MXPA06000089A

MXPA06000089A - Tricyclic delta opioid modulators

Info

Publication number: MXPA06000089A
Application number: MXPA/A/2006/000089A
Authority: MX
Inventors: Ellen Codd; John R Carson; Christine M Razler; Andrea Works
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2003-06-27
Filing date: 2006-01-05
Publication date: 2006-12-13

Abstract

The invention is directed to delta opioid receptor modulators. More specifically, the invention relates to tricyclic ?-opioid modulators. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using compounds of the invention are also described.

Description

TRICICLIC DELTA-OPIOID MODULATORS INTERREFERENCE WITH RELATED REQUESTS This application claims the priority of U.S. Provisional Patent Application No. 60 / 483,389, filed June 27, 2003, which is incorporated herein by reference in its entirety.

DECLARATION ON RESEARCH OR DEVELOPMENT WITH FEDERAL SPONSORSHIP The research and development of the invention described below was not federally sponsored.

BACKGROUND OF THE INVENTION The term "opioid" refers generically to all natural and synthetic drugs that have actions similar to morphine. Formerly, the term "opiate" was used to designate drugs derived from opium, for example, morphine, codeine and many semisynthetic congeners of morphine. After the isolation of peptide compounds with actions similar to morphine, the term opioid was introduced to refer generically to all drugs with actions similar to morphine.

Among the opioids included are several peptides that exhibit activity similar to morphine, such as endorphins, enkephalins and dynorphins. However, some sources have continued to use the term "opiate" in a generic sense and, in such a context, opiate and opioid are interchangeable. Additionally, the term opioid has been used to refer to antagonists of drugs similar to morphine, and also to characterize receptors or binding sites that combine with such agents. Opioids are generally used as analgesics, but they can also have many other pharmacological effects. Morphine and related opioids produce their main effects on the central nervous system and the digestive system. The effects are diverse, including analgesia, drowsiness, mood swings, respiratory depression, dizziness, obtundation, dysphoria, pruritus, increased pressure in the biliary tract, decreased gastrointestinal motility, nausea, vomiting and alterations of the endocrine systems and nervous self A significant characteristic of the analgesia produced by opioids is that it occurs without loss of consciousness. When therapeutic doses of morphine are administered to patients with pain, they report that the pain is less intense, less bothersome or disappears completely. In addition to experiencing pain relief, some patients experience euphoria. However, when morphine is administered at a selected pain-relieving dose to an individual without pain, the experience is not always pleasurable; Nausea is common and vomiting may also occur. It may happen drowsiness, inability to concentrate, difficulty remembering, apathy, decreased physical activity, decreased visual acuity and lethargy. Two different classes of opioid molecules can be bound to opioid receptors: opioid peptides (for example enkephalins, dynorphins and endorphins) and alkaloid opiates (for example morphine, etorphine, diprenorphine and naloxone). After the initial exposure of opiate binding sites (Pert, CB and Snyder, SH, Science (1973) 179: 1011-1014), the differential pharmacological and physiological effects of both the opioid peptide analogues and the alkaloid opiates , they served to delineate the multiple opioid receptors. Therefore, t types of opioid, anatomically and pharmacologically distinct receptors have been described: delta, kappa and mu. In addition, each type is believed to have subtypes (Wollemann, M., J Neurochem (1990) 54: 1095-1101; Lord, J. A., et al., Nature (1977) 267: 495-499). It seems that these t types of opioid receptors share the same functional mechanisms in the cell. For example, opioid receptors inhibit adenylate cyclase and inhibit neurotransmitter release by activation of the potassium channel and inhibition of Ca2 + channels (Evans, CJ, in: "Biological Basis of Substance Abuse", SG Korenman and JD Barchas, eds., Oxford University Press (in press), North, AR, et al., Proc Nati Acad Sci USA (1990) 87: 7025-29; Gross, RA, et al., Proc Nati Acad Sci USA (1990) 87: 7025 -29; Sharma, SK, et al., Proc Nati Acad Sci USA (1975) 72: 3092-96). Although the functional mechanisms are the same, the manifestations of receptor-selective drugs on behavior differ greatly (Gilbert, P. E. and Martin, W.R., J Pharmacol Exp Ther (1976) 198: 66-82). Such differences can be attributed in part to the anatomical location of the different receptors. The delta receptors have a more discrete distribution within the mammalian CNS than the mu or kappa receptors, with high concentrations in the amygdaloid complex, striatum, substantia nigra, olfactory bulb, olfactory tubercles, hippocampal formation and the cerebral cortex (Mansour, A. and others, Trends in Neurosci (1988) 11: 308-14). Notably, the rat cerebellum is devoid of opioid receptors, including delta opioid receptors. D. Delorme, E. Roberts and Z. Wei, International Patent WO / 28275 (1998), describe methylidene piperidines which are opioid analgesics, but do not describe or suggest the compounds of the present invention. L. Hermann, C. Ullmer, E. Bellott and others, patent of E.U.A. No. 0166672 (2003), international patent WO / 035646 (2003), and EP 1321169 (2003), describe 4- (thio- or selenoxanthene-9-ylidene) -piperidines or acridines which are 5-HT2B receptor agonists, but they do not describe the compounds of the present invention. C. Kaiser et al., J. Med. Chem. 1974, volume 17, p. 57-61 describe some piperidylidene derivatives of thioxanthenes, xanthenes, dibenoxepines and acridans, which are neuroleptic agents. Nevertheless, these authors neither describe nor suggest the structure or activity of the compounds of the present invention. The British patent GB 1128734 (1966) describes derivatives of 6,11-dihydrodibenzo [b, e] oxepine which are anticonvulsant agents, muscle relaxants, sedatives, diuretics, or with activity on the circulatory system. However, these agents differ significantly from the compounds of the present invention, both structurally and pharmacologically. There is a continuing need for new delta-opioid receptor modulators as analgesics. In addition, there is a need for selective delta-opioid receptor agonists as analgesics, which have reduced side effects. There is also a need for delta-opioid receptor antagonists such as immunosuppressants, anti-inflammatories, agents for the treatment of neurological and psychiatric conditions, agents for the abuse of drugs and alcohol, agents for the treatment of gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases, which have reduced side effects.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to compositions comprising a compound of formula (I): Formula (I) wherein: R-i and R2 are substituents independently selected from the group consisting of hydrogen and alkanyl of d-s; R3 is selected from the group consisting of hydrogen, Cis alkanyl, Cis-halo-3-alkanyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkanyl, C? -8 cycloalkanyl-alkanyl, alkanoyloxy (C? 8) -alkanyl of C? -8, alkanylthio (C? .8) -alkanyl of C? -8, hydroxyalkanyl of C? -8, alkanoyloxy (C? -8) -carbonyl, halo-3-alkanil ( C -8) carbonyl, formyl, thioformyl, carbamimidoyl, phenylimino-alkanyl of Ci-β, phenyl-alkanyl of C 1-8, phenyl-alkenyl of C? -8, phenyl-alkynyl of C? .8, naphthyl-alkanyl of Ci-β and heteroaryl-alkanyl of Ci-s; wherein the phenyl, naphthyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C-? 6 alkanyl, C2-6 alkenyl. C 1-6 alkyloxy, amino, (C? -6) -amino, di (C? -6) alkanoyl-amino, (C? -6) -carbonyl, C 1-6 -carbonyloxy, alkanyl C? -6) -carbonylannino, C?, -6 alkanthio, C? -6-alkylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl, thioureido and fluoroalkannoxy; alternatively, when the phenyl and the heteroaryl are optionally substituted with two substituents bonded to adjacent carbon atoms, the two substituents can together form a single fused portion; wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -0 (CH2)? -3-O; R4 is one to three substituents independently selected from the group consisting of: hydrogen, Ci-β alkanyl, C -6 alkeniium, C?-6 alkanoyloxy, amino, (C ?6) alkanyl-amino, di (alkanyl) (C? 6)) - amino, (C? -6) -carbonyl, (C- | 6) alkanoylcarbonyloxy, (C 1-6) alkoxycarbonyl, (C? -6) -aminocarbonyl alkanyl, d-Ci-e ^ -aminocarbonyl, (C? 6) -carbonylamino, C-uis-alkanyl-C, -6-alkylsulfonyl, halogen, hydroxy, cyano, hydroxycarbonyl, C-1-aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiophenyl, fluoroalkanyl and fluoroalkannyloxy; or optionally, when R4 are two substituents attached to adjacent carbon atoms, the two substituents can together form a single fused portion, wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -0 ( CH2)? - 3-0-; Rs is one or two substituents independently selected from the group consisting of: hydrogen, C1-6 alkanyl, C2-6 alkenyl, C6-6 alkanoyloxy, amino, alkane (C6-6) -amino, di- ((C6-6) alkanyl) amino, (C1-6) alkanoylcarbonyl, (C6-6) alkanoylcarbonyloxy, (C6-6) alkanoyloxycarbonyl, (C6-6) alkanoylcarbonyl, aCanil (C1-6) -carbonylammon, alkanthio of C -? - 6, C 1-6 alkylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl and fluoroalkanyloxy; A is - (CH2) m-. where m is 0, 2 or 3; preferably, m is 2 or 3; preferably, m is 2; Y is - (CH2) nX- or -X (CH2) n-; X is O, or S n is 0 or 1; Z is O, or S; and enantiomers, diastereomers, tautomers, solvates or pharmaceutically acceptable salts thereof. Finally, the present invention is directed to pharmaceutical and veterinary compositions containing compounds of formula (I), wherein the compositions are used to treat mild to severe pain in warm-blooded animals.

