were combined and concentrated in vacuo to provide 270 mg of a waxy solid. The unpurified product was purified by flash chromatography using a stepwise gradient of 1% to 8% methanol: methylene chloride with 2% ammonia to provide 2.01 g (97%) of the desired product. The pure product was treated with l.OM HCl in diethylether to yield 49 (ADL-01-0024-8) as the HCl salt. 1H NMR (HCl salt, DMSO-de) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 6.1 (m, broad, 1H, -CH), 7.2 (complex , 9H, aromatic). MS (FAB) m / z 321. Anal. (C, H, N) C2? H27N30. 2HC1. 0.75 HzO.

Example 90 2- (2-N, N-Dimethylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -1- phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0060-2 To a solution of 49 (400 mg, 1.1 mmol) in 50 ml of dry methylene chloride were added 429 mL of triethylamine and MsCl (913 mL; 11.8 immoles) was dissolved in 6 mL of dry methylene chloride. The dark red solution was left to stir overnight. TLC (95: 5 methylene chloride methanol p / 2% ammonia) indicates that the initial material was consumed. The reaction solution was quenched with sat. Sodium bicarbonate. and the layers separated. The aqueous layer was extracted with methylene chloride and the combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was concentrated in vacuo to give 700 mg of a dark brown residue. The crude product was purified by flash chromatography using a gradient stepwise from 2% to 7% methanol: methylene chloride with 2% ammonia to provide 580 mg (97%) of the desired product. The pure product was treated with l.OM HCl in diethylether to produce 50 (ADL-01-0060-2) as the HCl salt. XH NMR (HCl salt, DMSO-d6) d 2.0 (m, broad, 4H, -CH2CH2-), 2.7 (s, broad, 3H, -NCH3), 3.5 (s, broad, (-S02CH3) 2), 6.2 (d, broad, 1H, -CH), 7.2-7.5 (complex, 9H, aromatic). MS (FAB) m / z 493. Anal. (C, H, N) C23H3? N3OsS2.HCl 0.25 H20.

EXAMPLE 91 2- (N-Methylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -1-phenyl] -2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0075-0 To a solution of 50 (500 mg, 1.0 mmol) in 6 mL of 2: 1 MeOH: TF was added 4.0 mL of l.OM NaOH. The solution was stirred for 20 minutes. Then TLC (95: 5 methylene chloride methanol p / 2% ammonia) indicates that the reaction was complete. The reaction was quenched with 10% HCl and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 381mg of a brown solid. The unpurified product was purified by flash chromatography using a step gradient of 2% to 4% methanol: methylene chloride with 2% ammonia to provide 326 mg (80%) of the desired product. The pure product was treated with l.OM HCl in diethylether to produce 51 (ADL-01-0075-0) as the salt of HCl. XH NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, 3H, -NCH3), 3.0 (s, 3H, -S02CH3), 6. 3 (m, broad, 1H, -CH), 7.0-7.2 (complex, 8H, aromatic), 7.5 (d, broad, 1H, aromatic). MS (FAB) m / z 415. Anal. (C, H, N) C22H29N303S.HC1. 0.25 H20. Example 92 2- (2-amino-4,5-dichlorophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0035-4 To a solution of 32 (495 mg, 1.0 mmol) in 25 mL of abs. EtOH was added 50 mg of 10% Pd / C. The mixture was placed in a Parr apparatus under lOpsi hydrogen. After Ih, the TLC (95: 5 methylene chloride: methanol) does not indicate remaining initial material. The mixture was filtered through a plug of Celite and basified with aqueous ammonium hydroxide. The solvent was concentrated in vacuo to obtain a residue which was dissolved in EtOAc and washed repeatedly with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 200 mg of free base without purification. The unpurified product was treated with l.OM HCl in diethyl ether and dried in a vacuum oven @ 80 degrees overnight to recover 120 mg (30%) of 52 (ADL-01-0035-4) as the salt of HCl. XH NMR (HCl salt, CDC13) d 1.6-1.7 (m, broad, 4H, -CH2CH2-), 2.7 (s, 3H, -NCH3), 5.9-6.1 (m, broad, 1H, -CH), 7.1 -7.2 (complex, 7H, aromatic). MS (FAB) m / z 406. Anal. (C, H, N) C2? H25N3OCl2. HCl. 1.5 H20. EXAMPLE 93 2- (N, N-Dimethylsulfonamido-2-amino-4,5-dichloro-enyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01- 0050-3 The same procedure as in 50 using 223 mg (0.54 mmoles) of 52, 0.5 mL (6.4 mmoles) of MsCl, 2.0 mL (14.3 mmoles) of triethylamine and 25 mL of dry methylene chloride. The unpurified product was purified by chromatography instantaneous using a step gradient of 1% to 3% MeOH: methylene chloride to produce 150 mg (49%) of the pure product which was treated with 1. OM of HCl in diethylether to give 53 (ADL-01-0050 -3) as the HCl salt. 1R NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.8 (s, 3H, NCH3), 3.3 (d, 6H, - (S02CH3) 2), 6.2 (m, broad , 1H, -CH). 7.0-7.1 (complex, 2H, aromatic), 7.3 (complex, 5H, aromatic). MS (FAB) m / z 562. Anal. (C, H, N) C23H29N305S2C12.HCl. 0.5H20 Example 94 2- (2-Amino-, a, a-Trifluoro-4-toli) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] cetamide; ADL-01-0068-5 The same procedure as in 49 using 710 mg (1.6 mmoles) of 37, 0.5 mL (16.3 mmol) of hydrazine hydrate in 50 mL of EtOH. The recovered product, 650 mg (98% recovered without purification) was not purified in any additional way. A small amount of the desired product was treated with 1 μM of HCl in diethyl ether to form 54 (ADL-01-0068-5) as the HCl salt. 1 NM NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 6.3 (m, broad, 1H, -CH), 7.2-7.5 (complex , 8H, aromatic). MS (FAB) m / z 405. Anal. (C, H, N) C22H26N3OF3 1.5 HCl. EXAMPLE 95 2- (2-N, N-Dimethyl-3-sulfonamido-2-amino-a,, α-trifluoro-4-tolyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl ) ethyl] cetamide; ADL-01-0069-3 The same procedure as in 50 using 100 mg (0.24 mmol) of 54, 0.2 mL (2.4 mmol) of MsCl, 0.8 mL (6.3 mmoles) of triethylamine and 13 mL of dry methylene chloride. The unpurified product was purified by flash chromatography using a step gradient of 1% to 5% of MeOH: methylene chloride to yield 110 mg (80%) of the desired product. A small amount of the compound was treated with l.OM HCl in diethyl ether to give 55 (ADL-01-0069-3) as the HCl salt. XH NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 3.3 (d, 6H, - (S02CH) 2), 6.3 (m, broad, 1H, -CH), 7. 1-8. 0 (complex or, 8H, aromatic). EM (FAB) m / z 4 97. Anal (C, H, N) C 24 H 3 o N 3 OF 3 S 2. HCl. 0 5 H20. Example 96 2- (N-Methylsulfonamido-2-amino-a, a, α-trifluoro-4-tolyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] cetamide; ADL- 01-0077-6 The same procedure as in 51 using 51 mg (0.1 mmol) of 55, 30 mL of l.OM NaOH and 1.9 mL of 2: 1 MeOH: TF. The unpurified product was purified by flash chromatography using a step gradient of 1% to 5% MeOH: methylene chloride with 2% ammonia to yield 27 mg (63%) of the pure product which was treated with l.OM of HCl in diethyl ether to form 56 (ADL-01-0077-6) as the HCl salt. XH NMR (HCl salt, CDC13) d 2.0 (m, broad, 4H, -CH2CH2-), 2.9 (s, broad, 3H, -NCH3), 3.1 (s, broad, 3H, -S02CH3), 7.1-7.3 (complex, 8H, aromatic). MS (FAB) m / z 483. Anal. (C, H, N) C23H28 303SF3. HCl. 0.25 H20. Example 97 2- (2-aminophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0089-1 The same procedure as in 49 using 2.6 g (7.1 mmoles) of 40, 2.5 mL (80.2 mmol) of hydrazine hydrate in 70 mL of EtOH. The recovered product, 1.8 g, was purified by flash chromatography using a gradient stepwise from 1% to 9% MeOH: methylene chloride with 2% ammonia to yield 1.1 g (47%) of the pure product was treated with l.OM HCl in diethyl ether to give 57 (ADL-01-0089-1) as the HCl salt. H NMR (free base, CDC13) d 1.7- 1.9 (m, broad, 4H, -CH2CH2-), 2.7 (s, 3H, -NCH3), 6.1 (m, broad, 1H, -CH), 6.5-6.8 ( complex, 3H, aromatic), 7.0 (m, 2H, aromatic), 7.3 (complex, 4H, aromatic, EM (FAB) m / z 337. Anal. (C, H, N) C2? H27N30. 2HC1. 0.5 H20. EXAMPLE 98 2- (4-Aminophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) -ethyl] acetamide; ADL-01-0103-0 The same procedure as in 49 using 2.3 g (6.3 mmol) of 39, 2.4 mL (75.4 mmol) of hydrazine hydrate in 70 mL of EtOH. The recovered product, 1.7 g, was purified by flash chromatography using a step gradient of 2% to 3% MeOH: methylene chloride with 2% ammonia to produce 1.53 g (73%) of the pure product. A small amount of the compound was treated with l.OM HCl in diethyl ether to give 58 (ADL-01-0103-0) as the HCl salt. 1H NMR (free base, CDC13) d 1.8 (m, broad, 4H, -CH2CH2-), 2.7 (s, 3H, -NCH3), 6.1 (m, broad, 1H, -CH), 6.7 (m, 2H, aromatic), 7.0 (d, 2H, aromatic), 7.3 (complex, 5H, aromatic). MS (FAB) m / z 337. Anal. (C, H, N) C2? H27N30. 2HC1. 0.75 H20. Example 99 2- (N, N-Dimethylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -1- phenyl-2- (1-pyrrolidinyl) tyl] acetamide; ADL-01-0112-1 The same procedure as in 50 using 500 mg (1.5 mmoles) of 57, 1.1 mL (14.8 mmoles) of MsCl, 3.0 L (22.2 mmoles) of triethylamine and 8.0 mL of dry methylene chloride. The unpurified product was purified by flash chromatography using a step gradient of 1% to 4% of MeOH: methylene chloride with 2% ammonia to produce 308 mg (42%) of the pure product. A small amount of the compound was treated with l.OM HCl in diethylether to give 59 (ADL-01-0112-1) as the HCl salt. XH NMR (free base, CDC13) d 1.8 (m, broad, 4H, -CH2CH2-), 2.8 (s, 3H, -NCH3), 3.4 (s, 6H, (-S02CH3) 2), 6.1 (m, broad, 1H, -CH), 7.0-7.5 (complex, 9H, aromatic) .EM (FAB) m / z 493. Anal. (C, H, N) C23H3? N305S2. HCl. EXAMPLE 100 2- (N, N-Dimethylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -1- phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0127-9 The same procedure as in 50 using 400 mg (1.2 mmol) of 58, 0.55 mL (7.1 mmol) of MsCl, 1.6 mL (11.8 mmol) of triethylamine and 12.0 mL of dry methylene chloride. The unpurified product was purified by flash chromatography using a step gradient of 2% to 5% MeOH: methylene chloride with 2% ammonia to yield 395 mg (68%) of the pure product. The compound was treated with l.OM HCl in diethyl ether to give 60 (ADL-01-0127-9) as the HCl salt. 1H NMR (free base, CDC13) d 1.8 (m, broad, 4H, -CH2CH2-), 2.8 (s, 3H, -NCH3), 3.4 (s, 6H, (-S02CH3) 2), 6. 1 (m, broad, 1H, -CH), 7. 0-7. 5 (complex o, 9H, aromatic). MS (FAB) m / z 493. Anal (C, H, N) C23H31N305Si. HCl. 0 25 H20. Example 101 2- (2-Hydroxyphenyl) -N-methyl-N-methyl- [(SS) -1- enyl-2- (1-pyrrolidinyl) ethyl] acetamide; ADL-01-0061-0 To a solution of 34 (700 mg, 1.8 mmol) in 10 mL of dry methylene chloride @ -78 degrees were added 10.8 mL (10.8 mmol, l.OM of solution of BBr3 in methylene chloride) ) during 15 minutes. The reaction mixture was allowed to warm to room temperature and stir overnight. TLC (95: 5 methylene chloride: MeOH p / 2% ammonia) indicated no remaining starting material. The reaction died with the addition of MeOH at 0 degrees. After 30 minutes, 3N HCl was added and the mixture was stirred for 30 minutes (a white precipitate is observed). The mixture was neutral with sat. Bicarbonate. and extracted with methylene chloride (3 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 610 mg of the crude product. The unpurified product was purified by flash chromatography using a step gradient of 2% to 3% MeOH: methylene chloride to yield 500 mg (82%) of the pure product. The product was treated with l.OM HCl in diethylether to give 61 (ADL-01-0061-0) as the HCl salt. XH NMR (free base, CDC13) d 1.7 (m, broad, 4H, -CH2CH2-), 2.9 (s, 3H, -NCH3), 6.1 (m, broad, 1H, -CH), 6.8-7.4 (complex, 9H, aromatic). MS (FAB) m / z 338. Anal. (C, H, N) C2? H26N202. HCl. 0.5 H20. Example 102 N-Methyl-N- [(SS) -l-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) -yl] -3,4,5-trimethoxyphenylacetamide HCl (A) ADL-01- 140-2 To a solution of 3, 4, 5-trimethoxyphenylacetic acid (1.0 g, 4.43 mmol) in 10 mL of CH2C12 under a nitrogen atmosphere was added pyridine (0.12 g, 1.5 mmol) and N, N-diisopropylethylamine (Hunig's Base) (0.57 g, 4.43 mmol).

The reaction mixture was cooled to 0 ° C and DCC (1.37 g, 6.65 mmol) was added in one portion. The reaction mixture The mixture was stirred at this temperature and a solution of diaminol (0.65 g, 3.0 mmol) in 10 mL of CH2C12 was added and stirring was continued while heating at room temperature for 20 h. The reaction mixture was poured into a saturated aqueous NaHCO 3 solution and the mixture was stirred for 30 min. The organic layer was separated and dried over anhydrous Na2SO4. After removal of the solvent, the product was purified on a silica gel column [solvent system: CHC13: CH3OH: 28% NH4OH (98: 2: 2)]. The free base was converted to the hydrochloride salt from 1M ethereal HCl and recrystallized from CH2Cl2: Et20 (1: 1) to give 0.64 HCl (46%) as a pale pink solid; mp 230-232 ° C; 1R NMR (200 MHz, CDC13) d 2.20 (m, 4H), 2.85 (s, 3H), 3.00-4.30 (m, 5H), 3.70 (ms, 9H), 4.50 (m, 2H), 5.30 (d, J = 15.0 Hz, 1H), 6.50 (m, 3H), 7.28 (m, 5H). Anal. Cale. for C24H32N205.HC1.0.25H2O: C, 61.40; H, 7.19; N, 5.97. Found: C, 61.36; H, 6.84; 8.96; N, 5.91. The structure of the compound is shown in the following.