DETAILED DESCRIPTION OF THE INVENTION As used here, the following underlined terms have the following meanings: "Ca-í?" (where a and b are integers) refer to a radical containing a to b carbon atoms, inclusive. For example, C1-3 denotes a radical containing 1, 2 or 3 carbon atoms. "Alkyl" refers to a monovalent hydrocarbon radical branched, straight or cyclic, saturated or unsaturated, derived from the removal of a hydrogen atom from a single carbon atom of an original alkane, alkene or alkyne. Typical alkyl groups include, without limitation, methyl; ethyl esters such as ethanyl, ethenyl, ethynyl; propyl such as propan-1-yl, propan-2-yl, cyrope-1-yl (), prop-1-en-1-yl, prop-1-en-2-yl, prop-2-enyl 1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc .; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl , but-1-en-2-y !, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta- 1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien- 1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc .; and similar. When considering specific degrees of saturation the nomenclature "alkanyl", "alkenyl" or "alkynyl" is used, as defined below. In preferred embodiments, the alkyl groups are CrC6 alkyl > with C1-C3 being particularly preferred. "Alkanyl" refers to a saturated, branched, straight or cyclic monovalent hydrocarbon radical derived by removal of a hydrogen atom from a single carbon atom of an original alkane. Typical alkanyl groups include, without limitation, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc .; butanyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, etc., and the like. In preferred embodiments, the alkanyl groups are C-i-s alkanyl, with d-3 being particularly preferred. "Alkenyl" refers to a monovalent hydrocarbon radical unsaturated, branched, straight or cyclic, having at least one carbon-carbon double bond, derived by removal of one hydrogen atom from a single carbon atom of an original alkene. The radical can be in the cis or trans conformation on the double bond. Typical alkenyl groups include, without limitation, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1 -ii; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2 -in-2-yl, buta-1, 3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, ciciobut-1-en-3-yl , cyclobuta-1, 3-dien-1-iio, etc .; and similar. "Alkynyl" refers to an unsaturated, branched, straight or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond, derived by removal of one hydrogen atom from a single carbon atom of an original alkyne. Typical alkynyl groups include, without limitation, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1 -N, etc .; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc .; and similar. "Heteroalkyl" and "heteroalkanyl" refer to alkyl or alkanyl radicals, respectively, in which one or more carbon atoms (and any associated hydrogen atom that is necessary) are independently replaced with one or more identical or different heteroatoms (including any hydrogen atom or other necessary atom). Typical heteroatoms for replacing carbon atoms include, without limitation, N, P, O, S, Si, etc. The preferred heteroatoms are O, N and S. this way, the heteroalkanyl radicals may contain one or more same or different heteroatomic groups including, by way of example and not limitation, the epoxy (-O-), epidioxy (-OO-), thioether (-S-) groups , epidithium (-SS-), epoxythium (-0-S-), epoxyimino (-O-NR1-), imino (-NR'-), biimino (-NR'-NR'-), azino (= NN = ), azo (-N = N-), azoxy (-NON-), azimino (-NR'-N = N-), phosphine (-PH-),? 4-sulfan (-SH2-), sulfonyl (- S (O) 2-), and the like, wherein each R 'is independently hydrogen or Ci-Cß alkyl. "Original aromatic ring system" refers to an unsaturated, cyclic or polycyclic ring system, which has a p-conjugated electron system. The definition of "original aromatic ring system" specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, cranberry, indene, phenalene, etc. . Typical original aromatic ring systems include, without limitation, aceanthylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronenne, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octazene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, piceno, pleiadene, pyrene, pyrantrene, rubiceno, triphenylene, trinaphthalene, and the like. "Aryl" refers to a monovalent aromatic hydrocarbon radical, derived by removal of a hydrogen atom from a single carbon atom of an original aromatic ring system. Typical aryl groups include, without limitation, the aceanthylene-derived radicals, acenaphthylene, acephenanthylene, anthracene, azulene, benzene, chrysene, coronenne, fluoranthene, fluorene, hexacene, hexafen, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octazene, octaphene, octalene, ovalene, penta-2, 4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picenum, pleiadene, pyrene, pyrantrene, rubicenne, triphenylene, trinaphthalene, and the like. In preferred embodiments, the aryl group is C5-20 aryl, with C5-? 0 being particularly preferred. Particularly preferred aryl groups are phenyl and naphthyl. "Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms attached to a carbon atom, usually a terminal carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, without limitation, benzyl, 2-phenylethan-1-yl, 2-phenyleth-1-yl, naphthylmethyl, 2-naphthyletan-1-yl, 2-naphthyleten-1-yl, naphthobenzyl, 2-naphthofeniletan -1-ilo and the like. When the specific alkyl portions are considered, the arylalkanyl, arylalkenyl or arylalkynyl nomenclature is used. In preferred embodiments, the arylalkyl group is C6-26 arylalkyl; for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is C -6 and the aryl portion is C5.2o- In particularly preferred embodiments, the arylalkyl group is C6-13; for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is C1-3 and the aryl portion is C5-? 0. The most preferred arylalkyl groups are phenylalkanyl. "Alkanyloxy" refers to a saturated, branched, straight or cyclic monovalent hydrocarbon alcohol radical, derived by removal of the hydrogen atom of oxygen hydroxide of alcohol. Typical alkanoyloxy groups include, without limitation, methanoyloxy; ethanyloxy; propanyloxy groups such as pro-an-1-yloxy (CH 3 CH 2 CH 2 O-), propan-2-yloxy ((CH 3) 2 CHO-), cyclopropan-1-yloxy, etc .; butanyloxy groups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc .; and similar. In preferred embodiments, the alkanoyloxy groups are C -8 alkanoyloxy groups, with C-? - 3 being particularly preferred. "Original heteroaromatic ring system" refers to an original aromatic ring system in which a carbon atom is replaced with a heteroatom. Heteroatoms to replace the carbon atoms include N, O, and S. The definition of "original heteroaromatic ring system" specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, arsindol, chroman, chromene, indole, indoline, xanthene, etc. The original heteroaromatic ring systems include, without limitation, carbazole, imidazole, indazole, indole, indoline, indolizine, isoindol, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine. , pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. "Heteroaryl" refers to a monovalent heteroaromatic radical derived by removal of a hydrogen atom from a single atom of an original heteroaromatic ring system. Typical heteroaryl groups include, without limitation, the radicals derived from carbazole, imidazole, indazole, indole, indoline, indolizine, isoindol, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine , pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In preferred embodiments, the heteroaryl group is a heteroaryl of 5-20 members, with 5-10 membered heteroaryl being particularly preferred. "Cycloheteroalkyl" refers to a saturated or unsaturated, monocyclic or bicyclic alkyl radical, in which a carbon atom is replaced with N, O, or S. In some specific embodiments, the cycloheteroalkyl may contain up to four heteroatoms independently selected from N , O, or S. the typical cicioheteroalquilo portions include, without limitation, radicals derived imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferred embodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl. "Cycloheteroalkanyl" refers to a saturated, monocyclic or bicyclic alkanyl radical, in which a carbon atom is replaced with N, O, or S. In some specific embodiments, the cycloheteroalkanyl may contain up to four heteroatoms independently selected from N, 0, or S. Typical cycloheteroalkanyl portions include, without limitation, radicals derived imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like. In preferred embodiments, the Cycloheteroalkanyl is a cycloheteroalkanyl of 3-6 members. "Cycloheteroalkenyl" refers to a saturated, monocyclic or bicyclic alkenyl radical, in which a carbon atom is replaced with N, O, or S. In some specific embodiments, the cycloheteroalkenyl may contain up to four heteroatoms independently selected from N, O , or S. Typical cycloheteroalkenyl moieties include, without limitation, the radicals derived from imidazoline, pyrazoline, pyrroline, ndoline, pyran, and the like. In preferred embodiments, the cycloheteroalkanyl is a 3-6 membered cycloheteroalkanyl. "Substituted" refers to a radical in which one or more hydrogen atoms are independently replaced with one or more identical or different substituents. Typical substituents include, without limitation, -X, -R, -O ", = O, -OR, -O-OR, -SR, -S-, = S, -NRR, = NR, -CX3, -CN , -OCN, -SCN, -NCO, -NCS, -NO, -NO2, = N2, -N3, -NHOH, -S (O) 2O ", -S (0) 2OH, -S (O) 2R, -P (0) (0") 2, -P (O) (OH) 2, -C (0) R, -C (0) X, -C (S) R, -C (S) X, - C (0) OR, -C (0) O ", -C (S) OR, -C (0) SR, -C (S) SR, -C (O) NRR, -C (S) NRR and - C (NR) NRR, wherein each X is independently a halogen (preferably -F, -Cl or -Br) and each R is independently -H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene, alkylidino, aryl, arylalkyl, arylheteroalkyl , heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein. Preferred substituents include hydroxy, halogen, Ci-β alkyl, C -8 alkanoyloxy, fluorinated alkanoyloxy, fluorinated alkyl, Ci-β alkylthio, C 3-8 cycloalkyl, C 3-8 cycloalkanyloxy, nitro, amino, alkylamino Cia, dialkylamino from Ci- a, C3..8 cycloalkylamino, cyano, carboxy, alkanyloxy (C - ?. 7) alkoxycarbonyl, (C -? -) alkylcarbonyloxy, formyl, carbamoyl, phenyl, aroyl, carbamoyl, amidino, alkylamino (C? -8) -carbonyl, (arylamino) carbonyl and aryl-alkyl (C? 8) -carbonyl. With respect to substituents, the term "independently" means that when more than one of these substituents is possible, the substituents may be the same or different from each other. Throughout this diption, the terminal portion of the designated side chain is first dibed, followed by functionality adjacent to the point of attachment. Thus, for example, a substituent "phenyl-alkanyl (C6-6) -aminocarbonyl-C1-6alkyl" refers to a group of formula: alcanilíd.6 One embodiment of the present invention is directed to a compound of formula (I) wherein the structure is numbered as defined herein: Formula (I) The present invention is directed to analgesic and antipyretic uses of compositions comprising a compound of formula (I): Formula (I) wherein: Ri and R2 are substituents independently selected from the group consisting of hydrogen and alkanyl of C-i-s; R3 is selected from the group consisting of hydrogen, C1.8 alkanyl, C1-8 halo-3-alkanyl, C2.8 alkenyl, C2-8 alkynyl, C3-8 cycloalkanyl, cycloalkanyl-alkanyl C1-8, (C? -8) alkanoyloxy-C8? -alkanyl, (C? -8) alkanyl-Cis alkane, C-? -8 hydroxyalkanyl, (C- | 8) alkanoyloxy -carbonyl, 3H-alkenyl (C ?.8) carbonyl, formyl, thioformyl, carbamimidoyl, phenylimino-alkanyl of C?, 8, phenyl-alkanyl of C?-8, phenyl-alkenyl of C?-8, phenyl-alkynyl of Ci-s, naphthyl-alkanyl of C? .β and heteroaryl-alkanyl of Ci-β; wherein phenyl, naphthyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C6-6 alkanyl, C2-6 alkenyl, C- | 6 alkanoyloxy, amino, alkanyl (C? -6> -amino, di (alkanyl (C? -6)) -amino, alkanol (C? -6) -carbonyl, alkanyl (C? -6) -carbonylloxy, alkanyl (C? -6) ) -carbonylamino, C-? - 6 alkanthio, Ci-β, alkylsulfonyl, halogen, 8 hydroxy, cyano, fluoroalkanyl, thioureido and fluoroalkannoxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion; wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -O (CH2)? -3-O-; R4 is one to three substituents independently selected from the group consisting of: hydrogen, C6-6 alkanyl, C2-6 alkenyl, Ci-β alkanoyloxy, amino, (C6-6) -amino, di ( alkenyl (C? .. 6)) - amino, alkanyl (C? -6) -carbonyl, (C-? 6) -carbonyloxy, (C? -6) -aminocarbonyl, (C6) alkanoyl-aminocarbonyl, (C? -6) -carbonylamino, C?, .6 alkanoyl, C6-C6 alkylsulfonyl, halogen, hydroxy, cyano, hydroxycarbonyl, C6-? o aryl, chromanyl, chromenyl, furanyl, midazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl , pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiophenyl, fluoroalkanyl and fluoroalkanyloxy; or optionally, when R4 are two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -0 (CH2 ) 1-3-0-; Rs is one or two substituents independently selected from the group consisting of: hydrogen, C? -6 alkanyl, C2-6 alkenyl, C-? -6 alkanoyloxy, amino, (C? -6) -amino, (alkanil (C? _ 6)) amino, (C1-6) alkanoylcarbonyl, (C6-6) alkanoylcarbonyloxy, (C6-6) alkoxycarbonyl, (C1-6) alkanoylcarbonyl, (C6-6) alkanyl -carbonylamino, C3-6 alkanoylthio, C6-6 alkylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl and fluoroalkanyloxy; A is - (CH2) m-. where m is 0, 2 or 3; Y is - (CH2) nX- or -X (CH2) n-; X is O, or S n is 0 or 1; Z is O, or S; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof. For the embodiments of the present invention, preferably: a) Ri and R2 are substituents independently selected from the group consisting of hydrogen and C2 alkanyl; b) R1 and R2 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl and propyl; c) R1 and R2 are substituents independently selected from the group consisting of hydrogen and ethyl; d) R3 is selected from the group consisting of hydrogen, Cis alkanyl, C2-8 alkenyl, C2-8 alkynyl, (C1.8) alkynyloxy-Cis alkynyl, (C? -8) alkanyl-C1-alkynyl -8, hydroxyalkanyl of C ^ s, thiomorhyl, phenylimino-alkanyl of C -? - 8, phenyl-alkanyl of C 1-8 and heteroaryl-alkanyl of Cis; wherein the phenyl and the heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C-α-6 alkanoyloxy and hydroxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion; wherein the portion is selected from -0 (CH2)? -3-O-; e) R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methy1-allyl, propynyl, hydroxyethyl, methylthioethyl, methoxyethyl, thiomorhyl, phenyliminomethyl, phenethyl and heteroaryl-C1-alkanyl; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group; f) R3 is hydrogen, methyl, allyl, or heteroaryl methyl; g) R4 is one to three substituents independently selected from the group consisting of hydrogen, C? -6 alkanyl, C-alkanoyloxy, (C? 6) -aminocarbonyl alkanyl, (C? -6) -carbonylamino, halogen, hydroxy, C6-aryl, crymanyl, chromanyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazoinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl and thiophenyl; h) R is one to two substituents independently selected from the group consisting of hydrogen, C 4 alkanyl, C- alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolinium, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy; i) R4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy; j) R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen; k) R5 is hydrogen; l) A is - (CH2) 0-2-; m) A is - (CH2) 2-; n) X is O, or S; o) n is 0; p) Z is 0; and q) combinations of a) to p) above. One embodiment of the present invention is a compound of formula (I) wherein: R- \ is alkanoyl of C? _3; R 2 is C 4 alkanyl hydrogen; R3 is selected from the group consisting of hydrogen, C -? - 8 alkanyl, C2 - s alkenyl, C2 - 8 alkynyl, C -? 8 alkanoyloxy - C 1-8 alkane, C - alkylthio (C? -8) -C1-8 alkanyl) C1-8 hydroxyalkanyl, thiomorhyl, phenyl-alkanyl of C? -8, phenyl-alkanyl of Cis and heteroaryl-alkanyl of C? .8; wherein the phenyl and the heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C-i-β alkanoyloxy and hydroxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the portion is selected from -O (CH2)? 3-0-; R4 is one to three substituents independently selected from the group consisting of hydrogen, C-? 6 alkanyl, C1-6 alkanoyloxy, (C1-6) alkanyl-aminocarbonyl, (C6-6) -carbonylamino, halogen, hydroxy, C 6-10 aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl and thiophenyl; R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen; A does not exist or is CH2CH2; Y is O, S, CH2O, or OCH2; Z is O; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. Another embodiment of the present invention is a compound of formula (I) wherein: R-i is C- | 3 alkanyl; R2 is C3-C3 hydrogen alkanyl; R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-amino, propynyl, hydroxyethyl, methoxyethyl, methylthioethyl, thioformyl, phenyliminomethyl, phenethyl and heteroaryl-alkanyl of C? -8; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group; R4 is one to two substituents independently selected from the group consisting of hydrogen, C? -4 alkanyl, C1.4 alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy; R5 is hydrogen; A does not exist or is CH2CH2; Y is O, S, CH2O, or OCH2; Z is O; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. Another embodiment of the present invention is directed to compositions comprising a compound of formula (I) wherein R 1 is ethyl; R2 is ethyl or hydrogen; R3 is a substituent selected from the group consisting of benzo [1,3] dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl- methyl, hydroxyethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-yl-methyl, thiophen-2-yl-methyl; R4 is one to two substituents independently selected from the group consisting of hydrogen, C? -4 alkanyl, C? -4 alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl , oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy; A does not exist or is CH2CH2; And it is O, or S; and Z is O. Another embodiment of the present invention is a compound of formula (I) wherein: Ri is C3-C3 alkanyl; R 2 is C 1 .3 alkanyl or hydrogen; R3 is selected from the group consisting of hydrogen, C1-8 alkanyl, C2-s alkenyl, C2-8 alkynyl, C7-8 alkanoyloxy-C1-8 alkenyl, alkanoylthio (C? -8) - C? -8 alkanyl, Ci-s hydroxyalkanyl, thioformyl, C? -8-phenylimino-alkanyl, C-? -8 phenyl-alkanyl, and Cia heteroaryl-alkanyl, wherein phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C6-6 alkanoyloxy and hydroxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion; wherein the portion is selected from -0 (CH2) -? _ 3-O-; R4 is one to three substituents independently selected from the group consisting of hydrogen, C-? 6 alkanyl, alkanoyloxy alkanylCi-eJ-aminocarbonyl, (C -6) -carbonylamino, halogen, hydroxy, Cß-io-aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl , pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinium, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl and thiophenyl; R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen; A is CH2CH2; Y is O, S, CH2O, or OCH2; Z is O; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. Another embodiment of the present invention is a compound of formula (I) wherein: R-i is C- | 3 alkanyl; R2 is C3_3 alkanyl or hydrogen; R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methoxyethyl, methylthioethyl, thioformyl, phenyliminomethyl, phenethyl and heteroaryl-alkanyl of Ci-s; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group; R4 is one to two selected substituents 6 independently of the group consisting of hydrogen, C 1-4 alkanoy, C 4 -4 alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl , pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy; R5 is hydrogen; A is CH2CH2; And it is O, S, CH20, or OCH2; Z is O; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. Another embodiment of the present invention is directed to compositions comprising a compound of formula (I) wherein R-j is ethyl; R2 is ethyl or hydrogen; R3 is a substituent selected from the group consisting of benzo [1,3] dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl- methyl, hydroxyethyl, methoxyethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-yl-methyl, thiophen-2-yl-methyl; R4 is one to two substituents independently selected from the group consisting of hydrogen, C-? 4 alkanyl, C1.4 alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl , oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy; A is CH2CH2; And it is O, or S; and Z is O. Another embodiment of the present invention is directed to compositions comprising a compound of formula (I) wherein Ri is ethyl; R2 is ethyl; R3 is a substituent selected from the group consisting of benzo [1,3] dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl-methyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl, furan-3-yl-methyl, H, Me, methylthioethyl and phenethyl; R4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromine, fluorine, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy; A is CH2CH2; And it is O, or S; and Z is O. Another embodiment of the present invention is directed to compositions comprising a compound of formula (I) wherein Ri is ethyl; R2 is ethyl; R3 is a substituent selected from the group consisting of H, benzo [1, 3] dioxol-5-ylmethyl, 1-H-imidazol-4-yl-methyl, furan-3-ylmethyl, pyridin-2-ylmethyl, and phenyliminomethyl; R 4 is a substituent independently selected from the group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy; A is CH2CH2; And it is O, or S; and Z is O. Another embodiment of the present invention is directed to a compound of formula (I) wherein the R4 substituent is preferably in the 5 or 6 position of the formula (I). Another embodiment of the present invention is directed to compositions comprising a compound selected from the group it consists of: a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is benzo [1,3] dioxol-5-ylmethyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is OR; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is phenethyl, R is H, R 5 is H, A does not exist, Y is CH 2 O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is allyl, R 4 is H, R 5 is H, A does not exist, Y is CH 2 O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is methyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is allyl, R is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is methyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is 1,1,1-trichloroethoxycarbonyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is H, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 2-methyl-but-2-enyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein 1 is ethyl, R 2 is H, R 3 is thiophen-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; . a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 2-methyl-allyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (!) wherein R1 is ethyl, R2 is H, R3 is cyclopropylmethyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is pyridin-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 2 O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 1-H-imidazol-4-yl-methyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is OR; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 4-hydroxy-3-methoxyphenyl-methyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is allyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is phenethyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is phenethyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, 2 is ethyl, R3 is methyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is furan-3-yl-methyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R2 is H, R3 is phenethyl, R4 is H, R5 is H, A is CH2CH2, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is phenethyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is furan-3-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is pyridin-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is 2-hydroxyphenyl-methyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is carbamimidoyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is 1-prop-2-ynyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 ethylcarbonylamino, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 or, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 ethyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R ^ is ethyl, R2 is ethyl, R3 H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is methylcarbonylamino, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 methyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-t, is ethyl, R 2 is ethyl, R 3, R is H, R 5 is H, A is CH 2 CH 2) Y is O, and Z is O; a compound of formula (1) wherein Ri is ethyl, R 2 is ethyl, R 3 is 1-H-imidazol-4-yl-methyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is OR; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is benzo [1,3] dioxol-5-ylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is OR; a compound of formula (I) wherein R ^ is ethyl, R2 is ethyl, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is cyclopropylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methylthiopropyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is hydroxyethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein RT is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is methyl, R 2 is methyl, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is isopropyl, R 2 is H, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is methyl, R 2 is sobutyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is n-propyl, R 2 is n-propyl, R 3 is H, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is / 7-propy, R2 is H, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is H, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is H, R2 is H, R3 is H, R4 is H, R5 is H, A is CH2CH2) Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-methyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (!) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-methoxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-fluoromer, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is 1 - / - / - midazole-5-ylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R2 is n- butyl, R3 is H, R is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is 1- / - imidazol-4-ylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-hydroxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is trifluoromethylcarbonyl, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is H, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-hydroxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-bromo, R is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-phenyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-pyridin-4-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-j is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-furan-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-benzothiophen-2-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7- (N-α-butoxycarbonyl) pyrrol-2-yl, R 5 is H, A is CH 2 CH 2, Y is O , and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R is 7-pyridin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-t is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-thiophen-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 7- (3,5-dimethyl) isoxazol-4-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (i) wherein R1 is methyl, R2 is isopropyl, R3 is H, R is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 7-pyrrol-2-yl, R5 is H, A is CH2CH2) Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-bromo, R 5 is H, A is CH 2 CH, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-phenyl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-pyridin-4-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-furan-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R is 5-quinolin-3-yl, R5 is H, A is CH2CH, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-thiophen-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-hydroxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-pyridin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; and a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-fluoro, R5 is H, A is CH2CH2, Y is O, and Z is O. Another embodiment of the present invention invention is directed to compositions comprising a compound selected from the group consisting of: a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is H, R4 is H, R5 is H, A does not exist, and is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 2-methyl-but-2-enyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is thiophen-2-yl-methyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 2-methyl-allyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (!) wherein R-i is ethyl, R2 is H, R3 is pyridin-2-yl-methyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 1-H-imidazol-4-yl-methyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is allyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is H, R 3 is phenethyl, R 4 is H, R 5 is H, A is CH 2 CH, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is H, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is 1-H-imidazol-5-yl-methyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is OR; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-hydroxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is 1-H-imidazol-4-ylmethyl, R is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (!) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-methoxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-pyridin-4-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-furan-3-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 6-hydroxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein Ri is methyl, R 2 is isopropyl, R 3 is H, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-bromine, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1. is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is n-propyl, R 2 is n-propyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 7-fluoro, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-pyridin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is methyl, R 2 is isobutyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is n-butyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-quinolin-3-yl, R 5 is H, A is CH CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R4 is 5-thiophen-3-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; and a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R4 is 5-phenyl, R5 is H, A is CH2CH2, Y is O, and Z is O.

Another embodiment of the present invention is a composition that it comprises the dextrorotatory enantiomer of a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; wherein said composition is substantially free of the levorotatory isomer of said compound. In the present context, substantially free means less than 25%, preferably less than 10%, preferably less than 5%, preferably less than 2%, and most preferably less than 1%, of the levorotatory isomer, calculated as: (levorotatory mass)% levorotatory = x 100 (dextrorotatory mass) + (levorotatory mass) Another embodiment of the present invention is a composition comprising the levorotatory enantiomer of a compound of formula (I) in where R1 is ethyl, R2 is ethyl, R3 is H, R4 is H, R is H, A is CH2CH2, Y is O, and Z is O; wherein said composition is substantially free of dextrorotatory isomer of said compound. In the present context, substantially free means less than 25%, preferably less than 10%, preferably less than 5%, preferably less than 2%, and very less than 1% preference, of the dextrorotatory isomer, calculated as: (dextrorotatory mass)% dextrorotatory = x 100 (dextrorotatory mass) + (levorotatory mass) The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm Sci., 1997 (January) , 66, 1, 1). However, other salts well known to those skilled in the art may be useful in the preparation of the compounds according to this invention or their pharmaceutically acceptable salts. Organic or inorganic acids representative include, without limitation, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Representative organic or inorganic bases include, without limitation, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