Compounds of formula IV Intermediaries The following intermediates were prepared (±) -trans-2-pyrrolidinyl-N-methylcyclohexylamine (3) The racemic diamine (3) was prepared by a number of processes reported in the literature.1 '1. Alternatively, the amine was also prepared from cyclohexene (1) following the procedure described in Scheme I and literature12 in 70% overall yield as a brown oil. A sample was purified by distillation (e.g. 75-82 ° C / 1.0 mm, lit.2 p.p.76-80 ° C / 1.2 min); XH NMR (200 MHz, CDC13) d 1.04-1.36 (m, 4H), 1.49-1.89 (m, 8H), 2.18 (d, J = 5.0 Hz, 1H), 2.52 (s, 3H), 2.56-2.70 ( m, 4H), 2.80-2.93 (m, 1H), 7.75 (broad, 1H). The corresponding chiral amine (3) could be prepared following the procedures of the literature. Ref (10) Szmuszkovicz, J., Von Voigtlander, P.F. J. Med. Chem. 1982, 25, 1125-1126. (11) DeCosta, B. George, C; Rothman, R. B .; Jacobson, A. E .; Rice, K. E. FEBS Lett. 1987, 223, 335-339. (12) Freeman J. P .; Michalson, E. T .; D 'Andrea, S. V .; Baczynskyj, L .; Von Voigtlander, P. F .; Lahti R. A .; Smith M.; Lawson, C. F .; Scahill, T. A .; Mizsak, S.A .; Szmuszkovicz, J. J. Med. Chem. 1991, 34, 1891-1896. Synthesis of Arylacetamide General procedure for the preparation of arylacetamides (±) 5 HCl To a stirred solution of arylacetic acid (4) (1.5 mmoles) in 20 mL of dry CH2C12 was added pyridine (0.5 mmol) at 0-> > 5 ° C under a nitrogen atmosphere. N, N'-dicyclohexylcarbodiimide (2.0 mmoles) was added in one portion and the reaction mixture was continued stirring for minutes while heating to room temperature. A solution of (±) 3 (1.0 mmol) in 10 mL of dry CH2C12 was added and the progress of the reaction was monitored by TLC in a solvent system corresponding to CHC13: CH30H: 28% NH4OH (93: 5: 2). After the disappearance of diamine 3, the reaction mixture was quenched with saturated NaHCO 3 and stirring was continued for an additional 15 minutes. He precipitate N, '-dicyclohexylurea (DCU) was removed by filtration and the filter cake was washed with additional amounts of CH2C12. The combined filtrate was evaporated to dryness and the residue was purified either on a column of silica gel or using Croatotran silica gel plate from the aforementioned solvent system for each compound to give (±) 5 as a free base. The hydrochloride salts were prepared from dissolving (±) 5 in a minimum amount of CH2C12 and the addition of 2.0 equivalents of 1M ethereal HCl. The solvents were removed under reduced pressure and the CH1 salts were recrystallized from the solvents indicated in the following. The yields given in the following are for global stages. Example 103 Hydrochloride [(±) 5a HCl] of (±) -trans-2-Nitro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] enylacetamide ADL-01-0012-3 Prepared from acid 2-nitrophenylacetic [solvent for purification CH2C12: CH30H: 28% NH40H (98: 2: 2)]: yield of 21% as a white solid (2-propanol); mp 267-269 ° C (d); *? NMR (200 MHz, CDC13) d 1.00-1.44 (m, 2H), 1.60-2.35 (m, 8H), 2.85 (m, 1H), 3.15 (s, 3H), 3.18-3.35 (m, 4H), 3.40 (m, 1H), 3.85 (m, 1H), 4.33 (dd, J = 10.0 Hz, 2H), 4.64 (m, 1H), 7.35 (m, 1H), 7.56 (m, 2H), 8.05 (d, J = 7.8 Hz, 1H), 11.02 (broad s, 1H). Anal. Cale. for C? 9H27N303.HCl: C, 59.75; H, 7.39; Cl, 9.28; N, 11.00 Found: C, 59.98; H, 7.38; 8.96; N, 10.85. Example 104 Hydrochloride [(±) 5b HCl] of (±) -trans-Amino-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] phenylacetamide AD -01-0014-9 To a solution of (±) 5a HCl (0.5 g, 1.31 nmol) in 30 mL of CH3OH was added 10% Pd / C (100 mg) and hydrogenated at 50 PSI in a Parr Apparatus at room temperature for 3 h. The catalyst was removed by filtration through a pad of celite and washed with hot CH3OH and the combined filtrate was evaporated to dryness.

The residue was recrystallized from 2-propanol to give (±) 5b HCl as a white solid, 0.45 g (95%); mp 213-215 ° C; 2H NMR (200 MHz, CDC13) d 1.05-1.40 (m, 2H), 1.65-2.25 (m, 8H), 3.10 (s, 3H), 2.90-3.25 (m, 4H), 3.50 (d, J = 12.0, 1H), 3. 65 (m, 1H), 3.88 (m, 1H), 4.20 (d, J = 12.5 Hz, 1H), 4.70 (m, 1H), 6.65 (m, 2H), 7.00 (m, 2H), 7.25 (broad s, 2H). Anal.

Cale, for C? 9H29N30. HCl .0.5H20: C, 63.23; H, 8.66; N, 11.64. Found: C, 63.59; H, 8.76; N, 11.61. Example 105 Hydrochloride [(±) 5c HCl] of (±) -trans-2-Nitro-4,5-dichloro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide AD -01-0015 -6 The compound was prepared according to the literature method (DeCosta, B .; Linda, B .; Rothman, R. B .; Jacobson, A. E .; Bykov, V .; Pert, A .; Rice, K., E. FEBS Lett. 1989, 249, 178-182); XH NMR (200 MHz, CDC13) d 1.15-1.45 (m, 2H), 1.55-2.30 (m, 8H), 3.10 (s, 3H), 2.85-3.20 (m, 4H), 3.40 (m, 1H), 3.88 (m, 1H), 4.25 (d, J = 14.5 Hz, 1H), 4.45 (d, J = 15.0 Hz, 1H), 4. 65 (m, 1H), 7.70 (s, 1H), 8.13 (s, 1H). Anal. Cale, for C? 9H25Cl2N3? 3 HCl: C, 50.62; H, 5.81; N, 9.32. Found: C, 50. 61; H, 5.61; N, 9.20. Example 106 Hydrochloride [(±) 5d HCl] of (+) - trans-2-Amino-4,5-dichloro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0016 -4 Obtained from (±) 5c CH1 following the literature procedure (DeCosta, B .; Linda, B .; Rothman, RB; Jacobson, AE; Bykov, V .; Pert, A.; Rice, KE FEBS Lett 1989, 249, 178-182); XH NMR (200 MHz, CDC13) d 1.10-1.40 (m, 4H), 1.48-2.20 (m, 8H), 3.00 (s, 3H), 3.10-3.30 (m, 4H), 3.55 (d, J = 14.0 Hz, 1H), 3.85 (d, J = 14.0 Hz, 1H), 4.50 (m, 1H), 6.75 (s, 1H), 7.08 (s, 1H). Anal. Cale, for C19H27C? 2N3O.HC10.75H20: C, 52.54; H, 6.84; N, 9.67. Found: C, 52,561; H, 6.63; N, 9.33. Example 107 Hydrochloride [(+) 5e HCl of (±) -trans-2-methanesulfonamido-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0025-5 To a solution of free base of (+) 5b (1.0 g, 3.2 mmol) in 40 mL of dry CH2C12 at 0 ° C under a nitrogen atmosphere was added Et3N (1.86 g, 18.4 mmol) . A solution of methanesulfonyl chloride (1.14 g, 9.92 mmol) in 15 mL of dry CH2C12 was added dropwise over 15 minutes. After 2h at room temperature the TLC [solvent system: CHCl3: CH3OH: 28% NH4OH (93: 5: 2)] showed that the initial material was still present. Additional amounts of Et3N (1.86 g) and methanesulfonyl chloride (1.14 g) were added and stirring was continued for another 2h. During this time no initial material was present in the reaction mixture. Then, the mixture was diluted with 40 mL of CH2C12, washed with saturated NaHCO3, water, saturated salt solution, and dried over anhydrous Na2SO4. Solvent removal under reduced pressure gave bis-sulfonamide as a brown foam which was used directly in the next hydrolysis. To a solution of bis-sulfonamide (1.0 g, 2.12 mmol) in 60 L of CH3OH: THF (2: 1) was added 10 M aqueous NaOH (0.96 mL, 9.6 mmol). The mixture was stirred at room temperature for 30 minutes and then acidified with 1N CH1. The solvent was evaporated under reduced pressure and the residue was redissolved in CH2C12. The CH2C12 layer was then washed with 5% NaHCO3, the salt solution was saturated, and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure chromatography on a silica gel column [solvent system: CH2C12: CH30H: 28% NH4OH (95: 5: 2)] gave the mono-sulfonamide (free base) as an oil; 1H NMR (200 MHz, CDC13) d 1.05-1.95 (m, 12H), 2.45-2.80 (m, 5H), 2.95 (s, 3H), 3.10 (s, 3H), 3.50 (d, J = 13.8 Hz, 1H), 3.65 (m, 1H), 3.85 (d, J = 14.0 Hz, 1H), 4.45 (m, 1H), 7.05 (m, 1H), 7.15 (m, 2H), 7.45 (d, J = 8.5 Hz, 1H). The hydrochloride salt was prepared by dissolving the free base in CH2C12 and adding 1.2 equivalents of 1M ethereal HCl and recrystallized from 2-propanol to give (±) 5e HCl as a solid color cream, 0.37 g (38%); mp 229-231 ° C; XH NMR (200 MHz, CDC13) d 1.10-2.20 (m, 12H), 2.90-3.20 (m, 4H), 3.00 (s, 3H), 3.15 (s, 3H), 3.50 (m, 1H), 3.65 ( d, J = 13.5 Hz, 2H), 3.80 (m, 1H), 4.40 (m, 1H), 7.05-7.30 (m, 3H), 7.60 (d, J = 8.0 Hz, 1H), 8.90 (s broad, 1H). Anal. Cale, for C20H3? N3O3 S. HCl .0.25H20: C, 55.28; H, 7.54; N, 9.67. Found: C, 55.40; H, 7.39; N, 9.49. Ref. (13) Li, C.-S .; Black,. C; Chan, C, C; Ford-Hutchinson, A. W .; Gautier, J.-Y .; Gordon, R .; Cool, D; Kargman, S .; Lau, C.K .; Mancini J .; Ouimet, N .; Roy, P .; Vickers, P .; Wong AND.; Young, R. N .; Zarnboni, R .; Prasit, R. J. Med Chem. 1995, 38, 4897-4905. Example 108 Hydrochloride [(±) 5f HCl] of N- [2- (±) -trans-N-Methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamido] glycine AD -01-0028-9 To one solution with stirring of (±) 5b (free base, 1.0 g, 3.2 mmol) in 15 mL of dry DMF at room temperature under a nitrogen atmosphere was added 95% NaH (0.083 g, 3.3 mmol). After stirring at room temperature for 30 minutes, the cloudy solution was added to a stirring solution of tert-butyl bromoacetate (0.66 g, 3.4 mmol) in 10 mL of dry DMF. The reaction mixture was continued stirring for 72 h; however, the TLC of the reaction mixture [solvent system: CHC13: CH30H: 28% NH4OH (93: 5: 2)] showed that the initial material was still present. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 / water. The product was purified on a silica gel column from CH2Cl2: CH3? H (9: 1) and recrystallized from CH2Cl2: Et20 (1: 1) to give the corresponding tert-butylester, 0.16 (12%). ); XH NMR (200 MHz, CDC13) d 1.05-1.35 (m, 4H), 1.35 (s, 9H), 1.55-2.20 (m, 8H), 2.92 (broad, 4H), 3.12 (s, 3H), 3.45 ( m, 1H), 3.60 (d, J = 14.0 Hz, 2H), 3.78 (broad t, 2H), 3.95 (m, 1H), 5.75 (broad, 1H), 6.38 (d, J = 6.5 Hz, 1H) , 6.60 (t, J = 5.5 Hz, 1H), 7.00 (m, 2H). The initial material was also recovered in 50% yield.

The tert-butylester (0.16 g, 0.372 mmol) was suspended in 10 mL of 4N aqueous CH1. A drop of anisole was added and the mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue was redissolved in CH 3 CN and filtered. The filtrate was evaporated under reduced pressure and the residue was recrystallized from 2-propanol: ether (1: 1) to give (±) 5f HCl as a white solid, 0.070 g (42%); mp 212-214 ° C (d); XH NMR (200 MHz, DMSO-d6) d 1.15-2.25 (m, 12H), 2.90 (m, 1H), 3.05 (s, 3H), 3.14-3.70 (m, 6H), 3.85 (broad s, 2H) , 4.55 (broad, 1H), 6.37 (d, J = 6.0 Hz, 1H), 6.55 (t, J = 5.0 Hz, 1H), 6.95 (m, 2H), 9.80 (broad, 1H). Anal. Cale, for C2? H3? N303.HCl. H20: C, 58.93; H, 8.00; N, 9.81 Found: C, 58.79; H, 7.64; N, 9.43. Example 109 Hydrochloride [(+) 5g HCl] of (±) -trans-4-Tri-luromethyl-N-methyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0066- 9 To a solution of 4-trifluoromethylphenylacetic acid (1.45 g, 7.08 mmol) in 10 mL of dry CH2C12 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. The reaction mixture was cooled to 0-> 0. 5 ° C and solid EDCI was added ([1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide HCl]) (1.35 g, 7.08 mmol) and stirred to this temperature for 30 min. A solution of (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2C12 was added followed by N, N-diisopropylethylamine diisopropylethylamine (Huni g Base) (0.915 g, 7.08 mmol). The reaction mixture was stirred for 24 h while heating to room temperature. The reaction mixture was then poured into an excess of saturated ice cold aqueous NaHC 3 solution and stirred for 30 minutes. After dilution with CH2C12, the organic layer was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of the solvent gave a brown oil which was chromatographed on a column of silica gel [solvent system: CH2C12: CH30H: 28% NHOH (99: 1: 2)] to give the desired product as a free base. The hydrochloride salt was prepared from 1M ethereal HCl and recrystallized from CH2C12: Et20 (1: 1) to give (±) 5g CH1 as a cream solid, 0.68 g (30%); 213-215 ° C; XH NMR (200 MHz, CDC13) d 1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J = 15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J = 15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J) = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H). Anal. Cale, for C20H27F3N2O. HCl .0.25H20: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69. Nitration of 4-tri luoromethyl-enylacetic acid: General procedure: Preparation of 2-trifluoromethyl-enylacetic acid [4, R = 2-NQ2 (4-CF3) -C6H4CH2] To a solution of 4-trifluoromethylphenylacetic acid (2.5 g, 12.25 mmol) in 8 mL of glacial acetic acid at 0 ° C under an anhydrous atmosphere was added 5 mL of fuming H2SO4 (11% S03) (caution!) followed by careful addition of 90% HNO3 (3.5 mL, 73.14 mmol) for 10 minutes. The reaction mixture was then stirred at room temperature for 2 h and emptied into ice water. The resulting solid was filtered and washed with cold deionized water to give the desired product after drying as a creamy white solid, 2.5 g (82%); XH NMR (200 MHz, CDC13) d 4.02 (s, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 8.28 (s, 1H). The product was used directly in the following reactions. Example 110 Hydrochloride [(±) 5h HCl] (±) -trans-2-Nitro-4-trifluoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide AD £ -02-006"5 -l Prepared from 2-nitro-4-trifluoromethylphenylacetic acid following the procedure described in Example II to give (±) 5h HCl as a cream colored solid in 56% yield; mp 259-261 ° C (d); *? NMR (200 MHz, CDC13) d 1.10-1.42 (m, 4H), 1.51-2.25 (m, 8H), 2.95-3.25 (m, 3H), 3.14 (s, 3H), 3.40 (m, 1H), 3.90 (m, 1H), 4.35 (d, J = 13.8 Hz, 1H), 4.55 (d, J = 14.0 Hz, 1H), 4.60 (m, 1H), 7.80 (dd, J = 7.8 Hz, 2H), 8.25 (s, 1H). Anal. Cale, for C2oH26 3 303 HCl 0.25H2O: C, 52.86; H, 6.10; N, 9.25. Found: C, 52.85; H, 6.02; N, 9.13. Example 111 Hydrochloride [(+) 5i HCl] (±) -trans-2-Amino-4-tri-loromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0080-0 To a solution of free base 4h (0.4 g, 0.97 mmol) in 20 mL of absolute alcohol was added 2 mL of hydrazine hydrate and the reaction mixture was stirred at 50 ° C under a nitrogen atmosphere. Raney® nickel (50% suspension in water) was added slowly and the progress of the reaction was monitored on TLC plates [solvent system: CHC13: CH30H: 28% MHOH (99: 1: 2)]. If needed, more Raney® nickel is added to the reaction mixture. When the reaction was complete, an excess of Raney® nickel was introduced to decompose in the hydrazine hydrate. The reaction mixture was filtered through a pad of celite and the pad was washed with hot CH3OH. The filtrate was evaporated to dryness. The residue was purified on a column silica gel [solvent system: CHC13: CH30H: 28% NH4OH (99: 1: 2)] and the hydrochloride salt was prepared from 1M ethereal HCl. Recrystallization from CH2Cl2: Et20 (2: 1) gave (+) 5i HCl as a white solid, 0.2 g (48%); mp "" 248-250 ° C (d); 1H NMR (200 MHz, DMS0-d6) d 1.15-2.18 (m, 12H), 3.00 (s, 3H), 3.15-4.10 (m, 7H), 4.50 (m, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 10.0 (broad s, 1H). Anal. Cale, for C2oH28F3N3O.HCl .0.5H20: C, 56.01; H, 7.05; N, 9.80. Found: C, 55.70; H, 7.03; N, 9.65. Example 112 Hydrochloride [(±) 5j HCl] (±) -trans-2-bismetanesulfonamido-4-trifluoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0118-8 The compound was prepared from the free base (±) 5i (0.5 g, 1.30 mmol) following the procedure described in the first part of the preparation of (±) 5e. The bismetanesulfonamide was purified on a silica gel column [solvent system: CH2C12: CH3OH: 28% NH40H (96: 2: 2)] to give the desired product as a foam. The hydrochloride salt was prepared from 1M ethereal HCl and recrystallized from 2-propanol: Et20 (1: 1) to give (+) 5j HCl as a beige solid, 0.23 g (30%); mp 224-226 ° C (d); XH NMR (200 MHz, CDC13) d 1.12-1.51 (m, 4H), 1.53-2.24 (m, 8H), 1.82-3.17 (m, 2H), 2.98 (s, 3H), 3.32-3.56 (m, 2H) ), 3. 28 (s, 3H), 3.33 (s, 3H), 3.77 (m, 1H), 3.97 (d, J = 14.0 Hz, 1H), 4.27 (d, J = 14.0 Hz, 1H), 4.62 (m, 1H) ), 7.39 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H). Anal. Cale, for C22H32F3N3? 5S2.HCl: C, 45.87; H, 5.77; N, 7.29. Found: C, 45.53; H, 5.81; N, 7.00. Example 113 Hydrochloride [(±) 5 HCl] of (±) -trans-2-methanesulfonamido-4-trifluoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0137-8 To a solution of (±) 5j HCl (0.16 g, 0.23 mmole) in 9 mL of CH3OH: THF (2: 1) at room temperature was added 0. 12 mL of 10M aqueous NaOH and the mixture was stirred for minutes. The reaction mixture was neutralized with 1N HCl and evaporated to dryness. The residue was redissolved in CH2C12 and basified with a saturated aqueous solution of NaHC03. The organic cap was separated, washed with water, saturated salt solution, and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the product as a free base. The hydrochloride salt was prepared from 1M ethereal HCl and recrystallized from CH2Cl2: Et20 (1: 1) to give (±) 5k HCl as a beige solid, 0.085 g (61%); 209-211 ° C (d); XH NMR (200 MHz, CDC13) d 1. 15-1.24 (m, 4H), 1.50-2.10 (m, 8H), 2.20 (m, 2H), 2.90-3.10 (m, 2H), 3.05 (s, 6H), 3.55 (m, 2H), 3.80 ( m, 1H), 4.64 (m, 1H), 7.20 (dd, J = 7.8 Hz, 2H), 7.88 (s, 1H), 9.00 (s, 1H). Anal. Cale, for C21H30F3N3O3S. HCl .0.125 H20: C, 50.42; H, 6.30; N, 8.40. Found: C, 50.62; H, 6.49; N, 8.00 Example 114 Hydrochloride [(±) 51 HCl] of N- [2- (±) -trans-4-trifluoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide] licin ADL-01- 0130-3 To a solution of free base (±) 5i (0.767, 2.0 mmoles) in 10 mL of anhydrous THF under a nitrogen atmosphere at 0 ° C was added N, N-diisopropylethylamine (Hunig's Base) (1.55 g, 12.0 immoles). The reaction mixture was stirred at 0 ° C for 15 minutes then bromoacetic acid t-butylester (1.95 g, 10.0 mmol) was added and the reaction mixture was continued stirring while heating at room temperature for 72 h. The solvent was evaporated under reduced pressure and the residue was partitioned between CH2C12 and water. The organic layer was then washed with saturated NaHCO 3, saturated salt solution, and dried over anhydrous Na 2 SO 4. Removal of the solvent gave the unpurified product which was purified on a silica gel column [solvent system: CHC13: CH30H: 28% NH40H (96: 2: 2)] to give the t-butyl ester intermediate 0.477 g ( 40%); XH NMR (200 MHz, CDC13) d 1.05-1.25 (m, 4H), 1.38-1.90 (m, 8H), 1.40 (s, 9H), 2.15-2.75 (m, 5H), 2.85 (s, 3H), 3.60 (m, 2H), 3.75 (d, J = 4.0 Hz, 2H), 4.45 (m, 1H), 5.85 (m, 1H), 6.55 (s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H). The above t-butyl ester (0.47 g, 0.77 mmol) was suspended in 10 mL of 4N aqueous HCl and 2-3 drops of anisole were added. The reaction mixture was stirred at room temperature for 72 h and filtered. The filtrate was evaporated to dryness, redissolved in CH3CN, filtered again, and concentrated. The addition of the ether gave the product which was filtered, washed with ether, and dried to give (±) 51 HCl as a beige solid, 0.17 g (41%); mp 178-180 ° C (d); MS (FAB) 442 (M + 1); XH NMR (200 MHz, CDC13) d 1.05-2.20 (m, 12H), 2.75 (s, 3H), 2.90-3.25 (m, 5H), 3.30-3.55 (m, 2H), 3. 70-4.35 (m, 4H), 4.65 (m, 1H), 6.72 (s, 1H), 6.80 (m, 1H), 6. 95 (d, J = 7.7 Hz, 1H). Anal. Cale. for C22H3oF3 3? 3. HC1.0.125Et2O: C, 55.47; H, 6.67; N, 8.62. Found: C, 55. 64; H, 7.06; N, 9.00 Example 115 Hydrochloride [(±) 5m HCl] of (±) -trans-3-Tri luoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cislohexyl] -phenylacetamide ADL-01-0083-4 Following the Example 2, (5) 5m HCl was prepared from 3-trifluoromethylphenyl acetic acid in 67% yield as a cream colored solid; mp 245-247 ° C; 1 HOUR NMR (200 MHz, CDC13) d 1.15-1.55 (m, 4H), 1.60-2.30 (m, 8H), 2.80-3.05 (m, 2H), 3.00 (s, 3H), 3.18 (m, 1H), 3.45 (m, 1H), 3. 75 (d, J = 15.0 Hz, 1H), 3.85 (m, 1H), 4.25 (d, J = 14.8 Hz, 1H), 4.65 (m, 1H), 7.40 (m, 4H). Anal. Cale. for C20H27F3N2O.HC1.0.25H2O: C, 58.68; H, 7.02; N, 6.84.