The present invention includes prodrugs within its scope of the compounds of this invention. In general, said prodrugs will be functional derivatives of the compounds, which are easily convertible in I live in the required compound. Thus, in the methods of treatment of the present invention, the term "administer" encompasses the treatment of the various disorders indicated with the specifically described compound, or with a compound that may not be specifically described but that is converted in vivo in the specified compound after its administration to the patient. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The compounds according to this invention having at least one chiral center can consequently exist as enantiomers. Additionally, compounds that possess two or more chiral centers can exist as diastereomers. It is understood that such isomers and their mixtures are included within the scope of the present invention. In addition, some of the crystalline forms of the compounds can exist as polymorphs and as such are considered included in the present invention. In addition, some of the compounds may form solvates in water (i.e., hydrates) or common organic solvents, and such solvates are also considered to be included within the scope of this invention. When the methods of preparing the compounds according to the invention produce a mixture of stereoisomers, these isomers can be separated by conventional techniques, such as preparative chromatography. The compounds can be prepared in racemic form, or individual enantiomers can be prepared by stereospecific synthesis or by resolution. For example, the compounds can be resolved into their component enantiomers by standard techniques, such as formation of diastereomeric pairs by salt formation with an optically active acid, such as (-) - di-p-toluoyl-d-tartaric acid or (+) - di-p-toluoyl-l-tartaric, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column. During any of the methods of preparing the compounds of the present invention it may be necessary or desirable to protect the sensitive or reactive groups in any of the molecules involved. This can be done by means of conventional protecting groups, such as those described in: "Protective Groups in Organic Chemistry", ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. Protective groups can be removed in a convenient subsequent step using known methods. Although the compounds of the present invention (including their pharmaceutically acceptable salts and solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, appropriately selected for the route of administration. intended administration and according to normal pharmaceutical or veterinary practice. Thus, the present invention is directed to pharmaceutical and veterinary compositions comprising the compounds of formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents. By way of example, in the pharmaceutical and veterinary compositions of the present invention, the compounds of the present invention can be mixed with any binder, lubricant, suspension agent, coating agent or suitable solubilizing agent. Tablets or capsules of the compounds can be administered one to one or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations. Alternatively, the compounds of general formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or powder. An alternative means of transdermal administration is the use of a skin patch. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They may also be incorporated, at a concentration between 1% and 10% by weight, into an ointment consisting of a white wax base or white soft paraffin, together with stabilizers and preservatives as required. For some applications it is preferable to administer the compositions orally in the form of tablets containing excipients such as starch or lactose.; or in capsules or ovules, alone or in mixture with excipients; or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. The compositions (and also the compounds alone) can be injected parenterally, for example intracavernously, intravenously, intramuscularly or subcutaneously. In this case, the compositions will comprise a suitable vehicle or diluent. For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example salts or monosaccharides, to make the solution isotonic with the blood. For buccal or sublingual administration, the compositions can be administered in the form of tablets or lozenges that can be formulated in the conventional manner. By way of further example, pharmaceutical and veterinary compositions containing one or more of the compounds of the invention described herein as active ingredient, can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to the conventional techniques of pharmaceutical composition. The vehicle can take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral). In this way, for liquid oral preparations such as suspensions, elixirs and solutions, suitable vehicles and additives include water, glycols, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations can also be coated with substances such as sugars, or with enteric coatings, in order to modulate the greater site of absorption. For parenteral administration, the vehicle will usually consist of sterile water, and other ingredients may be added to increase solubility or preservation. Suspensions or injectable solutions can also be prepared using aqueous vehicles together with the appropriate additives. Conveniently, the compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times a day. In addition, the compounds of the present invention can be administered in intranasal form by the topical use of suitable intranasal vehicles, or by means of transdermal patches well known to those skilled in the art. Of course, for administration in the form of a transdermal delivery system, the dosage will be continuous instead of intermittent throughout the dosing regimen. It is also evident to the person skilled in the art that the therapeutically effective dose of the active compounds of the invention, or a pharmaceutical composition thereof, will vary according to the desired effect. Therefore, doses can easily be determined by administer, and vary with the particular compound used, the mode of administration, the concentration of the preparation and the progress of the pathological condition. In addition, it will be necessary to adjust the dose to an appropriate therapeutic concentration taking into account the factors associated with the particular subject treated, including the subject's age, weight and diet, and the administration schedule. Thus, the above dosages are exemplary of the average case. Of course, there may be individual cases that merit higher or lower dosing scales and are within the scope of this invention. Whenever it is required to use the compounds of the invention as analgesics or antipyretics for a subject in need thereof, the compounds of this invention can be administered in any of the aforementioned compositions and dosage regimens, or by means of the compositions and dosage regimens established in the art. The invention also provides a pharmaceutical or veterinary package or equipment comprising one or more containers containing one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention. Optionally, there may be an instruction associated with said containers, in the form prescribed by the government agency that regulates the manufacture, use or sale of pharmaceutical or biological products; said instruction indicates the approval, by the agency, of the manufacture, use or sale for human administration.

The compounds of the present invention can be used to treat pain, mild to moderately severe, in warm-blooded animals such as humans, by administering an analgesically effective dose. The dosage scale would be from about 0.01 mg to about 15,000 mg, in particular from about 0.1 mg to about 3500 mg or, more in particular, from about 0.1 mg to about 1000 mg of active ingredient, at a rate of about 1 to 4 times a day for an average person (70 kg); however, it is evident to the person skilled in the art that the therapeutically effective amount of the active compounds of the invention will vary according to the types of pain treated. For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing 0.01, 10.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for symptomatic adjustment of the dose to the treated subject. Examples of pain types considered within the scope of the present invention include, without limitation, inflammatory pain, centrally mediated pain, peripherally mediated pain, pain related to structural or soft tissue injury, pain related to progressive disease, neuropathic pain and acute pain, such as that caused by acute injury, trauma or surgery, and chronic pain such as headache and that caused by neuropathic conditions, conditions subsequent to stroke and migraine. The compounds of the present invention are also useful as immunosuppressants, anti-inflammatories, agents for the treatment and prevention of neurological and psychiatric conditions, for example depression and Parkinson's disease, agents for the abuse of drugs and alcohol, agents for the treatment of gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases. The compounds of the present invention are also useful in the treatment of pain caused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, snake bite (particularly venomous snake bite), sting spider, insect bite, neurogenic bladder, benign prosthetic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis , polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome, postherpetic neuralgia, Trigeminal neuralgia, cluster headache, migraine headache, neur peripheral opathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, post-febrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinusitis headache, tension headache, work of labor, delivery, menstrual cramps and cancer. With respect to the use of the present compounds in the treatment of diseases or conditions such as those mentioned above, those skilled in the art can determine a therapeutically effective dose using the established animal models. Such a dose would probably be on the scale of about 0.01 mg to about 15,000 mg of active ingredient, administered 1 to 4 times a day, for an average person (70 kg).