Found: C, 58.46; H, 7.17; N, 6.69. Nitration of 3-tritrif luoromethyl-enylacetic acid: Preparation of 2-nitro-3-trifluoromethylphenylacetic acid [4, R = 2-? 2 (3-CF3) -C6H4CH2 and preparation of 5-nitro-3-trifluoromethylphenylacetic acid [4, R = 5-NQ2 (3-CF3 ) -C6H4CH2] The nitration of 3-trifluorophenylacetic acid as shown in the above result in 1: 1 without separable mixture of 2- and 5-nitro compounds in 66% yield. Structural assignments of the compounds were made based on the XH NMR spectrum. The mixture was used in the condensation reaction. Example 116 Hydrochloride [(±) 5n HCl] of (1) -trans-5-Nitro-3-trifluorophenyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide and Hydrochloride [(±) 5o HCl] of (±) -trans-2- Nitro-3-trifluoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0087-5 and AD-01-0088-3 The compounds were prepared as shown in Example 109 and the mixture of 2- and 5-nitrophenylacetic acids to give the product mixture. Initially the compounds were separated on a silica gel column [solvent system: CHC13: CH30H: 28% NHOH (96: 2: 2)] which resulted in the free base of the compounds as a pure mixture. The products were again purified on Cromatotran using a 4mm silica gel plate [solvent system: CHCl3 containing 2% NH4OH]. The first product was isolated and converted to the hydrochloride salt and the salt was recrystallized from 2-propanol: ether (1: 1) to give (±) 5n HCl as a cream colored solid in 10% yield; mp 236-238 ° C; 1 H NMR (200 MHz, CDC13) d 1.15-1.55 (m, 4H), 1.65-2.30 (m, 8H), 2.85-3.20 (m, 3H), 3.10 (s, 3H), 3.40 (m, 1H), 3.70 (d, J = 14.0 Hz, 1H), 3.85 (m, 1H), 4.60 (broad d, 2H), 7.90 (s, 1H), 8.25 (s, 1H), 8.32 (s, 1H). Anal. Cale. for C20H26F3N3? 3.HCl: C, 53.39; H, 6.05; N, 9.34. Found: C, 53.28; H, 6.06; N, 9.36. The second product, (±) 5 HCl, was also isolated in 10% yield after recrystallization of the hydrochloride salt from 2-propanol: ether (1: 1) as a white solid; mp 243-245 ° C (d); XH NMR (200 MHz, CDC13) d 1. 10-1.50 (m, 4H), 1.55-2.20 (m, 8H), 2.90-3.20 (m, 3H), 3.10 (s, 3H), 3.44 (m, 1H), 3.65 (d, J = 13.5 Hz, 1H), 3.90 (m, 1H), 4. 65 (broad d, 2H), 7.70 (s, 1H), 7.82 (s, 2H). Anal. Cale. for C20H26F3N3O3. HCl. H20: C, 51.34; H, 6.25; N, 8.98. Found: C, 51.69; H, 6.24; N, 8.89. Example 117 Hydrochloride [(±) 5p HCl] of (±) -trans-2-trifluoromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0114-7 The compound was prepared from 2-trifluoromethylphenylacetic acid following Example 2. The hydrochloride salt was made from 1M of ethereal HCl and recrystallized from 2-propanol: ether (1: 1) to give (±) 5p HCl in 20%. % yield as a white solid; mp 282-284 ° C (d); XH NMR (200 MHz, CDC13) d 1.20-1.50 (m, 4H), 1.55-2.30 (m, 8H), 3.85-3.04 (m, 2H), 3.08 (s, 3H), 3.10-3.27 (m, 1H ), 3.40-3.60 (m, 1H), 3.90 (m, d, J = 14.5 Hz, 2H), 4.26 (d, J = 14.7 Hz, 1H), 4.63 (m, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.5 Hz, 2H). Anal. Cale, for C2oH2-7F3N2.O.HCl: C, 59.33; H, 6.97; N, 6.92. Found: C, 59.28; H, 6.73; N, 6.84. Nitration of 2-trifluoromethylphenylacetic acid: Preparation of 4-nitro-2-trifluoromethylphenylacetic acid [4, R = 4-NQ2 (2-CF3) -CeH4CH2] The nitration of 2-trifluorophenylacetic acid as described in Scheme III gave mainly the corresponding 4-nitro derivative and only a small amount of the 6-nitro compound was detected in the NMR proton; - "? NMR (200 MHz, CDC13) d 3.90 (s, 2H), 7.55 (d, J = 8.4 Hz, 1H), 8.35 (dd, J = 2.4, 8.0 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H) The compound was used directly in the following coupling reaction Example 118 Hydrochloride [(±) 5q HCl] of (±) -trans-4-Nitro-2-trifluoromethyl-N-methyl-N- [ 2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0116-2 The compound was prepared following the coupling method described in Example 109 from 4-nitro-2-trifluorophenylacetic acid. by a known method and recrystallized from 2-propanol: ether (1: 1) to give (±) 5q HCl as a beige solid in 37% yield, mp 265-267 ° C (d); XH NMR (200 MHz, CDC13) d 1.15-1.45 (m, 4H), 1.50-2.30 (m, 8H), 2. 85-3.20 (m, 3H), 3.05 (s, 3H), 3.45 (m, 1H), 3.90 (m, d, J = 14.0 Hz, 2H), 4.60 (broad d, 2H), 8.00 (d, J = 8.0 Hz, 1H), 8.25 (dd, J = 2.4, 8.0 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H). Anal. Cale. for C20H26F3N3? 3.HCl: C, 53.39; H, 6.05; N, 9.34. Found: C, 53.29; H, 5.93; N, 9.17. Example 119 Hydrochloride [(±) 5r 2HC1] of (±) -trans-4-Amino-2-tri-loromethyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamide ADL-01-0142- The compound was prepared from the free base (±) 5q following the reduction procedure described by the preparation of (±) 5h. The free base was converted to the dihydrochloride from 1M ethereal HCl and recrystallized from CH2C12: CH3OH: Et20 (6: 3: 1) to give (±) 5r 2HC1 as a white solid in 68% yield; mp 288-290 ° C (d); XH NMR (200 MHz, DMSO-d6) d 1.10-2.20 (m, 12H), 2.98 (s, 3H), 3.00-3.30 (m, 4H), 3.50 (m, 1H), 3.80 (d, J = 14.5 Hz, 1H), 4.20 (d, J = 14.8 Hz, 1H), 4.50 (m, 1H), 7.50 (m, 3H). Anal. Cale, for C20H28F3N30.2HC1: C, 52.64; H, 6.63; N, 9.21. Found: C, 52.67; H, 6.52; N, 9.06. Example 120 Hydrochloride [(+) 5s HCl] of (+) - trans-N-Methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -2,2-diphenylacetamide AD -01-0013-1 The compound was prepared from diphenylacetic acid following the general procedure for the preparation of arylacetamides. The hydrochloride salt was recrystallized from 2-propanol to give (±) 5s HCl as a white solid in 20% yield; mp 295-297 ° C (d); 1R NMR (200 MHz, CDC13) d 1.20-2.40 (m, 12H), 2.85-3.15 (m, 2H), 3.00 (s, 3H), 3.25-3.60 (m, 2H), 3.95 (m, 1H), 4.75 (m, 1H), 5.70 (s, 1H), 7.35 (m, 10H). Anal. Cale. for C25H32N2O.HC1.0.25H2O: C, 71.92; H, 8.09; N, 6.71. Found: C, 72.25; H, 8.40; N, 6.52. Example 121 Hydrochloride [(±) 5t HCl] of (±) -trans-4-Methylsulfonyl-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] phenylacetamide ADL-01-0071-9 The compound was prepared 4-methylsulfonylphenylacetic acid by the method of Example 109 and the hydrochloride salt was recrystallized from CH2Cl2: Et20 (1: 1) to give (±) 5t HCl as a cream-colored solid in 50% yield; mp 152-154 ° C (d); 1 H NMR (200 MHz, CDC13) d 1.10-2.30 (m, 12H), 2.95 (s, 6H), 3.00-3.25 (m, 2H), 3.40 (m, 1H), 3.65 (d, J = 14.5 Hz, 1H), 3.85 (m, 1H), 4.35 (d, J = 14.0 Hz, 1H), 4.67 (m, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H). Anal. Cale, for C20H30N2O3S. HCl .1.5H20: C, 54.35; H, 7.75; N, 6.34. Found: C, 54.20; H, 7.38; N, 6.15.

In one aspect of the composition, the kappa agonist compounds of the present invention are formulated in local and topical parenteral formulations. The compositions are formulated as injectables, as oral and rectal formulations for systemic administration and for local and topical administration as creams, aqueous or non-aqueous suspensions, lotions, emulsions, suspensions or emulsions containing micronized particles., gels, foams, aerosols, solids, and other vehicles suitable for application to the skin, eyes, lips, and mucosa such as suppositories or cream for vaginal administration and as combinations with bandages, bioadhesive patches and bandages. The compounds can be formulated in combination with other agents, such as local anesthetics and other therapeutic agents. The other agents that can be mixed in the compositions are provided and administered before, simultaneously with or subsequent to the administration of the compositions provided by the methods herein. Such agents include, but are not limited to: antibiotics, which include cephalosporins, β-lactam, tetracycline, vancomycins, sulfas and aminoglycoside; antivirals, which include acylovir; and antifungals that include clotrimazole. In one aspect of the method of the present invention provide methods for treating hyperalgesia by application of a quantity of a compound or composition to a mammal to lessen or eliminate pain. Therefore, the method of the present invention comprises a method of pain treatment in internal or external form present in the body of the mammal that includes: internal injuries, such as those caused by accidents or surgical procedures; abnormal functioning of bodily organs; irritation associated with inflammation followed by local infection, blisters, burns, or acute skin lesions, such as abrasions, burns, superficial cuts, surgical incisions, tooth aches, bruises, irritations, inflammatory skin conditions, including but not limited to ivy poisonous, and allergic rashes and dermatitis and any condition that produces a state of hyperalgesic pain and other similar conditions. Determination of anti-hyperalgesic activity The pharmacological activity of the compounds of the present invention can be determined by various in vitro and in vivo models recognized in the art. Some of the typical models are described here. (a) In the in vitro combination test (Also Primary) 14 The initial test for these compounds is the binding of [H] diprenorphine to the cloned human Kappa receptor.