General Methods of Synthesis Representative compounds of the present invention can be synthesized according to the general methods of synthesis described below and illustrated in the following schemes. Since the schemes are an illustration, the invention should not be considered as limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is within the domain of those skilled in the art. The preparation of the compounds of this invention is illustrated in schemes 1 and 2. Both schemes proceed with the same strategy general. In step 1, an intermediate 1 is prepared with two benzene rings linked by a linker -Y-. The linker -Y- would be of the form - (CH2) n -X-, where X can be oxygen or sulfur and n can be zero or one. A benzene ring carries a group, Q, which is a group easily convertible to a carboxylic acid amide. Examples of said Q groups are fluorine, bromine, iodine or trifluoromethanesulfonyloxy. A benzene ring must carry a carboxylic acid in ortho position with respect to the -Y- linker. The X atom can be attached to the benzene ring bearing the Q group or to the benzene ring lacking the Q group. Schemes 1 and 2 differ in that in scheme 1 the carboxylic acid is in the benzene ring that carries the group Q (1A and 1B), while in scheme 2 the carboxylic acid function is in the benzene ring that does not carry the group Q (1C, 1D and 1E).

Scheme 1 Scheme 2 Step 1 Step 2 Steps 3-d Monocyclic Intermediates In step 1, the linker -Y- is constructed between two monocyclic intermediates. For scheme 1, step 1, the bridge can be constructed by nucleophilic aromatic displacement of intermediate fluoride nt 2 (where Q 'is an electron-withdrawing group, easily convertible to a carboxylic acid, for example cyano or carbalkoxy), with a phenoxide, thiophene oxide, benzyl oxide or thiobenzioxide, int 1. Compounds 1A are then obtained by hydrolysis with an alkali metal hydroxide. For the construction of the bridge of the compounds of type 1B, an intermediate compound of benzyl halide (int 5) is prepared by means of NBS bromination of the corresponding toluene (nt 4). The reaction of int 5 with a phenoxide or thiophenoxide yields nt 6. Compound 1B can be obtained by hydrolysis of int 6 with alkali metal hydroxide.

Scheme 1, Step 1 For Scheme 2, Step 1, to prepare the compounds 1C, a phthalide (nt 7) is reacted with a phenoxide or thiophenoxide (int 8). To prepare the 1D compounds, the bridge can be constructed by nucleophilic aromatic displacement of the intermediate fluoride int 9 with phenoxides or thiophenoxides (nt 8). The compounds 1D are then obtained by hydrolysis of int 10 with an alkali metal hydroxide. For the construction of the bridge of the compounds of type 1E, the reaction of an intermediate compound of benzyl bromide (nt 12) with a phenoxide or thiophenoxide (int 11) produces the nt 13. Then the compound 1E can be obtained by hydrolysis of int 13 with an alkali metal hydroxide.

Scheme 2, Step 1 After step 1, the schemes come together. In step 2, compounds 1 are converted by cycloacylation to ketones 2, using for example, BF3, Et20-trifluoroacetic acid or polyphosphoric acid. Alternatively, the cyclization can be effected by converting the acid 1 to an acid chloride, for example with thionyl chloride, followed by Friedel-Crafts ring closure in the presence of a Lewis acid, such as aluminum chloride. In addition, steps 1 and 2 can be done in reverse to give compounds 2, which are ready to go to step 3. For example, cycloacylation between a methyl ether (int 14) and an appropriately substituted acid chloride, provides the ketone (int 16), which has been demethylated simultaneously under the Friedel-Crafts reaction conditions. The subsequent formation of the bridge -Y- by means of a nucleophilic aromatic displacement, gives the compounds 2 ready to enter step 3.

Scheme 3. Steps 1 v 2 int 14 Ipt lS intl lS In step 3, the Q function of the compounds 2 is converted to a carboxylic acid amide group to give the compounds of formula 3. This can be carried out first by conversion to an ester by alkoxycarbonylation, for example, with carbon monoxide, an aliphatic alcohol, a trialkanlamine and a palladium catalyst such as bis (triphenylphosphine) palladium dichloride (II). The ester can be hydrolyzed to form an acid and finally converted to a primary, secondary or tertiary amide, by a coupling reaction with ammonia, a primary amine, or a secondary amine. The conversion of acid to amide can be carried out first by conversion to an acid chloride, for example, using thionyl chloride, followed by a Schotten-Baumann reaction using ammonia or an amine and alkali metal hydroxide. Alternatively, the ester can be converted directly to the amide by the action of a dimethylaluminum amide. Instead of proceeding to the compounds 3 by means of an ester, the group Q can be converted into a carboxylic acid amide by means of a nitrile. The synthesis of the nitrile can be done by treatment of the compounds 2 with Zn (CN) 2 and a palladium catalyst such as (Ph3P) 4Pd, or by treatment of the compounds 2 with CuCN at elevated temperature. He Nitrile is hydrolyzed using an alkali metal hydroxide that produces the same acid derived from the ester. To perform step 4, a 4-piperidinylidene or 8-tropanilidene function is added to the tricyclic system, replacing the ketone to give the compounds of type 4 (in the case of piperidinylidene the function -A- does not exist, whereas in the case of of tropanilidene, represents - (CH2) 2-). This operation can be done by a McMurray condensation of the ketones 3 with 4-piperidinones or 8-tropinones, produced by a titanium reagent of lower valence, such as the reagent obtained from the addition of titanium tetrachloride to zinc powder. Alternatively, a 4-piperidinyl magnesium halide or 8-tropanylidene magnesium halide can be added to the ketone to produce carbinoles. Dehydration of these carbinols with acid reagents such as formic acid, sulfuric acid or trifluoroacetic acid, produces the type 4 compounds. If desired, the operation of steps 3 and 4 can be done in inverted order. As illustrated in Schemes 1 and 2, the nitrogen atoms of the compounds 4 carry a P group. This group may be an alkanyl, alkenyl or aralkanyl, in which case they are the therapeutically useful products of this invention. The group P can also be alkoxycarbonyl or aralkoxycarbonyl. These latter groups can be converted to secondary amines 5 as illustrated in step 5. These transformations can be performed using some acid reagents such as hydrogen bromide. or trimethylsilyl iodide. Compounds of type 4 carrying easily separable groups such as methyl, allyl or benzyl can be converted into the aforementioned alkoxycarbonyl derivatives by treatment with alkanylchloride formates such as ethyl chloroformate or 1-chloroethyl chloroformate, and thus, serve as sources of the compounds 5. Finally the secondary amines 5 can be converted to any desired end group of the invention 6 as shown in step 6. These transformations can be performed by reductive alkylation using a carbonyl compound and a reducing agent such as sodium borohydride. , sodium cyanoborohydride or sodium triacetoxyborohydride. They can also be carried out by alkylation, using an alkanyl, alkenyl or aralkyl halide, and an organic or inorganic base. The desired end products of the present invention may include chemical modifications in R4. Such transformations may include dealkylation of lower alkyl ethers to give the corresponding alcohols, using reagents such as boron trihalides. Compounds wherein R is a halogen atom may participate in transition metal-mediated coupling reactions, such as the Suzuki, Stille or Negishi chemistry. The compounds where the bridge -A- is - (CH2) 2- are chiral.

They can be separated into their enantiomers by chiral stationary phase chromatography after steps 4, 5, or 6. Alternatively, the basic compounds of type 4, 5 and 6 can be converted into salts diastereomers by mixing with a chiral acid, and can be resolved into their enantiomers by fractional crystallization. It is generally preferable that the respective product of each process step be separated from other components of the reaction mixture, and be subjected to purification before use as a starting material in a subsequent step. Separation techniques typically include evaporation, extraction, precipitation and filtration. Purification techniques typically include column chromatography (Still, W. C. et al., J. Org Chem. 1978, 43, 2921), thin layer chromatography, crystallization and distillation. The structures of the final products, intermediates and starting materials are confirmed by means of spectroscopic, spectrometric and analytical methods, including nuclear magnetic resonance (NMR), mass spectrometry (MS) and liquid chromatography (HPLC). In the descriptions for the preparation of the compounds of this invention, ethyl ether, tetrahydrofuran and dioxane are common examples of an ethereal solvent; benzene, toluene, hexane and cyclohexane are typical hydrocarbon solvents; and dichloromethane and dichloroethane are representative halogenated hydrocarbon solvents. In cases where the product is isolated as the acid addition salt, the free base can be obtained by techniques known to those skilled in the art. In cases where the product is isolated as an acid addition salt, the salt may contain one or more equivalents of the acid. The enantiomers of the compounds of the present invention are they can be separated using chiral HPLC. Representative compounds of the present invention can be synthesized according to the general synthesis methods described above, and are illustrated more particularly in the schemes that follow. Since the schemes are illustrations, the invention should not be considered limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is within the domain of those skilled in the art.