Compounds that inhibit binding by at least 80% of lμM are classified and Ki values are determined by Cheng-Prusoff transformations of IC50 values. The IC50 value is the concentration of inhibitor that inhibits the radio linkage labeled by 50% and the Ki value is the affinity of the inhibitor for the receptor. The compounds are also tested against [3H] U69593] linkage (agonist) for this receptor. No compound is known to inhibit only the agonist or antagonist linkage. However, such a compound may have a unique pharmacological profile, as a result of its specificity for a receptor region. The initial specificity is determined by the test compounds in [3 H] diprenorphine binding to human mu and delta receptors cloned at 10 μM and those compounds which inhibit the binding by at least 80% are classified. Compounds that do not have Ki values at least 100 times higher against the mu and delta receptors are likely to have no additional side effects and are not practiced to allow additional evaluation of the specific compounds. Ref. (14) Raynor et al., M Pharmacol. 45: 330-334 (1994) (b) Inflamed knee joint hyperalgesia model and blood pressure response for the understanding of the inflamed knee joint Inflammation in a joint is frequently associated with hyperalgesia [pain during normal flexion and extension and during the application of moderate mild pressure ] and / or persistent pain [persistent pain; Schaible et al .. (1993) Pain 55: 5-54]. During the course of inflammation of the knee joint, a succession of events occurs, which include: (i) synthesis and release of inflammatory mediators in the joint, (ii) release of neuropeptides from afferent fibers in the joint cavity, and (iii) increased primary afferent flow from the group of sensitive fibers II, III and IV [Schaible et al .. (1993) Pain 55: 5 -54]. An important result of this succession is that there is an increase in the response of small afferents slightly myelinated and not myelinated for low intensity stimuli. In this way, the inflamed tissue with innervations of peripheral nerves can evoke an exaggerated behavior response for otherwise innocuous stimuli, ie a state of hyperalgesia. Therefore, inflammation of the knee joint will result in increased spontaneous afferent activity, the appearance of an exaggerated discharge with flexion and extension of the joint [Schaible et al. .. (1995) J. Neurophysiol. 54: 1109-1122] and signs of autonomic reaction associated with pain [Sata et al. (1984) Neurosci. Lett. 52: 55-60]. The injection of a sample of kaolin and carrageenan into the knee joint induces experimental arthritis. As exemplified below, this treatment was characterized by a reliable increase in the volume and circumference of the joint. In a non-anesthetized rat, these articulation changes were accompanied by a tendency to avoid weight bearing, suggesting a painful state in progress. According to electrophysiological studies, in the course of the development of this acute arthritis, the C and Ad units respond normally only to the extreme joint distortion that is activated by light movements [Schaible et al. (1985) J. Neurophysiol. 54: 1109-1122]. Spinal neurons with knee-joint receptor fields in the deep dorsal horn of the spine show a clear development of hyperexcitability with acute inflammation in the joint [Neugebauer et al. . (1993) J. Neurosci. 70: 1365-1377]. This sensitization of group III and IV fibers was observed at 2-3 hours after injection of kaolin and carrageenan into the knee joint, a time course that closely matches the time course of hyperalgesia development in the model Rat knee joint understanding. These observations indicate that the neurons of the spinal column and the primary afferent fibers of the joint are sensitized and may be subject to hyperalgesia observed in this arthritic state. Such afferent input can drive autonomous responses that are typically associated with the processing of input from afferents typically activated by stimuli generated by the local inflammatory state. In addition to the aforementioned inflamed knee mechanism, changes in blood pressure (BP) can also be evoked reflexively by afferent neural activity from receptors located in skeletal muscle [Williamson et al. (1994) J. Physiol 475: 351-357]. This response depends on changes in intramuscular pressure and the quality of compressed muscle mass. This particular mechanical reflex seems to operate independently of the pain response and seems to play a lesser role in the experiments exemplified, such as the inflammation of the cut of the left normal knee joint that had no effect on BP. In any case, it is possible that the overflow of dwarf carcass from the joint capsule can serve to inflame the surrounding tissue as well. Sensitization of units C and A was observed in the gastronemius muscle of the rat by carrageenan infiltration [Handwerker et al. (1991) Pain and Inflamation. Proceeding of the VIth World Congress on Pain, Bond et al., Elsevier Science Publishers BV, pp. 59-70]. Based on these considerations, it seems that the understanding of inflamed knee joints produces a harmful stimulus and this in turn activates a sympathetic response that results in an increase in BP. Local inflammation of the knee results in a state where otherwise innocuous stimuli result in an important autonomous response, which include increased blood pressure and heart rate (BP). [see for example, Sata et al. (1984) Neurosci Lett. 52: 55-60]. Alternatively, the neural flow from the inflamed knee is recorded [see for example Neugebauer et al. (1993) J. Neurosci. 70: 1365-1377]. An in vitro test that measures the spontaneous discharge in the skin damaged by the utopian application was also used [see for example Andreev et al. (1994) Neurosci. 58: 793-798]. (c) In vivo evaluation of formalin-induced nociception The administration of formalin within the leg results in localized inflammation and a pain response that is moderate in intensity and of continuous duration. Unlike other nociception assays, the formalin assay measures the topical pain that is a result of the tissue injury and therefore is a model that is more relevant to clinical pain states in humans [see Tjolsen et al. (1992) Pain 51: 5-17]. In the rat the response to formalin-induced pain consists of spontaneous faltering behavior, characterized by elevation and agitation of the paw, and a rapid vibration of the paw after contraction under the body. The hesitant response can be quantified considerably and exhibits two activity peaks that are indicative of acute and tonic pain [Wheeler-Aceto and Cowan (1991) Psychopharmacology 104: 35-44]. The initial or acute phase lasts 0-5 minutes after formalin and is followed by a period of immobility that lasts approximately 15 minutes. The tonic phase occurs 20-35 minutes after the formalin injection and is the interval where the number of hesitant responses is maximum. This model has been characterized in several species [Tjolsen et al (1992) Pain 51: 5-17] and is sensitive to the analgesic effects of opiates administered by a variety of routes, including local administration directly on the paw. In addition, the test is particularly sensitive to the effects of K agonists [Wheeler-Aceto and Cowan (1991) Psychopharmacology 104: 35-44]. Inflammation is induced by subcutaneous injection of 50 μl of a 5% formalin solution into the dorsal surface of the right hind paw of male Sprague-Dawley rats weighing 70-90 grams. Drug injections occur on the dorsal surface of the paw before formalin • injection and the hesitant behavior is quantified by counting the number of responses that occur during the tonic phase of pain, which lasts 20-35 minutes after of formalin injection. The results are expressed as the average percentage antagonism of the formalin-induced hesitancy calculated for drug-treated formalin-injected rats and individually using the following formula: (mean response of formalin-response of saline solution) -an individual response x 100 response of Mean formalin - average saline response The average formalin response is the average behavioral record of vehicle-treated and formalin-injected rats Average saline responses is the combined behavior record from rats injected with 50 milliliters of saline Within the leg. (d) Randall-Selitto test Numerous variations and exemplifications of this test are known to those with experience in this technique [see, Randall et al. (1957) Arch. Int. Pharmacodyn. 111: 409- 419; see, also for example, U.S. Patent No. 5,434,292, the Patent No. 5,369,131, U.S. Patent No. 5,345,943, U.S. Patent No. 5,242,944, and U.S. Patent Number 5,109,135. The pain threshold is measured in this method as the amount of pressure in grams required to induce a succession reaction (stress) when applied to the foot of an experimental animal exhibiting hyperalgesia, typically an inflamed foot, compared to a control, such as, the same animal or equivalent in the absence of the inflammation, and / or in the absence of a test compound. The increased pressure is applied to the leg with a wedge-shaped blunt piston on the dorsal surface of the concealed leg by means of a leg analgesia meter. The pressure required to produce the removal of the leg, is determined, and the leg pressure threshold (PPT). Stein and his collaborators [Stein et al. (1988) Pharmacol, Biochem. Behav. 31: 445-451; Stein et al .. (1989) J. Pharmacol. Exp, Ther. 248: 1269-1275] have developed a model of peripheral inflammation and hyperalgesia in rats that support the role of opiates in mediating peripheral analgesia. In this protocol, the modified Freun's auxiliary is used as the inflammatory stimulus, and the paw pressure test is used to determine the response of the rat to a painful pressure stimulus. The model is sensitive to opiate agonists of subtypes μ, d and K, which produce analgesia about administration. [Antonijevic et al. . (1995) J. Neurosci. 15: 165-172; Stein et al. . (1988) " Neurosci, Lett. 84: 225-228; Stein et al. . (1989) J.

Pharmacol, Exp, Ther. 248: 1269-1275]. Histological verification of the location and density of the opiate receptor have confirmed that peripheral opiate receptors are accessible over primary afferent nerve fibers and are regulated after inflammation.

[Hassan et al. (1993) Neuroscience 55: 185-193; Przewlocki et al. . (1992) Neoroscience 48: 491-500]. The experiments are conducted in rats weighing 150-250 grams at the time of inoculation. The modified Freund's complete assistant (FCA) is used as the inflammatory stimulus. The rats are given an intra-peritonial injection of FCA suspension into the right leg. Hyperalgesia and anticiception are evaluated using the leg pressure test. The rat is moderately restrained and the pressure applied to the leg with a wedge-shaped blunt piston on the dorsal surface of the concealed leg is increased by means of a leg pressure analgesia meter. The pressure required to produce the removal of the leg, and the pain pressure threshold of the leg (PPT) is determined. A cutting pressure of 250 grams is used to avoid undue stress and pain to the animal. The baseline response is established by determining the average of three consecutive tests separated by 10 seconds. The same procedure was conducted on the contralateral side and the sequence of the sides alternated between animals to control order effects. Typically injections are not made in the contralateral leg (not inflamed); however, in selected cases the drugs can be administered to the contralateral leg to evaluate the potential of drug effects in the absence of inflammation. The analgesic activity is determined by the expression of the increase in PPT that results from the effect of the drug as a percentage of the baseline pre-injection thresholds. Hyperalgesia can also occur by inflammatory stimuli such as yeast or carrageenan, endogenous inflammatory mediators such as bradikinin, or prostaglandins, or other types of chemical irritants [see Hargreaves and Joris (1993) APS Journal 2: 51-59]. (e) Acetic acid-induced convulsion This test identifies novel agents that exhibit peripheral analgesic activity against visceral or chemical pain [see Barber and Gottschlich (1986) Med, Res. 12: 525-562 Ramabadran and Bansinath (1986) Pharm. Res: 3: 263-270]. The injection of acetic acid into the peritonial cavity is used as the noscive stimulus, and the number of convulsive responses that occur in response to acetic acid are counted in order to quantify the response to pain. The components that have analgesic activity reduce the number of seizure responses that occur. Opiate agonists of subtype μ and K exhibit analgesic activity in this model [Barber and Gottschlich (1986) Med. Res. 12: 525-562; Millan (1990) Trends Pharmacol. Sci. 11: 70-76]. The novel compounds that show potency and efficacy in this test are potential drugs for the treatment of various pathological conditions involving peripheral pain. The convulsion test is adapted from the procedure originally described by Taber et al, [(1969) J. Pharmacol. Exp. Ther. 169: 29-38] using male CF-1 mice weighing 20-25 g. The animals are treated with several doses of drugs before administration of an intraperitoneal injection of 0.6% acetic acid solution. The mice are then placed in observation chambers and the number of seizure responses is recorded, as defined by full extension and retraction of the hind limb. The mean number of seizure responses is calculated for control mice treated with vehicle, and percent inhibition (% I) of seizure is calculated for each mouse that is treated with the drug using the following formula:% l = 100 x (convulsion responses of control medium-response of individual test) convulsive responses of control medium (f) Hyperalgesia induced by separation with tape The objective of this test is to identify novel agents that exhibit peripherally mediated analgesia in circumstances, such as burns and abrasions that lead to hyperalgesia. In such lesions, loss of the corneal layer is followed by an inflammatory response (erythema) and a painful response to otherwise innocuous stimuli. The removal of the stratum corneum by repeated application and removal of cellophane tape, called tape separation, has shown that it is a simplified model of these lesions, which share the characteristics of first-degree burns [see Flynn (1985) Percutaneous Absorption, RL Bronaugh and HI Maibach eds., Marcel Dekker Inc., pp 18-42]. This method of barrier interruption avoids the application of potentially toxic chemical agents and allows the evaluation of peripheral analgesics following topical administration because the separation with tape removes the barrier of effective topical therapy (the stratum corneum), while It results simultaneously in inflammation and hyperalgesia. The separation with tape has been validated in humans as a model for the testing of topical agents [Pershmg et al (1994) Antimicrob. Agents Chemother. 38: 90-95; Roy and Flinn (1990) Pharm. Res 7: 842-847]. The experiments are conducted on male Sprague-Dawley rats weighing 250-300 grams at the time of treatment. After anesthesia of the rat with zetamine-cilamine, a patch of 1-3 cm2 of rat skin is treated by repeated application and removal of the tape. This procedure results in the removal of the cornea layer as. it is determined by a shiny appearance of the skin. The skin removed by tape is evaluated for a visible erythema and for sensitivity to contact by heat or stimuli, pressure using a focused light beam, testing the foot pressure device or by touching with von Frey hair. The diameter of the type hair, von Frey, will be selected based on the diameter that does not elicit response in the control rats but that has an easily detectable response in the treated rats. Analgesics will typically be formulated in a suitable topical medium and applied to the treated skin. Some rat will receive only the topical medium without analgesic, to control an effect of the topical environment alone. The presence of analgesia is determined by the latency to the response of the heat stimuli by the response to contact or pressure.

The pharmacological activities of the compounds of the present invention are shown in Tables I, II, III and IV in which Kj.:nM (3H-diprenorphine and 3H-U-69,593) show the results of in vitro binding assay as described in "(a) In vitro binding assay (Primary Screen) and A50 values (μg), the leg shows one of the results of formalin-induced nocecipitation in vivo as described in" (c) Evaluation in I live from formalin-induced noceciption. " TABLE I Compounds of Formula I TABLE II Compounds of Formula II TABLE III Compounds of the Formula lll 00 or 00 00 you 1 7 TABLE IV Compounds of Sa Formula IV Assessment and Testing of the Anti-prurific Activity The formulations of the present invention for anti-pruritic activity were tested as follows. TEST FOR ANTI-PRURITIC ACTIVITY The test was performed in a pattern scraping model under blind conditions. In the test groups of 8-10 male Swiss albino mice (Hilltop Lab Animáis, Inc., Scottsdale, PA), weighing 2.5-2.6 g were used. They were housed under controlled temperature of 23-25 ° C. Food and water were freely available. Before the experiments, the mice were weighed, placed in individual boxes and allowed to acclimate for 30 minutes.

Materials The vehicle used to dissolve the test compounds: cremophor EL 20% w / w. To induce the scraping compound 48/80 (Sigma, ~ St. Louis, USA) was used which showed that it produced a pruritus sensation in humans (Armstrong et al., J. Of Physiol., 120: 326, 1953 ). The compound to be tested for antipruritic activity was dissolved in the EL cremofor vehicle. 20% p / p. Method 100 μl of the vehicle (3-5 doses, n = 8-10) was injected into the back of the neck of the mice 20 minutes before testing with 100 μl of Compound 48/80 (2 mg / ml; 50 μg) ) injected into the back: dal_ neck. One minute later the mice were observed for 30 minutes and the number of scraping movements directed to the neck was counted. The mouse with injected vehicle was scratched 79 ± 16 ~~ times in the 30 minutes after the standard challenge with Compound 48/80. Each mouse in a group of 8-10 mice was previously subjected to the standard challenge of several doses of the compounds to be tested for antipruritic activity, which was administered to them in the posterior part.