EXAMPLES EXAMPLE A Procedure 1 4-Bromo-2-phenoxy-benzonitrile, 1a Sodium hydride (12 g, 300 mmol) (60% by weight) was weighed into a flask and washed oil-free with several hexane rinses. The hexane was decanted and discarded and DMF was added to the flask. A solution in DMF of phenol (23.5 g, 250 mmol in 100 mL of DMF) was added dropwise to the NaH mixture and stirred at room temperature. The phenoxide was added to drops a solution of 4-bromo-2-fluoro-benzonitrile (50 g, 250 mmol in 100 mL of DMF). After the addition was complete, the reaction was refluxed 20 h. The reaction was cooled to room temperature and emptied into cold 1 N NaOH. A fine tan precipitate formed and was collected by vacuum filtration to give 62.04 g (226 mmol) of compound 1a. MS m / z (MH +) 277. Procedure 2 4-Bromo-2-phenoxy-benzoic acid, 2a 4-Bromo-2-phenoxy-benzonitrile (35.3 g, 129 mmol) was added to 130 mL of EtOH, followed by 340 mL of 20% NaOH (ac). The reaction was heated to reflux for 20 h. The mixture was cooled to room temperature and poured into 6 N HCl to form a precipitate. The solid was collected by vacuum filtration and dissolved in THF ethyl ether, 3: 1, and washed with brine. The organic phase was dried over magnesium sulfate and concentrated. The solid was dried in a vacuum oven at 60 ° C overnight to give 35.1 g (128 mmol) of the desired product. MS m / z (MH +) 292. Method 3 3-Bromo-xanten-9-one. 3a To a suspension of 4-bromo-2-phenoxy-benzoic acid (35.1 g, 120 mmol) in CH2Cl2 (350 mL), at 0 ° C, trifluoroacetic anhydride (20.3 mL, 144 mmol) was added dropwise, and the reaction was stirred for 15 min. At that time, boron trifluoride diethyl ether (1.46 mL, 12.0 mmol) was added dropwise. The reaction was made homogeneous by stirring 1 h at room temperature. After completion, the reaction was emptied in 1N NaOH and the organic phase was dried over magnesium sulfate, filtered and concentrated to give compound 3a (32.14 g, 116 mmol). MS m / z (MH +) 275. Prure 4: 9-Oxo-9-xantho-3-carboxylic acid methyl ester, 4a A sample of compound 3a (20 g, 72.2 mmol) was dissolved in a MeOH / DMF solution 2: 1 (600 mL). To this solution was added triethylamine (40 mL, 290 mmol) and the solution was degassed with argon. To this was added dichlorobis (triphenylphosphine) palladium (II) (2.0 g, 2.85 mmol); the reaction was transferred to a pump and loaded with 10.5 kg / cm2 of CO (g). The reaction was stirred at 90 ° C for 24 h. After completion, the reaction was cooled to 40 ° C and CH2Cl2 was added. The reaction was filtered still hot and evaporated, to give the crude product. Recrystallization from ethanol gave 16.62 g (65.4 mmol) of compound 4a. MS m / z (MH +) 255. Prure 5 9-Oxo-9-xanthene-3-carboxylic acid. 5a A sample of the 9-oxo-9/7-xanthene-3-carboxylic acid methyl ester, compound 4a (16.6 g, 65.3 mmol), was suspended in 250 mL of 3 N NaOH and 250 mL of EtOH, and heated reflux for 1 h. At that time EtOH was evaporated, the reaction was poured into 6 N HCl on ice, and extracted with large volumes of THF / diethyl ether, 1: 1. The combined organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to yield 13.35 g of compound 5a (55.6 mmol) after drying overnight in a vacuum oven at 50 ° C.

Prure 6 9-Oxo-9H-xanthene-3-carboxylic acid diethylamide, 6a A sample of compound 5a (13.4 g, 55.6 mmol) was suspended in 220 mL of CH2Cl2 and 24.4 mL (330 mmol) of CH2Cl2 was added. thionyl. The mixture was refluxed for 6 h, adding approximately 10 mL more thionyl chloride per hour, until the reaction became homogeneous. At that time, the thionyl chloride and the solvent were removed in vacuo and the remaining residue was diluted with an additional 220 mL of CH2Cl2. To the suspension were added 100 mL of ice-cold 1.5 N NaOH, 100 mL of CH2Cl2, and 17 mL (166 mmol) of diethylamine.

After stirring 15 min at room temperature, the phases were separated and the organic phase was washed with HCl and brine, dried over magnesium sulfate, filtered and concentrated to give compound 6a (14.7 g, 49.8 mmol).

MS m / z (MH +) 296. 9-Oxo-9H-xanthene-3-carboxylic acid ethylamide. 7a Following prure 6, substituting diethylamine with ethylamine, compound 6a was converted to its monoethylamide. MS m / z (MH +) 267.9. Prure 7 Ethyl 3- (3-diethylcarbamoyl-xanten-9-ylidene) -8-aza-bicyclo3.2.noctane-8-carboxylic acid ethyl ester. 8a A suspension of metallic zinc powder (24.2 g, 370 mmol) in THF (325 mL) was treated dropwise with titanium (IV) tetrachloride (20.3 mL, 180 mmol), under argon and at 5 ° C. The reaction was then refluxed for 2 h. The heat was removed and a solution of compound 6a (13.69, 46 mmol) and N-carbetoxinortropinone (9.21 g, 46 mmol) in 100 mL of THF was added dropwise. The reaction was refluxed for another 2 h. At that time the reaction was cooled and added to an excess of potassium carbonate in ice water. The mixture was extracted with EtOAc and the combined extract was washed with brine, dried over magnesium sulfate, filtered and evaporated, to give 22 g of a gum. This crude product was subjected to chromatography using EtOAc / hexane 1: 1, to yield 17 g (36.9 mmol) of compound 8a. MS m / z (MH +) 461.8. 9- (8-phenethyl) -8-aza-bicyclo] "3.2.noct-3-ylden ') - 9 / -7-xanthene-3-carboxylic acid ethylamide, 9a The title compound is synthesized following prure 7, substituting the compound 7a with compound 6a, and substituting the N-phenethyl-4-tropinone with carbetoxinortropinone MS m / z = 465.1 (M + 1); 300 MHz (DMSO-de) d 1.1 (t, 3H), 1.3 (m, 2H), 2.1 (m, 2H), 2.5 (q, 2H), 3.0-3.4 (m, 8H), 4.05 (m, 2H), 7.1-7.7 (m, 11H), 8.5 (m, 1H). Method 8 9- (8-aza-bicichlor3.2.1"loct-3-ylide ') - 9H-xanthene-3-carboxylic acid diethylamide 10a A sample of compound 8a (16.0 g, 34.8 mmol) was dissolved in 35 mL of acetic acid and 100 mL of HBr were added under argon to the % in acetic acid, before heating in a steam bath for 1 h. The The reaction was cooled, added to ice-cooled NaOH and extracted with CH2C12. The combined organic phase was washed with brine and dried over potassium carbonate. Evaporation of the solvent yielded 12 g of crude compound 10a, which was purified by column chromatography with 2 N NH3 in 7% methanol / 93% CH2Cl2, to give 7.66 g (19.7 mmol) of compound 10a. MS m / z = 389.3 (M + 1); 1 H NMR 300 MHz (CDCl 3) d 1.1-1.4 (m, 6 H), 1.7 (m, 2 H), 2.7-3.0 (m, 4 H), 3.4 (br s, 4 H), 3.5-3.7 (m, 4 H), 7.0-7.3 (m, 7H). 9- (8-Methyl-8-aza-biciclof3.2.1loct-3-iiidenV 9 / - / - xanthene-3-carboxylic acid diethylamide, 11a Following procedure 7 and replacing with N-carbetoxinortropinone tropinone, compound 6a was converted to the title compound: MS m / z = 403.2 (M + 1); 1 H NMR 300 MHz (CDCl 3) d 1.2 (br s, 6 H), 1.9 (m, 2 H), 2.5 (s, 3 H), 2.8 (m, 2H), 3.1 (m, 2H), 3.3 (m, 2H), 3.4 (br s, 2H), 3.6 (m, 4H), 7.0-7.3 (m, 7H) Procedure 9 Acid diethylamide 9- (8-furan-3-ylmethyl-8-aza-bicyclo3.2.1] oct-3-ylidene) -9H-xanthene-3-carboxylic acid, 12a To a sample of compound 10a (0.65 g, 1.7 mmol) dissolved in 20 mL of CH2Cl2, sodium triacetoxyborohydride (0.53 g, 2.5 mmol) and 3-furaldehyde (0.17 mL, 2.0 mmol) were added. room temperature for 24 h. The reaction was diluted with 10 mL of CH 2 Cl 2 and washed with 1 N NaOH. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography in a flash column, eluting with NH30.5 M in methanol, 5% / CH2Cl2, to give compound 12a (0.25 g, 0.53 mmol). MS m / z = 469.0 (M + 1); 1 H NMR 300 MHz (DMSO-d 6) d 1.1 (br s, 6 H), 1.35 (m, 2 H), 2.1 (m, 2 H), 2.5 (m, 2 H), 3.0 (m, 2 H), 3.2 (m, 2H), 3.5 (m, 2H), 3.85 (br s, 2H), 4.05 (d, 2H), 6.8 (s, 1 H), 7.1-7.5 (m, 7H), 7.8 (s, 1 H), 7.9 (s, 1 H). Procedure 10 9-R8- (Methylsulfanyl-ethyl) -8-aza-bicyclo3.2.p-oct-3-ylidene-9- / - xanthene-3-carboxylic acid diethylamide, 13a A solution of p-acid toluenesulfonic acid monohydrate (1.4 g, 7.5 mmol) in 20 mL of water was added to a stirring solution of (methylthio) acetaldehyde dimethylacetal (1.0 mL, 7.5 mmol) in 15 mL of CH2Cl2, and the reaction was vigorously stirred for 4 hours. h. The aqueous phase was separated and saturated with NaCl and then extracted with CH2Cl2. The organic extract was washed with saturated aqueous sodium bicarbonate and then with brine. The extract was dried over magnesium sulfate and filtered. To the filtrate was added compound 10a (0.060 g, 0.15 mmol) and sodium triacetoxyborohydride (0.040 g, 0.19 mmol); the reaction was stirred at room temperature overnight. The reaction was washed with 1 M NaOH and the organic phase was dried over magnesium sulfate. The solution was concentrated and purified on silica gel using flash chromatography. The product was eluted with 0.5 M NH3 in methanol, 10% / CH2Cl2, and concentrated. Trituration in chloroform and diethyl ether gave pure compound 13a (0.040 g, 0.086 mmol). MS m / z = 463.8 (+1).