By the neck. One minute later the mice were observed for 30 minutes and the number of scraping movements directed towards the neck was counted. For each group of 8-10 mice, the mean values for scraping were normalized to a% relative scratching antagonism and then plotted against the dose of the test compounds. The interval estimates of the mean A50 were determined by non-linear regression analysis (Kaleidagraph) and the mean percent scrape inhibition was calculated. The tested compounds have shown, the dose-dependent anti-pruriric activity in the range from about 15 to about 95% based on the dose from about 0.5 to 10.0 mg / kg s.c. FORMULATIONS OF THE PRESENT INVENTION The effective concentrations of one or more of the compounds of the present invention or pharmaceutically acceptable derivatives thereof are mixed with a carrier or pharmaceutical carrier suitable for systemic, topical or local administration. The compounds are included in an amount effective to reduce the pruritic symptoms for which treatment is contemplated. The concentration of the active compound in the composition will depend on the absorption, inactivation, excretion ranges of the active compound, the dosing schedule, and the amount administered as well as other factors known to those skilled in the art. For topical and local administration, the dosages are higher, typically at least about 5 to 10, more than the amount delivered when administered systematically orally. The compounds of the present invention possess analgesic activity and can be used for pain relief without loss of consciousness. For example, compounds that can be used to treat muscle spasm, arthritis and other musculoskeletal conditions, for example, bursitis, mild relief, for post-operative and post-partum pain, dysmenorrhea and traumatic pain. Additionally, the compounds of the present invention can be administered for the treatment of severe pain, for example, pain associated with adenocarcinoma, limb amputation, and third degree burns on a larger portion of the body in animals and humans. "The selected compounds of the present invention have activity as narcotic antagonists, they can be used to counteract or prevent excessive central nervous system depression and preventive depression resulting from the administration of morphine or other drugs such as morphine, for example, hydromorphone, oxymorphone, methadone and meperidine. The compounds are also capable of including a withdrawal syndrome in addicted narcotic subjects, that is, they induce retraction effects for diagnostic purposes. The dosage of the compounds of Formulas I, II, III, IV and V for analgesic purposes is from about 0.001 to about 20 mg / kg body weight of the patient. The compounds of Formulas I, II, III, IV and V are conveniently prepared in 5, 10, 25, 50, 75, 100 and 200 mg of dosage units for administration 1 to 4 times a day. The preferred dose units are from 0.05 to 10 mg / kg body weight of the patient. The compounds are administered orally, parenterally, rectally and topically. Suitable carriers or pharmaceutical carriers for the administration of the compounds and for the methods provided herein include any such carrier known to those skilled in the art to be suitable for the particular mode of administration. a) Sistomic Formulations The formulations of the present invention are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, Y oil-water emulsions containing suitable amounts of a compound of Formula I or pharmaceutically-acceptable salts thereof. The dosage unit dosage forms provided are from about 0.05 mg to about 500 mg and preferably from about 1.0 to about 200 mg of the essential active ingredient or a combination of essential ingredients per unit dosage form. Oral pharmaceutical dosage forms. They are either solid or liquid. The solid dosage forms are tablets, capsules, granules, and powders in volume. Types of oral tablets include tablets and compressed, chewable tablets that may be enteric coated, sugar coated or film coated. The capsules can be hard or soft gelatin capsules, while the granules and powders can be supplied in an effervescent or non-effervescent form with the combination of other ingredients known to those skilled in the art. The pharmaceutically acceptable carriers used in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. The tablets coated with enteric coating, due to their enteric coating, resist the action of stomach acid and 1 dissolve or disintegrate in the intestines with neutral or alkaline characteristics. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances have been applied. The film coated tablets are compressed tablets that have been coated with water soluble polymers. Multiple compressed tablets are compressed tablets made by more than one compren cycle using pharmaceutically acceptable substances mentioned above. Coloring agents can also be used in the form of the above dosage. Flavoring or sweetening agents are used in compressed tablets, sugar-coated tablets, multiple and chewable tablets. Flavoring or sweetening agents are especially useful in the formation of chewable tablets and dragees. Examples of binders include glucose solution, acacia mucilage, gelatin solution, starch paste and sucrose. Lubricants include talc, starch, magnesium or calcium stearate, lycopodic and stearic acid For example, diluents include lactose, sucrose, "starch, kaolin, salt, mannitol, and diethyl phosphate." Disintegrating agents include corn starch, starch of potato, bentonite, methylcellulose, agar and carboxymethylcellulose For example, the coloring agents include any of the water soluble FD and C dyes approved and certified, mixtures thereof, and water insoluble FD and C dyes suspended in alumina hydrate. The sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of dry spray flavorings. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. The enteric layers include fatty acids, fats, waxes, shellac, ammoniated lacquer and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. For example, aqueous solutions include elixirs and syrups. The emulsions are either oil in water or water in oil. The elixirs are hydroalcoholic, transparent sweetened preparations. The pharmaceutically carriers Acceptable used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules through another. liquid. The pharmaceutically acceptable carriers used in the emulsions are non-aqueous liquids, emulsifying agents and preservatives. The suspensions use pharmaceutically acceptable and conservative suspending agents. The pharmaceutically acceptable substances used in the non-effervescent granules, to be reconstituted in oral, liquid dosage form, include diluents, sweeteners and wetting agents. The pharmaceutically acceptable substance used in effervescent granules, to be reconstituted in a liquid oral dosage form, includes organic acids and a source of carbon dioxide. The coloring and flavoring agents are used in all the above dosage forms. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and agents surfactants such as polyoxyethylene sorbitan monooleate. "Suspending agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum and acacia." Diluents include lactose and sucrose Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin. propiienglicoi monostearate, sorbitan morrooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether Organic acids include citric and tartaric acid Sources of carbon dioxide include sodium bicarbonate and sodium carbonate Coloring agents include any of the FD dyes and approved water soluble Cs, and mixtures thereof Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste sensation.Parenteral administration of the formulations herein invention includes adm Intravenous, hypodermic and intramuscular administration. Preparations for parenteral administration include ready sterile solutions prepared for injection, sterile dry soluble products prepared to be combined with a solvent prepared before use, including hypodermic tablets, suspensions. sterile ready for injection, sterile dry insoluble products ready to be combined with a vehicle just before use and sterile emulsions. The solutions can be aqueous or non-aqueous. The pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, pH regulators, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Ringers Injection with Dextrose and Lactate. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations should be added to parenteral preparations packaged in multiple-dose containers that include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, esters of methyl and propyl p-hydroxybenzoic acid, thimerosal, benzalkonium and benzethonium chloride. "Isotonic agents include sodium chloride and dextrose .: PH regulators that include phosphate and citrate. Loa antioxidants that include sodium bisulfate. Local anesthetics including procaine hydrochloride Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (Tween 80). A metal ion chelating or sequestering agent includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for vehicles miscible in water and sodium hydroxide, hydrochloric acid, or citric acid. lactic acid for Ph adjustment. The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The dose depends on the age, weight and condition of the patient or animal as is known in the art. Parenteral preparations of unit doses are packaged in a vial or syringe with a needle. All preparations for parenteral administration must be sterile as known and practiced in the art. Illustratively, intravenous or intraarterial infusion of a sterile aqueous infusion containing a Active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. - The pharmacological dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories as used herein, represent solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. The pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents for raising the melting point. Examples of the bases include cocoa butter (theobroma oil), glycerin-gelatin, carbox, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. The combinations of several bases can be used. Agents for raising the melting point of suppositories include whale white and wax. Rectal suppositories can be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is approximately 2 to 3 grams.

Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and through the same methods as for oral administration formulations. The pharmaceutically and therapeutically active compounds of the Formula I are administered orally, parenterally or rectally in the form of unit doses or in the form of multiple doses. The unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and are packaged individually as is known in the art. Each unit dose contains a predetermined quantity of therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, carrier or diluent. Examples of unit dosage forms include individually packed ampules and syringes, tablets or capsules. Unit dosage forms may be administered in fractions or multiples thereof. A unit dosage form is a plurality of identical unit dose forms packaged in a single container to be administered in the form of a segregated unit dose. Examples of multiple dosage forms include bottles, bottles of tablets or capsules or bottles of different capacities. Therefore, the form of Multiple dose is a multiple of the unit doses that are not segregated in the packaging. The compounds of the present invention in the formulations can be included with other active compounds to obtain desired combinations of properties. Other active compounds with known pharmacological properties include analgesics such as aspirin, phenacetin acetaminophen, propoxyphene, pentazocine, codeine, meperidine, oxycodone, mefenamic acid, and ibuprofen; relaxants of muscle such as methocarbamol, orphenadrine, carisoprodol, meprobamate, chlorphenesin carbamate, diazapam, chlordiazepoxide and chlorzoxazone; analeptics such as caffeine, methylphenidate and pentylenetetrazole; corticosteroids such as methylprednisolone; prednisone, prednisolone and dexamethasone; antihistamines such as chlorpheniramine, cyproheptadine, promethazine and pyrilamine. b) Local and Topical Formulations Normally, an therapeutically effective dose is formed to contain a concentration of at least 0.1% w / w up to about 50% w / w more preferably, more than 1% w / w of the active compound for the treated tissue. The active ingredient can be administered at one time, or it can be divided into a number of smaller doses to be administered at intervals. It is understood that the dosage Accurate and duration of treatment is a function of the tissue being treated and can be determined empirically using test protocols or by screening in addition to in vivo or in vitro test data. It should be noted that the concentrations and dose values may also vary with the age of the individual treated. It should also be understood that for any particular subject, the specific dose regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges Established herein are illustrative only and are not intended to limit the scope or practice of the claimed formulations. The compound can be suspended in micronized or other suitable form or can be derivatized to produce a more soluble active product or to produce a pro-drug. The shape of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the carrier or vehicle selected. The effective concentration is sufficient to reduce the pruritic condition and can be determined empirically. The compounds are usually included in concentrations of 0.001% w / w or more than 1% w / w up to 50% w / w or plus . The concentration is generally greater than the concentration for systemic administration of the compound. Preferred concentrations are in the range of 0.01% w / w about 25% w / w, more preferably 1% w / w 25% w / w, even more preferably more than about 1% w / w about 10% w / w , and more preferably greater than "l% w / w to about 5% w / w." The aqueous suspensions and formulations contain 1% w / w more.The resulting mixture can be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, dyes, pastes, foams, aerosols, irxigados, aspersiones, suppositories, bandages or any other formulation suitable for topical or local administration. is topical or local administration and the compositions are formulated in a manner suitable for each route of administration.Preferred modes of administration include topical administration to the skin, eyes or mucosa and the application thereof. Local joints, such as intra-articular injections. Therefore, typical vehicles are those suitable for pharmaceutical or cosmetic application to body surfaces or for local injection.

The pharmaceutical carriers and vehicles suitable for the administration of the compounds provided herein include any carriers known to those known in the art to be suitable for the particular mode of administration. In addition, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. The active compound is included in the carrier in an amount sufficient to exert a therapeutically useful effect in the absence of serious toxic effects on the treated individual. The effective concentration can be determined empirically by testing the compounds using in vitro and in vivo systems. For topical administration, the compounds can be formulated into compositions in the form of gels, creams, lotions, solids, solutions or suspensions, or aerosols. Compositions for the treatment of human skin are formulated for topical application with an effective anthropuritic amount of one or more of the selected compounds as described herein, in an effective concentration range [by weight] between about 0.1% and 80%. %, preferably "0.1 to 50%, more preferably more than about 1% to about 50% or more" in a cream, ointment / lotion, gel, solution or solid base or vehicle known in the art to be non-toxic and dermatologically acceptable or suitable for application to the mucosa. Aqueous suspensions are preferably formulated in concentrations greater than about 1% w / w, more preferably 2% w / w. To formulate a composition, the weight fraction of the compound is dissolved, suspended or dispersed, otherwise mixed in a selected vehicle at an effective concentration so that the hyperalgesic condition is relieved or improved. Generally, emollient or lubricant vehicles that can help hydrate the skin are more preferred than volatile vehicles, such as ethanol, which dries the skin. Examples of suitable bases or vehicles for preparing compositions for use with human skin are petrolatum, petrolatum plus volatile silicones, lanolin, [USP], hydrophilic ointment [USP]. The choice of an acceptable vehicle is determined to a large extent by the mode of application and the fabric to be treated. Pharmaceutically and determatologically acceptable vehicles for topical application include those suitable for use which include lotions, creams, solutions, gels, tapes and the like. In general, the vehicle is organic by nature or a aqueous emulsion and capable of having the selected compound or compounds that can be micronized, dispersed, suspended or dissolved therein. The vehicle can include pharmaceutically acceptable emollients, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents and solvents. For local internal administration, such as intra-articular administration, the compounds are preferably formulated as a suspension in an aqueous-based medium, such as isotonicly-regulated salt solution or combined with a biocompatible or bioadhesive support intended for internal administration. Lotions Lotions contain an effective concentration of one or more of the compounds. The effective concentration is preferably effective to deliver an anthropytic amount, typically a concentration of between about 0.1-50% w / w or more than one or more of the compounds provided herein. The lotions also contain from 1% to 50% w / w, preferably from 3% to 15% w / w of an emollient and the remainder water, a suitable regulator, a C2 or C3 alcohol, or a water mixture of the pH regulator and alcohol. Any emollients known to those skilled in the art as have been suitable for application to the skin human can be used. These include, but are not limited to the following: (a) Hydrocarbon and paraffin oils, which include mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and perhydrosqualene. (b) Silicone oils that include dimethylpolysiloxanes, methylphenylpolysiloxanes, water soluble and silicone-soluble silicone-glycol copolymers. ~ (c) Triglyceride fats and oils including those derived from vegetable, animal and marine sources. Examples include, but are not limited to, castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, sesame oil and oil. of soybeans. (d) Acetoglyceride esters such as acetylated monoglycerides. (e) Ethoxylated glycerides such as ethoxylated glyceryl monostearate. (f) Alkyl esters of fatty acids having from 10 to 20 carbon atoms. Methyl, isopropyl and butyl esters of fatty acids are useful in the present. Examples include, but are not limited to, hexyl laurate, isohexyl laurate, isohexyl palmitate, palmitate, and isopropyl, isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate diisopropyladipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl lactate . (g) Alkenyl esters of fatty acids having from 10 to 20 carbon atoms. Examples thereof include, but are not limited to, oieyl myristate, oleyl stearate and oleyl oleate. _ _ (h) fatty acids having from 9 to 22 carbon atoms. Suitable examples include, but are not limited to, pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oieic, linoleic, ricinoleic, arachidonic, behenic, and erucic acids. (i) Fatty alcohols having from 10 to 20 carbon atoms, such as, but not limited to, lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleilic, behenyl, erucyl and 2-octyl dodecyl alcohol. (j) Fatty alcohol ethers, including, but not limited to, ethoxylated fatty alcohols of 10 to 20 carbon atoms, such as, but not limited to, lauryl acetyl, stearyl, isostearyl alcohols, oleic and cholesterol having attached thereto from 1 to 50 ethylene oxide groups or from 1 to 50 propylene oxide groups or mixtures thereof. (k) Ether esters such as fatty acid esters such as ethoxylated fatty alcohols (1) Lanolin and derivatives, including but not limited to lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate , ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, lanolin alcohol linoleate, lanolin alcohol ricinoleate, lanolin alcohol ricinoleate acetate, alcohol ester alcohol ethoxylates, lanolin hydrogenolysis, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin absorption bases. (m) Polyhydric alcohols and polyether derivatives, including, but not limited to, propylene glycol, dipropylene glycol, polypropylene glycol, [M.W. 2000-4000], polyoxyethylenepolyoxypropylene glycols, polyoxypropylene polyoxyethylene glycols, glycerol, ethoxylated glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol [M. W. 200-6000], methoxypolyethylene glycols, 350, 550, 750, 2000, 5000, poly) ethylene oxide) homopolymers [M.W. 100,000 ,000,000], polyalkylene glycols and derivatives, hexylene glycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-l, 3-hexanediol), vicinal glycol of C15-C18 and polyoxypropylene derivatives of trimethylolpropane. (n) Polyhydric alcohol esters, including, but not limited to, fatty acid esters of diethylene glycol mono- and di-fatty acid esters of diethylene glycol mono and di-fatty acids, polyethylene glycol [M.W. 200-6000], mono- and di-fatty esters, acid esters of propylene glycol mono- and di-, propylene glycol monooleate 2000, propylene glycol monostearate 2000, ethoxylated propylene glycol monostearate, esters of glyceryl mono- and di-fatty acids, esters polyglycerol polyglycerol acid, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. (o) Wax esters, including, but not limited to. a beeswax, whale white, myristyl myristate and stearyl stearate and beeswax derivatives, including, but not limited to, polyoxyethylene sorbitol beeswax, which are products of the reaction of beeswax with sorbitol ethoxylated with variable content of ethylene oxide forming a mixture of ether-esters. (p) Vegetable waxes, which include, but are not limited to carnauba and candelilla waxes. (q) Phospholipids, such as lecithin and derivatives. (r) Sterles, including, but not limited to; cholesterol and fatty acid esters are cholesterol.- (s) Amides, such as fatty acid amides, ethoxylated fatty acid amides and solid fatty acid alkanolamides. The lotions preferably further contain from-1% w / w to 10% w / w, more preferably from 2% w / w to 5% w / w of an emulsifier. The emulsifiers can be non-ionic, anionic, or cationic. Examples of satisfactory nonionic emulsifiers include, but are not limited to, fatty alcohols having from 10 to 20 carbon atoms, fatty alcohols having from 10 to 20 carbon atoms, condensed with 2 to 20 moles of ethylene oxide or propylene oxide. , alkylphenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters of ethylene oxides of mono- and di-fatty acid esters of ethylene glycol wherein the fatty acid portion contains from 10 to 20 carbon atoms, diethylene glycol, "polyethylene glycols of molecular weight from 200 to 6000, molecular weight propylene glycols of £ 20) to "3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and Jaidxophilic wax esters Suitable anionic emulsifiers include, but are not limited to, fatty acid soaps, eg, soaps sodium, potassium and triethanolamine, wherein the fatty acid portion contains from 10 to 20 carbon atoms, other suitable anionic emulsifiers, but not limited to, alkali metal, ammonium or substituted ammonium sulfates, alkylarylsulfonates, and alkyl ethoxyether sulfonates having from 10 to 30 carbon atoms in the alkyl portion The alkylethylether sulfonates contain from 1 to 50 units of ethylene oxide Among the satisfactory cationic emulsifiers are quaternary ammonium, morpholinium and pyridinium compounds. Some of the emollients, described in the previous paragraphs, also have properties, emulsifiers. n containing such an emollient, an additional emulsifier is not needed but may be included in the composition. - The rest of the lotion is water or a C2 or C3 alcohol, or a mixture of water or alcohol. The lotions are formulated by simply mixing all the components together. Preferably, the compound is dissolved, suspended or otherwise dispersed in the mixture.

Other conventional components of such lotions may be included. Such an additive is a thickening agent at a level from 1% to 10% w / w of the composition. Examples of suitable thickening agents include, but are not limited to: crosslinked carboxymethylene polymers, ethylcellulose, polyethylene glycols, gum, tragacanth, karaya gum, xanthan gum and bentonite, hydroxyethylcellulose and hydroxypropylcellulose. Creams The creams are formulated to contain effective concentration to deliver an effective antipruritic amount of the compound to the treated tissue, typically between about 0.1%, preferably greater: 1% up to and greater than 50%, preferably between about 3% and 50%, more preferably between about 5% and 15% of one or more of the compounds provided herein. The creams also contain from 5% to 50%, preferably from 10% to 25% of an emollient and the remainder is water or another suitable non-toxic carrier, such as an isotonic pH regulator. The emollients, as described above for the lotions, can be used in the cream compositions. The cream may also contain a suitable emulsifier as described above. The emulsifier is included in composition at a level from 3% to 50%, preferably from % up to 20%. Solutions and suspensions for topical and local administration The solutions are formulated to contain an amount of one or more effective compounds to deliver an antipruritic amount, typically at a concentration of between about 0.1 to 50% w / w, preferably at least more than of 1% w / w, more preferably more than 2% w / w of one or more of the compounds provided herein. The rest is water, a suitable organic solvent or another suitable solvent or pH regulator. Suitable organic materials useful as the solvent or a part of the solvent system are the following: propylene glycol, polyethylene glycol, [M.W. 200-600], polypropylene glycol [M.W. 425-2025], glycerin, sorbitol esters, 1, 2, 6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol, and mixtures thereof. Such solvent systems may also contain water. Solutions or suspensions used for local application may include any of the following components: a sterile diluent, such as water for injection, saline, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; [EDTA]; pH regulators such as acetates, citrates and phosphates; and agents for the tonicities such as sodium chloride or dextrose. The liquid preparations can be enclosed in ampoules, disposable syringes or multiple dose containers made of glass, plastic or other suitable material. Suitable carriers can include physiological salt solution cr-saline regulated in its pH with phosphate [PBS], and the suspensions and solutions can contain thickening and solubilizing agents, such as glucose, polyethylene glycol and polypropylene glycol and mixtures thereof. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. These compositions which are formulated as solutions or suspensions may be applied to the skin, or may be formulated as an aerosol or foam and applied to the skin as a spray. The aerosol compositions typically contain from 25% to 80% w / w, preferably from 30% to 50% w / w of a suitable propellant. Examples of such propellants are hydrocarbons of low molecular weight, chlorinated, fluorinated and chlorofluorinated. Nitrous oxide, carbon dioxide, butane and propane are also used as propellant gases. These propellants are used as known in the art in an amount and under a suitable pressure to expel the contents of the container. Solutions and suspensions prepared in a suitable manner can also be applied topically to the eyes and mucosa. Solutions, particularly those intended for ophthalmic use, can be formulated as isotonic solutions of 0.01% -10% w / w, pH of about 5-7, with "appropriate salts and preferably contain one or more of the compounds herein in a concentration of 0.1% w / w preferably greater than 1% w / w, up to 50% w / w or more .. Suitable ophthalmic solutions are known [See for example, US Patent No. 5,116,868, which describes typical compositions of solutions of Ophthalmic irrigation and solutions for topical application.] Such solutions, which have a pH adjusted to about 7.4, contain for example 90-100 mM sodium chloride, 4-6 mM dibasic potassium phosphate, 4-6 mM phosphate sodium dibasic, 8-12 mM sodium citrate, 0.5-1.5 mM magnesium chloride, 1.5-2.5 mM calcium chloride, 15-25 mM sodium acetate, 10-20 mM DL-hydroxybutyrate of sodium and 5-5.5 mM of glucose. The present invention can also be mixed with other active materials, those that do not deteriorate the desired action, or with materials that complement the desired action, including viscoelastic materials, such as hyaluronic acid, which is sold under the brand HEALON [solution of a high molecular weight fraction (MW of approximately 3 million) of sodium hyaluronate, manufactured by Pharmacia, Inc. See for example, U.S. Patent Nos. 5,292T, 362, "5,282,851, 5,273,056, 5,229,127, 4,517,295 and 4,328,803], VISCOAT [methacrylates containing fluorine, such as 1H, 2H, 2H-heptadecafluorodecylmethacrylate, see for example, "North American Patents Nos. 5,278,126, 5,273,751 and 5,214,080; (commercially available from Alcon Surgical, Inc.], ORCOLON [see for example, U.S. Patent No. 5,273,056, commercially available from Optical Radiation Corporation], methylcellulose, methyl hyaluronate, polyacrylamide and polymethacrylamide; [see for example, "Patent North American No. 5,273,751.] Viscoelastic materials are generally present in amounts ranging from about 0.5 to 5.0% w / w, preferably from 1% to 3% w / w of the conjugate material and serve to coat and protect the Treated Tissues The compositions may also include a dye, such as methylene blue or other inert dye, so that the composition can be seen when injected into the eye or brought into contact with the surgical site during surgery.

Gels The gel compositions can be formulated by simply mixing a suitable thickening agent to the solution or suspension composition previously described. Examples of suitable thickening agents have been previously described with respect to lotions. The gelled compositions contain an effective amount of one or more antipruritic amount, -normally at a concentration between about 0.1-50% w / w or more than one of the compounds provided therein; from 5% to 75% w / w, preferably from 10% to 50% w / w, of an organic solvent as previously described; from 0.5% to "20% w / w, preferably from 1% to 10% w / w of the thickening agent, the remainder being water or other aqueous carrier Solids The solid form compositions can be formulated as adhesive-like compositions intended for application to the lips or other body parts Such compositions contain an effective amount of one or more of the compounds provided in the present invention, the amount is usually an amount effective to deliver an antipruritic amount, typically at a concentration of between about 0.1-50% w / w more than one or more of the compounds provided herein The solids also contain from about 40% to 98% w / w of preference from about 50% to 905% w / w of the. emollients described above. The composition may also contain from 1% to 20% w / w, preferably from 5% up to. 15% p / p, from a thickening people, and, if desired or needed, emulsifiers and water or pH regulators. Thickening agents previously described with respect to lotions are suitably employed in the composition in solid form. Other ingredients such as preservatives, including methylparaben or ethylparaben, perfumes, dyes. or the like, which are known in the art to provide desirable stability, fragrance or color, or desirable properties, such as to protect from the actinic rays of the sun, to the compositions for application in. the skin that can also be employed in the composition for such topical applications. Additional Ingredients Other active ingredients include, but are not limited to, antibiotics, antivirals, antifungus, anti-inflammatory, including spheroidal and non-inflammatory steroidal drugs, anesthetics and mixtures thereof. Such additional ingredients include any of the following:. Antimicrobial Agents Aminoglycosides, such as Amicacin, Apra icina, "Arbecacine, Bambermycins, Butirosin, Dibecacin, Dihydrostreptomycin, Fortimycin (s), Fradiomycin, Gentamicin, Ispamycin, Kanamycin, Micronomycin, Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomycin, Spectomyomycin, Streptomycin, Streptonicozide and Tobramycin; Amfenicoles, such as Azidamfenicoi, Chloramphenicol, Cloramfenicoi, PalmiratóT "Cloramphenicoi Pantothenate, Florfenicol, Tiamfenicoi, Ansamycins, such as Rifamide, Rifampin, Rifamycin and Rifaximin, β-Lactams, Carbapenems, such as Imipenema; Cephalosporins, such as Cephalosporin 1-Carba (detia), Cefactor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Cefixime, Cefmenoxim, Cefodizima, Cefodizide, Cefoonzone, Ceforanide, Cefotaxime, Cefotiama, Cefpimizole, Cefpirimide, Proxetil Cefpodoxime, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibutene, Ceftizoxime, Ceftriaxone, Cefuroxime , Cefuzonam, Sodium of Cefacetril, Cephalexin, Cephaloglycine, Cefaloridin, Cephalosporin, Cefalotin, Cefapirin Sodium, Cefradine and Pivzefalexin, Cefamycins such as Cefbuperazone, Cefmetazole, Cefminox, Cefetan and Cefoxitin; Monobactams such as Aztreonam, Carumonam and Tigemonan; Oxacefems such as Flomoxef and Moxolactam; Penicillins such as Amidinocillin, Amdinocillin, Pivoxil, Amoxicillin, Ampicillana, Apaccilin, Aspoxycillin, Azidocilane, Azlocilane, Bacampicillin, Benzylpenicillinic Acid, Benzylpenicillin, Carbenicillin, Carbecillin, Carindacillin, Clometocillin, Cloxacillin, Cyclacillin, Dicloxacillin, Difenicillin, Epicillin, Fenbenicillin, Floxicillin, Hetacycline, Lenampicillin, Metampycillin, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penamecillin, Pentamate Hydriodide, Penicillin G Benetamine, Benzatine G Penicillin, Penicillin G Benzidrilaroin, Penicillin G Penicillin Calcium, Penicillin G Hydragamine, Penicillin G Potassium, Penicillin G Procaine, Penicillin N, Penicillin O, Penicillin V, Penicillin V Benzathine, Penicillin V Hydrylamide, Penimepicycline, Feneticiline, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Sulbenicillin, Talampicillin, Temocillin and Ticarcillin; Lincosamides such as Clindamycin and Lincomycin; "Macrolides such as Azithromycin, Carbomycin, Clarithromycin, Erythromycin (s) and Derivatives, Josamycin, Leucomycins, Midecamycins, Miocamycin, Oleandomycin, Primicin, Rokitamycin, Rosaramycin, Roxithromycin, Spiramycin and Troleandomycin; Polypeptides such as Amfomycin, Bacitracin, Capreomycin, Colistin, Enduracidin, Enviomycin, = Fusefungin, Gramicidin (s), Gramicidin S, Mikamycin, Polymyxin, Polymyxin β-Methanesulfonic acid, Pristinamycin, Ristocetin, Teicoplanin, Thiostreptone, Tuberactinomycin, Tirocidin, Thyrothricin, Vancomycin, Viomycin (s), Virginiamicin and Zinc Bacitracin; Tetracyclines such as Spicycline, Chlortetracycline, Clomocycline, Demeclocycline, Doxycycline, Guamecycline, Limecycline, Meclocycline, Metacycline, Minocycline, Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline, Sancycline, Senocycline and Tetracycline; and others such as Cycloserine, Mupirocin, Tuberine. b. Synthetic Antibody 2, 4-Diaminopyrimidines such as Brodimoprima, Tetroxoprime and Trimethoprim; Nitrofurans such as Furaltadone, Furazolium, Nifuradene, Nifuratel, Nifurfolina, Nifurpirinol, Nifurprazina, Nifurtoinol and Nitrofurantoina; Quinolones and analogs thereof, 'such as' Amifloxacin, Cinoxacin, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine, Lomefloxacin, "Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, Oxolinic Acid, Perfloxacin, Pipemidic Acid, Pyromide Acid, Rosoxacin, Temafloxacin and Tosufloxacin; Sulfonamides such as Acetyl Sulfamethoxypyrazine ", -" Sulfisoxazole Acetyl, Azosulfamide, Benzylsulfamide, Cloxamine B, Chloramine-T, Dicloramine-T, Formosulfatiazole, "N2-Formyl-Sulfisomidine, N4-β-D-Glucosylsulfanilamide, Mafenide, '- (Methyl) -sulfamoyl) sulfanilanilida, p-Nitrosulfatiazol, Noprilsulfamida, Ftalilsulfacetamida, phthalylsulfathiazole, Salazosulfadimidina, succinylsulfathiazole, sulfabenzamide, sulfacetamide, Sulfachlorpyridazine, Sulfacxisoidina, Sultacitina, Sulfadiazine Sulfadicramida, Sulfadimethoxine, Sulfadoxine, Sulfaetidol, sulfaguanidine, Sulfaguanol, sulfalene, Sulfalóxico acid, sulfamerazine, Sulfameter, Sulfamethazine, Sulfametizol, Sulfamethoxidine, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfametol, Sulfamidochisoidine, Sulfamoxol, Sulfanilamide, Acid Salt Triethanolamine Sulfanilamidomethanesulfonic, 4-Sulfanilamidoalicyclic Acid, N-β-D-Sulfenylsulfanilamide, Sulfanilylurea, N-Sulfanilyl-3, 4 -xylamide, Sulfanitran, Sulfaperine, Sulfafénazole, Sul faproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizol, Sulfasimazine, Sulfatiazole, Sulfatiourea, Sulfatolamide, Sulfisomidine and Sulfisoxazole; Sulfones, such as Acedapsone, Acetylsulfone, Acylsulfone, Dapsone, Diatimosulfone, Glucosulfone, Sulasulfon, Succisulfone, Sultanilic acid, p-Sulfanylyl-benzylamine, p, p'-sulphonylidiane-N, N'-digalactoside, Sulfoxone and Thiazolsulfone; Others such as Clofoctol, Hexedine, Magainins, Metenamine, Metenamma Anhydromethylene Nitrate, Metenamine Hippurate, Metenamine Manterate, Metenamine Sulfosalicylate, Nitroxoline, Squalarnin and Xibornol. c. Antifungal (antibiotics) Polyenes such as Amfotericin-B, Candicidin, Dennostatin, Philippine, Fungicromin, Hachymycin, Hamicin, Lucensomycin, Meparticin, Natamycin, Nystatm, Pecillin, Perimycin; and others, such as Azaserin, Griseofulvin, Oligomycins, Pyrrolnitrine, Siccanin, Tubercidin and Viridine. d. Antirungal (synthetic) Allylamines such as Naftifine and Terbinafine; Imidazoles such as Bifonazole, Butoconazsl, Chlordantoin, Clormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Finticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole, Oxiconazole Nitrate, Sulconazole and Tioconazole; Triazoles such as Fluconazole, Itraconazole, Terconazole; Others such as Acrisorcina, Amorolfina, Bifenamine, Bromosalicyliccloranilide, Buclosamide, Clofenesin, Cyclopirox, Cloxyquin, Coparafinate, Diamtazole, Dichlorohydrate, Exalamide, Flucytosine, Haletazole, Hexetidine, Loflucarban, Nifuratel, Potassium iodide, Propionic acid, Pyrithione, Salicylanilide, Sulbentin, Tenonitrozole, Tolciclate, Tolindate, Tolnaftate, Tricetin, Ujotion, and Undeclenic Acid. e. Antiglaucoma Agents Antiglaucoma agents, such as Dapiprazoke, Dichlorphenamide, Dipivefrin and Pilocarpine. f. Anti-inflammatory agents other Corticosteroids, Aminocarylcarboxylic Acid Derivatives such as Etofenamate, Meclofenamic Acid, Mefenamic Acid, Nifluminic Acid; Derivatives Arylactic Acids such as Acemetacin, Amfenac, Cinmetacin, Clopyraco, Diclofenacb, Fenclofenac, Fenchloraco, Fencofocic Acid, Fentiazaco, Glucametacin, Isozepaco, Lonazolaco, Metiazinic Acid, Oxametacin, Proglumetacin, Sulindaco, Tiaramide and Tolmetin; Derivatives Arylbutyric Acids such as Butibufen and Fenbufen; Arylcarboxylic acids such as Clidanaco, Ketorolac and Tinoridine; Derivatives Arylpropionic Acids such as Bucilloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Ibuprofen, Ibuproxama, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, Protizinic Acid. and Tiaptofénico Acid; Pyrazoles such as Mepirizol; Pyrazolones such as Clofezone, Feprazone, Mofebutazone, Oxifenbutazone, Phenylbutazone, Phenyl-pyrazolidininones, Suxibuzone and Thiazolinobutazone; ~~ Salicylic acid derivatives such as Bromosaligenin, Fendosal, Glycol Salicylate, Mesalamine, -1-Naphthyl Salicylate, Olsalazine and Sulfasalazine; Thiazinecarboxamides such as Droxicam, Isoxicam and Piroxicam; Others such as Acetamidocaproic Acid, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric acid, Amixetrine, Bendazaco, Bucoloma, Carbazonas, Difenpyramide, Ditazole, Guaiazulene, Aminoalkyl Heterocyclic Esters of Mycophenolic Acid and Derivatives, Nabumetone, Nimesulide, Orgotein, Oxaceprol, Derivatives Oxazoles, Paraniline, Pifoxime, 2-substituted-4,6-di-tertiary-butyl-s-hydroxy-l, 3-pyrimidines, Proquazone and Tenidap. g. Antiseptics Guanidines such as Alexidine, Ambazone, Chlorhexidine and Picloxidine; Halogen / Halogen Compounds such as Chloride Bornilo, Calcium Iodium, Iodine, Monochloride Iodine, Iodine Trichloride, Yodoform, Povidone-Iodine, Sodium hypochlorite, Sodium iodate, Simclosin, Thymol iodide, Triclocarban, Triclosan and Potassium Troclosin; Nitrofurans such as Furazolidone, 2- (Methoxymethyl) -5-Nitrofuran, Nidroxizone, Nifuroxime, Nifurzide and Nitrofurazone; Phenols such as Acetomeroctol, Chloroxylenol, Hexachlorophene, 1-Naphthyl Salicylate, 2,4,6-Tribromo-m-cresol and 3 ', 4', 5-Trichlorosalicylanilide; Quinolines such as Aminoquinuride, Cloroxin, Chlorquinaldol, Cloxiquine, Ethylhydrocuprein, Halquinol, Hydrastine, 8-Hydroxyquinoline and Sulfate; and others, such as Boric Acid, Chlorozodine, m-Cresyl Acetate, Cupric Sulfate and Ichtammol. h. Purine Antivirals / Pyrimidinones, such as 2-Acetyl-Pyridine 5 ((2-pyridylamino) thiocarbonyl) thiocarbonohydrazone, Acyclovir, Dideoxyzinosine, Dideoxycytidine, Dideoxyinosine, -Edoxudin, Floxuridine, Ganciclovir, Idoxuridine, MADU, Pyridinone, Trifluridine, Vidrarbine and Zidovudline; Others such as Acetylleucine Monoethanolamine, Acridinamine, Alkylisoxazoles, Amantadine, Amidinomycin, Thiosemicarbzone Cuminaldehyde, Sodium Foscarnet, Ketoxal, Lysozyme, Methisazone, Moroxidine, Podofillotoxin, Ribavirin, Rimantadine, Stallimycin, Statolon, Thymosins, Tromantadine and Xenazoic Acid. Combinations and equipment The compounds and compositions containing the compounds can also be covered with bandages, mixed with bioadhesives or included in preparations. ~ Thus, combinations of bandages, bioadhesives, preparations and other materials and compositions formulated as described herein are provided. Equipment containing these combinations is also provided which may also include compositions containing the agents listed in the foregoing. Manufacturing articles The compounds and compositions provided herein may be emplaketed as articles of manufacture containing packaging material., one or more of the compounds provided herein, which is effective in improving peripheral hyperalgesia within the material. of packaging, and a label indicating that the compound, N-oxide, acid, salt or other derivative thereof is used to treat hyperalgesic conditions. Methods of treatment The compositions for use with human skin can be preferably applied at least once a day, or if necessary, achieve the desired result, more often, to the areas of the skin for which the treatment is sought. . It is understood that the precise treatment regimen depends on the individual treated and can be determined depending empirically on the formulation, and particularly, the age of the individual treated. Any regimen is acceptable as long as the desired anti-hyperalgesic effects are achieved without deadly or undesirable side effects. Methods for treating human skin are practiced by applying to the skin, preferably at least daily, a composition suitable for the treatment of human skin or treatment of mucus membranes and other body tissues, including the vagina, rectum, mouth, eyes and other tissues. The compositions can be injected into joints or other inflamed areas. The compositions may be combined with bandages, bioadhesives and other preparations and applied to the body in combination therewith. The following examples are included only for "illustrative purposes and are not intended to limit the scope of the invention." Example A - Capsules Active compound 2.5 gm Corn starch 23.0 gm Lactose 145.0 gm Talc 15.0 gm Magnesium stearate 3.0 gm The ingredients are mixed and encapsulated using techniques known in the art. Example B - Tablet Active Compound 150 gm Lactose 125 gm Corn starch 50 grn Magnesium stearate 2.0 gm Liquid petrolatum 2.0 gm The ingredients were mixed, then placed in American standard sieves to produce fine granules. The granules were compressed into the tablets, each tablet containing about 150 mg of an active compound of the present invention. Example C - Syrup C Coommppuueessttoo aaccttiivvoo 25 gm Lemon oil 2 ml Sucrose 650 gm Citric acid 4 gm Benzoic acid 3 gm T Trraaqgaaccaannttoo 16 gm Deionized water qs 1000 ml The ingredients without the active compound are dispersed in water to form approximately 800 to 900 ml of solution. The active compound is then added and the solution It is stirred in a syrup. The water is then added to form 1000 ml of syrup. Example D - Parenteral Solution Active compound 30 gm Methylparaben 3 gm Propylparaben 1 gm Lidocaine 5 gm Deionized water q.s. 1000 ml The ingredients were dissolved in water to provide a solution followed by sterilization by filtration. Example E - Rectal Suppository Active compound 80 gm Propylene glycol 95 gm Polyethylene glycol 4000 1800 gm The active compound is added to the propylene glycol and ground until a finely divided uniform mixture is formed. Polyethylene glycol 4000 is melted and the propylene glycol dispersion is added with stirring to obtain a suspension. The suspension is poured into molds allowing it to solidify and removed from the packaging molds. Example F - Ointment washable with water _ Active compound 1.4% w / w Lanolin alcohol 0.1% w / w Emulsifying Wax NF 7.5% w / w Glycerides PEG-20 5.0% w / w Petrolatum 86.0% w / w The ingredients are melted together and mixed until the resulting ointment coagulates. Example G - Oil in water cream _ _ Active compound 10.0% w / w Benzyl alcohol 4.0% w / w Propylene glycol 10.0% w / w Polyethylene glycol-400 10.0% w / w Petrolatum 20.0% w / w Stearyl alcohol 10.0% p / p Poloxamer 10.0% p / p Water qs 100 Regulator for pH 7.0% p / p In the preparation of the oil cream in water, water, glycol and propylene glycol 400 are heated to approximately 70 to 80 ° C, followed by the addition of a mixture of petrolatum, alcohol of stearyl and poloxamer and the mixture is stirred until homogeneous. The pH is then adjusted with a regulator to about 7.0. Example H - Aqueous Gel Active compound 10.0% w / w Benzyl alcohol 4.0% w / w Hydroxyethyl cellulose 3.0% w / w Water q.s. 100 Regulator for pH 7.0% w / w The aqueous gel is prepared by mixing the active compound, benzylalcohol and adding the mixture to water regulated by PH. The hydroxyethyl cellulose is then added with stirring to the gel mixture. Having described the invention with reference to its embodiments, it is understood that modifications within the scope of the invention will be apparent to those skilled in the art.

Claims (8)

CLAIMS 1. A method for the prevention or treatment of pruritus in a patient comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. where n = l 3, Rir AND R2 are independently = CH3; - (CH2) m, wherein m = 4-8, -CH2CH (OH) (CH2) 2; CH2CH (F) (CH2) 2; (CH2) 20 (CH2) 2! or (CH2) 2CH = CHCH2-; Ar = unsubstituted or mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of halogen, OCH3, S02CH3, CF3, amino, alkyl, and 3,4-dichlor; benzothiophenyl; benzofuranyl; naphthyl; diphenylmethyl; or 9-fluorene; Z is P (0) (OBn) 2; -P (0) (0H) 2; - (CH2) PC (0) NHOH; - (CH2) PC02H; S02CH3; S02NH2; -CO (CH2) pCH (NH2) (C02H); -COCH (NH2) (CH2) pC02H; C02CH3; CONH2; - (CH2) P0 (CH2) pC02H; - (CH2) P0 (CH2) pCONHOH; (CH2) pNHS02CH3; (CH2) PNHC (S) NHCH (C02H) (CH2) pC02H; (CH2) pS03H; or or Z is where p = 0-20; R3 = -Ho -Ac; X2 = -CO2H; -NHSO, CH3; NHP (O) (OBn) 2; NHP (O) (OH) 2; -QP (O) (OBn) -; or OP (O) (OH) 2; X and Y are independently -CH2NHSO2CH3, -CH2fsSHP (O) (OBn) 2, -CH2NHP (O) (OH) 2, -CH2OP (0) (OBn) 2, -CH2OP (O) (OH) 2, - ( CH2) qO (CH2) qCO2H, - (CH2) qO (CH2) qSO3H, - (CH2) qO (CH2) qCHNHOH, -CH2NHC (S) NHCH (C? 2H) (CH2) qCO2H or where r = 1-20 R4 = -Ho -Ac X3 = -CO2H; -NHSO2CH3; -NHP (O) (OBn) 2; -NHP (O) (OH) 2; -OP (O) (OBn) 2; or -OP (O) (OH) 2 2 8 in a pharmaceutically acceptable carrier. 2. The method according to claim 1, characterized in that the compound is selected from the group consisting of: acid. { 4- [1- (3, 4-Dichlorophenyl) acetyl-2R- (1-pyrrolidinyl) -methyl] piperazinyl-acetic acid; [1 (3,4-Dichloropheneyl) acetyl-4-methanesulfonyl-2R- (1-pyrrolidinyl) methyl] piperazine; [4-S-aspartic acid-a-amido-1- (3, -dichlorophenyl) -acetyl-2R- (1-pyrrolidinyl) methyl] piperazine; methyl- [2R (0-2-acetic acid) hydroxymethyl-4- (3,4-dichlorophenyl) acetyl-3R- (1-pyrroiidinyl) methyl] -1-piperazinecarboxylate; methyl- [2R- (O-S-aspartic acid-acetyl) hydroxymethyl-4- (3,4-dichlorophenyl) -acetyl-3R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate; Methyl- [4- (3, 4-dichlorophenyl) acetyl-2R- (N-methanesulfonamido) -aminomethyl-3R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate; Methyl-. { 4- [3,4-dichlorophenyl] acetyl-3R- [1-pyrrolidinyl] methyl-2R- [N- (succinic acid-2S-thioureido)] aminomethyl} -l-piperazine carboxylate; Methyl- [2S- (0-2 -acetic acid) hydroxymethyl-4- (3,4-dichlorophenyl) acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperaxazinecarboxylate; Methyl- [2 S- (O-S-aspartic acid-acetyl) hydroxymethyl-4- (3, -dichlorophenyl) acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate; Methyl-. { 4- (3,4-dichlorophenyl) acetyl-2S- (N-methanesulfonamido) aminomethyl-5R-Jipyrrolidinyl) methyl] -1-piperazinecarboxylate; Methyl-. { 4- [3,4-dichlorophenyl] acetyl-5R- [1-pyrrolidinyl] methyl-2S- [N- (succinic acid-2S-thioureido)] aminomethyl} -1-piperazinecarboxylate; Methyl- [2R- (0-2-acetic acid) hydroxymethyl-4- (3,4-dichloro-phenyl) -acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylato; Methyl- [2R- (O-S-aspartic acid α-acetyl) hydroxymethyl-4- (3,4-dichlorophenyl) acetyl-5R- (1-pyrrolidinyl) methyl] -1-piperazinecarboxylate; Methyl- [4- (3, 4-dichlorophenyl) acetyl-2R- (N-methanesulfonamido) aminomethyl-1-5R- (l-pyrrolidinyl) methyl] -1-piperazinecarboxylate; and Methyl-. { 4- [3, -Dichlorophenyl] acetyl-5R- [l-pyrrolidinyl] methyl-2R- [N- (succinic acid-2S-thioureido)] -aminomethyl} 1-piperazinecarboxylate. 3. The method of compliance with the claim

1, characterized in that the compound is selected from the group consisting of: (R) -4- (phenylmethyl) -1 - [(3, -dichlorophenyl) acetyl] -2 - [(1-l-pyrrolidinyl) methyl] piperazine hydrochloride; ~ (R) -1 - [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine hydrochloride; (R) -4-Methanesulfonyl-1- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine hydrochloride; (R) 4-t-Butyl-acetyl-l- [(3,4-dichlorophenyl) acetyl] -2- [(l-pyrrolidinyl) methyl] -piperazine hydrochloride; (R) -4- [(3,4-Dichlorophenyl) acetyl] -3- [(1-pyrrolidinyl) methyl] -piperazine hydrochloride; (R) -4-N-t-Boc-D-aspartic acid-β-benzyl- [(3,4-dichlorophenyl) acetyl] -2- [(l-pyrrolidinyl) rae-tyl] -piperazine hydrochloride; (R) 4 Aspartic acid hydrochloride-1- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine; (R) -4-Acetyl-l- [(3,4-dichlorophenethyl) acetyl] -2- [(l-pyrrolidinyl) methyl] -piperazine hydrochloride; - (R) -4- (diethoxyphosphonate) -1 - [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine hydrochloride; (R) -4-Trifluoroacetyl-1- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine hydrochloride; (R) -4 - [(3,4-Dichlorophenyl) acetyl] -3- [(1-pyrrolidinyl) methyl] -1-piperazinecarboxamide hydrochloride; (R) -4- [(3,4-Dichlorophenyl) acetyl] -3- [(1-pyrrolidinyl) methyl] -1-piperazinecarboxaldehyde hydrochloride; (R) -4 - [(3,4-Dichlorophenyl) acetyl] -3- [(1-pyrrolidinyl) methyl] -1-piperazine sulfonamide hydrochloride; (R) -4- (4-Methylphenylsulfonyl) -1 - [(3,4-dichlorophenyl) acetyl] -2- [(l-pyrrolidinyl) methyl] -piperazine hydrochloride; (R, 5) -4-methanesulfonyl-1- [(3,4-dichlorophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine hydrochloride; (R, S) -4-Methanesulfonyl-1- [(4-methyl-sulfonylphenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] piperazine hydrochloride; (R, S) -4-methanesulfonyl-1- [(2-nitro-phenyl) acetyl] -2 - [(1-pyrrolidinyl) -methyl] piperazine hydrochloride; (R, S) -4-methanesulfonyl-1- [(4-trifluoromethylphenyl) acetyl] -2- [(l-pyrrolidinyl) methyl] piperazine hydrochloride; (R, S) -4-methanesulfonyl-1- [(3-indolyl-acetyl) -2- [(l-pyrrolidinyl) methyl] piperazine hydrochloride; (R, S) -methyl hydrochloride 4- [(-methylsulfonyl-phenyl)] acetyl] -3- [(1-pyrrolidinyl) -methyl] -1-piperazinecar- "-boxylate; (R, S) -Methyl hydrochloride [4- (4-trifluoromethyl-phenyl) -acetyl] -3- [(1)] -pyrrolidinyl) -methyl] -1-piperazinecarboxylate; (R, S) -Methyl 4- [(3-indolyl) acetyl] -3- [(l-pyrrolidinyl) -methyl] -1-piperazinecarboxylate hydrochloride; (R, S) -Methyl 4- [(2-nitrophenyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] -1-piperazinecarboxylate hydrochloride; (R, S) -Methyl 4- [(2-methoxyphenyl) - "" acetyl] -3- [(1-pyrrolidinyl) methyl] -1-piperazinecarboxylate hydrochloride; (R, S) -Methyl 4- [(2-aminophenyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] -1-piperazinecarboxylate hydrochloride; (R, S) -4-Acetyl-l- [(4-methylsulfonyl-1"phenyl) acetyl] -3- [(1-pyrrolidinyl) -methyl] -piperazine hydrochloride; Hydrochloride of (R, S) -4 Acetyl-1- (4-trifluoromethyl-phenyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] -piperazinecarboxylate; (R, S) -4-acetyl-1 - [(2-trifluoromethyl-phenyl) hydrochloride] Acetyl] -3- [(l-pyrrolidinyl) methyl] piperazincarboyl; (R, S) -4-acetyl-l- [(3-nitrophenyl) -acetyl] -3 - [(l-pyrrolidinyl)] - hydrochloride methyl] -piperazinecarboxylate; (R, S) -4-Acetyl-l- [(2-nitrophenyl) -acetyl] -3- [(1-pyrrolidinyl) -methyl] piperazinecarboxylate hydrochloride; (R, S) -4-Acetyl-l- [(4-nitrophenyl) -acetyl] -3 - [(1-pyrrolidinyl) -methyl] piperazinecarboxylate hydrochloride; and (R, S) -4- (Phenylmethyl) -1 - [(4,5-dichloro-2-nitrophenyl) acetyl] -2- [(1-pyrrolidinyl) methyl] -piperazine dihydrochloride. 4. A method for the prevention or treatment of pruritus in a patient comprising administering to the patient an effective amount of a composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof. where: n = 1-3; R ± and R2 are independently = CH3; - (CH2) where m = 4-8, -CH2CH (OH) (CH2) 2-, -CH2CH (F) (CH2 (CH2) 20 (CH2) 2-, or - (CH2) 2CH = CHCH2-; Ar = unsubstituted or mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of halogen, OCH3, S02CH, CF3, amino, alkyl, and 3,4-dichlor; benzothiophenyl; benzofuranyl; naphthyl; diphenylmethyl; or 9-fluorene; X-i and X5 are independently -OP (O) (OBn) 2; -OP (0) (0H); -C02H; -S03H; -S03H; -0 (CH2) nC02H; -NHS02CH3; -CONH (CH2) sC02H; or -S02NH (CH2) sCO, H; where s = 1-5 or X4 and X5 are independently where t - 1-20 R5 = -H or -Ac Q = -CO2H; -NHSO2CH3; -f HP (0) (OBn) 2; -NHP (0) (OH) 2; -OP (O) (OBn) 2; or -OP (0) (OH) 2. 44 in a pharmaceutically acceptable carrier. 5. The method according to claim 4, characterized in that the compound is selected from the group consisting of: (±) -2- (3,4-dichlorophenyl) -N-methyl-N- 1- [1, 2 , 3,4-tetrahydro-5- (0-2-acetic acid) -hydroxy-2- (l-pyrrolidinyl) -naphthyl] acetamide; (±) -2- (3, 4- "dichlorophenyl) -N-methyl -N-1- [1,2,3,4-tetrahydro-7- (0-2-acetic acid) -hydroxy-2- (l-pyrrolidinyl) -naphthyl] acetamide; (±) -2- (3,4-dichlorophenyl) -N-methyl-N- 1- [1,2,3,4-tetrahydro-7- (N-methanesulfonamido) -amino-2-. { l-pyrrolidinyl) -naphthyl] acetamide; (±) -2- (3,4-dichlorophenyl) -N-methyl-N- 1- [1,2,3,4-tetrahydro-5- (N-methanesulfonamido) -amino-2- (l-pyrrolidinyl) -naphthyl] acetamide; (±) -2- (3,4-dichlorophenyl) -N-methyl-N-1- [1, 2, 3, 4-tetrahydro-5- (N-2-acetic acid) -carboxamido-2- (l pyrrolidinyl) naphthyl] acetamide; (±) -2- (3,4-dichlorophenyl) N-methyl-Nl- [l, 2,3,4-tetrahydro-5- (N-2-acetic acid) -sulfonamido-2- (l-pyrrolidinyl) naphthyl] acetamide; (±) -2- (3,4-dichlorophenyl) N-methyl-Nl- [1,2,3,4-tetrahydro-7- (N-2-acetic acid) -carboxamido-2- (1-pyrroli- -dinil) naphthyl] acetamide; Y (±) -2- (3,4-dichlorophenyl) N-methyl-N-1- [1,2,3,4-tetrahydro-7- (N-2-acetic acid) -sulfonamido-2- (l- pyrrolidinyl) naphthyl] acetamide. 6. The method according to claim 4, characterized in that the compound is selected from the group consisting of: Acid 2-. { 7- [(±) -trans-1- (N -3,4-dichlorophenylaceta-mido-N-methylamino) -2- (1-pyrrolidinyl) -1,2,3,4-tetrahydrase-toxy]} acetic; 2, 2-Diphenyl-N-methyl-N- [(±) -trans-2- (l-pyrrolidinyl) -7-methoxy-l, 2,3,4-tetrahydronaphth-l-yl] acetamide; 2, 2-Diphenyl-N-methyl-N- [(±) -trans-2- (l-pyrrolidinyl) -7-hydroxy-l, 2,3,4-tetrahydronaphth-l-yl] acetamide; 2- (2-Nitro-4, 5-dichlorophenyl) -N-methyl-N- [(±) -trans-2- (l-pyrrolidinyl) -7-nitro-l, 2,3,4-tetrahydronaph-l -yl] acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N- [(+) - trans-2- (1-pyrrolidinyl) -7-nitro-l, 2,3,4-tetrahydronaphth-l-yl] acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N- [(+) - trans-2- (1-pyrrolidinyl) -7-amino-1, 2,3,4-tetrahydronaphth-l-yl] acetamide; 2- (4-Methylsulfonylphenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7-nitro-l, 2,3,4-tetrahydronaphth-l-yl] acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [±] -trans-2- [1-pyrrolidinyl] -7- [N, N-bis- (t-butoxycarbonylmethyl) -amino] -1,2,3,4-tetrahydronaphth-1-yl} acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [±] -trans-2- [1-pyrrolidinyl] -7- [N, N-bis- (carboxymethyl) amino] -1,2,3,4-tetrahydronaphth-1-yl} acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [±] -trans-2- [1-pyrrolidinyl] -7- [N, -bis- (ethoxycarbonylmethyl) -amino] -1,2,3,4-tetrahydronaphth-1-yl} acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -7- (N-diethylphosphoramidate-amino) -1,2,3,4-tetrahydronaft -l-il] acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [±] -trans-2- [1-pyrrolidinyl] -7- [-N-2- (diethylphosphoxyl) ethylamino] -1,2,3,4-tetrahydronaphth-1-yl} acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -6-methoxy-7- (N-benzyl-N-methylaminosulfonyl) -1,2 , 3,4-tetrahydronaphth-l-yl] acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N- [(+) - trans-2- (1-pyrrolidinyl) -7- (N-benzyl-N-methylaminosulfonyl) -1, 2, 3, 4 -tetrahydronaphth-l-yl] acetamide; 2- (2-Nitro-4, 5-dichlorophenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -indan-1-yl] acetamide; 2- (2-Nitro-4-trifluoromethylphenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -indan-1-yl] acetamide; 2, 2-Diphenyl-N-methyl-N- [(±) -trans-2- (l-pyrrolidinyl) -indan-1-? L] acetamide; Y 24 2- (4-Methylsulfonylphenyl) -N-methyl-N- [(±) -trans-2- (1-pyrrolidinyl) -indan-1-yl] acetamide. A method for the prevention or treatment of pruritus in a patient comprising administering to the patient an effective amount of a composition comprising a compound of formula III or a pharmaceutically acceptable salt thereof wherein n = 1-3; Ri and R2 are independently = CH3; - (CH2) m, wherein m = 4-8, -CH2CH (OH) (CH2) 2-; -CH2CH (F) (CH2) 2-; - (CH7) 20 (CH2) 2-; or - (CH2) 2CH = CHCH2-; Ar = unsubstituted or mono- or di-substituted phenyl wherein the substituent is selected from the group "consisting of .. halogen, 0CH3, S02CH3, CF3, amine, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl;; diphenylmethyl; or 9-fluorene; X7 is -NHS02CH3; -NHP (0) (OBn) 2; -NHP (O) (0H) 2; - (CH2) uNHS02CH3; (CH2) UNHC (S) NHCH (C02H) (CH2) uC02H; -CONHOH; or (CH2) uCONHOH; where u = 1-5; or X7 is Re = Xg = in a pharmaceutically acceptable carrier. The method according to claim 7, characterized in that the compound is selected from the group consisting of: 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1- [3- (N-2-acetic acid) carboxamide] phenyl-2- (l-pyrrolidinyl) ethyl} acetamide; 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1- [3- (N-methansulfo-namido) aminomethyl] -phenyl-2- (l-pyrrolidinyl) ethyl} acetamide; 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1- [3- (N-succinic acid-2S-thioureido) aminomethyl] phenyl-2- (l-pyrrolidinyl) -ethyl-acetamide; and 2- (3,4-dichlorophenyl) -N-methyl-N-. { 1- [3- (N-2-acetic acid) sulfonamido] pheny1-2- (l-pyrrolidinyl) ethyl} acetamide. 9. The method according to claim 7, characterized in that the compound is selected from the group_ consisting of: 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [S] -1- [N- (S-aspartic acid-cc-amide-S-aspartic acid-a-amido) -3-aminophenyl] -2- [l-pyrrolidinyl] ethyl} acetamide; 2- (3,4-Dichlorophenyl) -N-methyl-N-. { [1 S] -l- [N- (bis-methylsulfonamido) -3-aminophenyl] -2- [1-pyrrolidinyl] -ethyl) acetamide; 2- (2-Nitrophenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (2-Aminophenyl) -N-methyl-N- [(SS) -1- (3-aminophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Diethylphosphoramidate-2-aminophenyl) -N-methyl-N- [(1S) -1- (N-diethylphosphoramidato-3-aminophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Bis-sulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -1- (N-bis-sulfonamido-3-aminophenyl) -2- (l-pyrrolidinyl) -ethyl] acetamide; 2- (2-Nitro-4, 5-dichlorophenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (4-Methylsulfonylphenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Butyloxycarbonyl-4-aminophenyl) -N-methyl-N- [(1S) -1- (3-nitrophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (4-Aminophenyl) -N-methyl-N- [(1-S) -1- (3-nitrophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Bis-sulfonamido) -4-aminophenyl) -N-methyl-N- [(SS) -1- (3-nitrophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Bis-sulfonamido-4-aminophenyl) - N-methyl-N- [(SS) -1- (3-aminophenyl) -2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Bis-sulfonamido--aminophenyl) -N-methyl-N- [ (ÍS) -1- (N-Diethylphosphoramidate-3-aminophenyl) -2- (l-pyrrolidinyl) -ethyl] acetamide, 2- (2-Nitrophenyl) -N-methyl-N- { [ÍS] -1 phenyl-2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl.} acetamide; 2- (2-Nitro-4,5-dichlorophenyl) -N-methyl-N- { [ÍS] -1-phenyl-2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl.}. Acetamide; 2- (4-Methylsulfonylphenyl) -N-methyl-N- { [1 S] -l-phenyl -2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl} acetamide; 2- (2-Nitro-4-trifluoromethylphenyl) -N-methyl-N- { [IS] -l-phenyl -2- [1- (3S) - (3-hydroxypyrrolidinyl)] ethyl} acetamide; 2- (2-Amino-4-trifluoromethylphenyl) - N-methyl-N-. { [SS] -l-phenyl-2- [l- (3S) - (3-hydroxypyrrolidinyl)] ethyl} acetamide; 2, 2-Diphenyl-N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; N ', N' -Diphenyl-N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] urea; 2- (2-Nitrophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (2-Nitro-4, 5-dichlorophenyl) -N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (4-Methylsulfonylphenyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (2-Methoxyphenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (3-Indolyl) -N-methyl-N- [(SS) -I-phenyl-2- (1-pyrroli-dinyl) ethyl] acetamide; 2- (a,, a-Trifluoro-p-tolyl) -N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (2-Nitro-a, a, a-Trifluoro-4-tolyl) -N-methyl-N- [(ls; -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (1 - [4-Chlorobenzoyl) -5-methoxy-2-methylindol) -N- [(SS ") -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (4-Nitrophenyl) -N-methyl -N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (3-Nitrophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1 -pyrrolidinyl) ethyl] acetamide; 2- (2-pyridyl) -N-methyl-N- [(SS) -lf nyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (3-pyridyl) -N- methyl-N- [(SS) -1-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- ((+) - 6-Methoxy-a-methyl-2-naptalen) -N- [(1S) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (a, a, a-Trifluoro-3-tolyl) -N-methyl-N- [(SS) -1- -phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; - 2- (4-Pyridyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (a, a, a-Trifluoro-2-tolyl) -N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- ((S) - (+) -4-Isobutyl-a-methylphenyl) -N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (3,, 5-trimethoxyphenyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (2-Aminophenyl) -N-methyl-N- [(1S) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (2-N, N-Dimethylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N-Methylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (2-amino-4,5-dichlorophenyl) -N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N, N-Dimethylsulfonamido-2-amino-, 5-dichlorophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) -ethyl] acetamide; 2- (2-Amino, a, a, a-Trifluoro-4-tolyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide;

2- (2-N, N-Dimethylsulfonamido-2-amino-a, a, α-trifluo-rs-4-tolyl) -N-methyl-N- [(SS) -l-phenyl-2- (l- pyrrolidinyl) ethyl] -acetamide; 2- (N-Methylsulfonamido-2-amino-a, a, α-trifluoro-4-tolyl) -N-methyl-N- [(1S) -l-phenyl-2- (l-pyrrolidinyl) ethyl] -acetamide; 2- (2-Aminophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (4-Aminophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (1-pyrrolidinyl) ethyl] acetamide; 2- (N, N-Dimethylsulfonamido-2-aminophenyl) -N-methyl-N- [(1S) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (N, N-Dimethylsulfonamido-2-aminophenyl) -N-methyl-N- [(SS) -l-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; 2- (2-Hydroxyphenyl) -N-methyl-N-methyl-N- [(SS) -1-phenyl-2- (l-pyrrolidinyl) ethyl] acetamide; and N-Methyl-N- [(1S) -l-phenyl-2- ((3S) -

3-hydroxypyrr-lyrin-1-yl) ethyl] -3,4,5-trimethoxyphenylacetamide. A method for the prevention or treatment of prufitus in a patient comprising administering to the patient an effective amount of a composition comprising a compound of formula IV or a pharmaceutically acceptable salt thereof where n = l 3, Ri / and R2 are independently = CH3; - (CH2) m, where

4-8, -CH2CH (OH) (CH2) 2 -; - CH2CH (F) (CH2) 2 ~; - (CH2) 20 (CH2) _ -; or - (CH2) 2CH = CHCH2-; R3 and R4 are independently H; OCH3; the alkyl; "or c-0 (CH2) 2; Xg = 1-4 substituents selected from the groups consisting of halogen, -CF3; -0CH3; -S02NH (CH2) qC02H; -CONH (CH) qC02H; NH2; -NHS02CH3; -NHP (0) (OBn) 2; -NHP (0) (OH) 2; NH (CH2) qC02H; -S02CH3; OP (O) (OBn) 2; -OP (0) (OH) 2; -C02H; -O (CH2) qC02H; -O (CH2) qS03H, -O (CH2) qOP03H2; wherein q = 1-20; in "where t = -1-20; - R

5- = -Ho-Ac; -X

6- = -C02H; -NHS02CH3; -NHP (O) (OBn) 2; -NHP (O) (0H) 2; OP (O) (OBn) 2; or -OP (O) (OH) 2 in a pharmaceutically acceptable carrier 11. The method according to claim 10", characterized in that the compound is selected from the group consisting of: (-) - (5a, 7a, 8ß) -N-methyl-N- [

7- (l-pyrrolidinyl) -1-oxaspiro- [4, 5] dec-8 il] -3- (N-methane-sulonamido) aminophenyl acetamide; (-) - (5a, 7a, 8β) -N-methyl-N- [7- (l-pyrrolidinyl) -1-oxaspiro- [4, 5] dec-

8-yl] -3- (N-2- acetic acid) sulfonamidophenyl acetamide; Y (-) - (5a, 7a, 8β) -N-methyl-N- [7- (l-pyrrolidinyl) -1-oxaspiro- [4,5] dec-8-yl] -3- (N-2- acetic acid) carboxamidophenyl acetamide; The method according to claim 10, characterized in that the compound is selected from the group consisting of: (+) - Trans-2-Nitro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] hydrochloride] phenylacetamide; (±) -Trans-2-amino-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] phenylacetamide hydrochloride; (±) -trans-2-Nitro-4,5-dichloro-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenelacetamide hydrochloride; (±) -Trans-2-Amino-4,5-dichloro-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -el-phenylacetarnide hydrochloride; (±) -trans-2-methanesulfonamido-N-methyl hydrochloride -N- [2- (l-pyrrolidinyl) cycloexil] -phenylacetamide; N- [2- (+) - Trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -phenylacetamido] glycine hydrochloride; (±) -trans-4-Trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamide hydrochloride; (±) -trans-2-nitro-4-tnfluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamide hydrochloride; (±) Trans-2-amino-4-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamide hydrochloride; (±) -trans-2-bismetanesulfonamido-4-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamide hydrochloride; (+) - Trans-2-methanesulfonamido-4-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -fe-ylacetamide hydrochloride; N- [2- (±) -trans-4-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamido] glycine hydrochloride; (±) Trans-3-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamide hydrochloride; (±) -trans-5-nitro-3-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] phenylacetamide hydrochloride; (±) -trans-2-nitro-3-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] phenylacetamide hydrochloride; (±) -Trans-2-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] -phenylacetamide hydrochloride; (±) -trans-l-Nitro-2-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] phenylacetamide hydrochloride; (±) -trans-4-amino-2-trifluoromethyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] phenylacetamide hydrochloride; (±) -trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] -2,2-diphenylacetamide hydrochloride; and (±) -trans-4-methylsultonyl-N-methyl-N- [2- (l-pyrrolidinyl) cyclohexyl] phenylacetamide hydrochloride.