Procedure 11 9- (8-Allyl-8-aza-biciclof3.2.noct-3-ylidene) -9H-xanthene-3-carboxylic acid diethylamide, 14a To a sample of compound 10a (0.37 g, 0.95 mmol) in 6 mL of acetonitrile was added potassium carbonate (0.53 g, 3.81 mmol) and allyl bromide (80 μL, 0.95 mmol). The mixture was stirred at room temperature for 20 h. The reaction was diluted with water and extracted with CH CI2. The combined organic extract was dried over magnesium sulfate and concentrated. The product was purified by flash column chromatography on silica gel, eluting with 0.5 M NH3 in methanol, % / CH 2 Cl 2, to yield 0.11 g (0.25 mmol) of compound 14a. The product was converted to its HCl salt using ethereal hydrogen chloride. MS m / z = 429.0 (M + 1); 1 H NMR 300 MHz (CDCl 3) d 1.1-1.4 (m, 6H), 1.7 (m, 2H), 2. 3 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.6 (m, 4H), 4.0 (m, 2H), 4.4 (m, 2H), 4.7 (m, 2H), 5.5 -5.9 (m, 4H), 6.3 (m, 2H), 7.1-7.4 (m, 7H). 9-R8- (2-Methoxy-Ethyo-8-aza-bicichlor3.2.11oct-3-ylidene-9H-xanthene-3-carboxylic acid diethylamide, 15a Following procedure 11 and substituting allyl bromide with 3 equivalents of 2-bromoethyl methyl ether, compound 10a was converted to the title compound 15a The product was converted to its HCl salt using ethereal hydrogen chloride MS / z- A? 1A (M + 1); 1 H NMR 300 MHz (CDCl 3) d 1.0-1.2 (m, 6H), 1.3 (m, 2H), 2.0 (m, 2H), 2.95 (m, 2H), 3.1-3.2 (m, 2H), 3.3 (s) , 3H), 3.4 (m, 2H), 3.6 (m, 4H), 3.8 (m, 2H), 4.0 (m, 2H), 7.1-7.4 (m, H).

EXAMPLE B 9-Piperidin-4-ylden-9H-xanthene-3-carboxylic acid diethylamide fumarate, 1b Following procedure 7, substituting the N-carbetoxinortropinone with N-Boc-piperidone, compound 1b was synthesized in one step, starting from compound 6a, with the simultaneous removal of the Boc protecting group. Purified on silica gel using flash chromatography. The product was eluted with 2 N NH3 in methanol, 10% / CH2Cl2. A salt of 2-PrOH fumarate was prepared. MS m / z (MH +) 363.2; 1 H NMR 300 MHz (DMSO-d6) d 1.1 (br s, 6 H), 2.8 (m, 4 H), 2.95 (m, 4 H), 3.3, 3.4 (br s, 4 H), 6.4 (s, 2 H) 7.1- 7.5 (m, 7H). 9-Piperidin-4-ylidene-9H-xanthene-3-carboxylic acid ethylamide, 2b The title compound 2b was synthesized following the procedure 7, substituting the compound 6a with the compound 7a, and substituting the N-carbetoxinortropinone with N-Boc-piperidone. MS m / z (MH +) 334.8. 9- (1-furan-3-ylmethyl-piperidin-4-ylidene) -9 V-xanthene-3-carboxylic acid diethylamide hydrochloride. 3b Following procedure 9, compound 1b was converted to the title compound 3b. The crude product was purified by flash column chromatography on silica gel, eluting with 3% methanol / CH2Cl2, to give the product. An Et20 / HCl hydrochloride salt was prepared. MS m / z (MH +) 363.2; 1 H NMR 300 MHz (DMSO-d6) d 1.2 (br d, 6 H), 2.4 (m, 2 H), 3.3-3.6 (m, 10 H), 4.0 (s, 2 H), 6.8 (s, 1 H) 7.1- 7.3 (m, 7H), 7.5 (s, 1 H), 7.7 (s, 1 H), 13.1 (s, 1 H). Procedure 12 9-d-carbamimidoyl-piperidin-4-ylidene-9H-xanthene-3-carboxylic acid diethylamide, 4b A solution of compound 2b (0.025 g, 0.069 mmol) and c (0.015 g, 0.36 mmol) in 4 mL of water was refluxed. After 3 h, the reaction was 50% complete. More cyanamide was added and the mixture was heated 24 h more. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by HPLC: 15-70% acetonitrile / water / 0.1% TFA. The TFA salt of compound 4b (1.4 mg, 3.5 μmol) was isolated. MS m / z = 405.1 (M + 1); H NMR 300 MHz (DMSO-d6) d 1.1 (br s, 6H), 2.8 (m, 4H), 3.2 (m, 2H), 3.5 (m, 6H), 7.1-7.5 (m, 7H). 9- (R3-pperidin-4-ylidene) -9 / - / - xanthene-3-carboxylic acid diethylamide, 5b-8b The following compounds were prepared following the procedure 9, substituting 3-furaldehyde with the appropriate aldehyde: Ex. # Aldehyde R3 MS m / z (MH +) 5b 2-pyridinecarboxaldehyde pyridin-2-ylmethyl 454.5 6b salicylaldehyde 2-hydroxy-benzyl 469.2 7b formalin methyl 377.26 8b phenylacetaldehyde phenethyl 467.33 9- (1-prop-2-ynyl-p-peridin-4-ylidene) - 9 - xanthene-3-carboxylic acid diethylamine hydrochloride. 9b Following procedure 11, substituting allyl bromide with propargyl bromide, compound 1b was refluxed for 12 h in acetonitrile. The crude product was purified by flash chromatography on a column of silica gel, eluting with 3% methanol / CH 2 Cl 2, and then converted into its hydrochloride salt with ethereal hydrogen chloride. MS / z (MH +) 401.4; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 2.6 (s, 1 H), 2.9 (m, 2 H) 3.1-3.6 (m, 10 H), 3.9 (s, 2 H),) 7.15-7.3 (m, 7H), 13.5 (s, 1H). 9-Ri- (2-Hydroxy-ethyl) -piperidin-4-ylidene-9 / - / - xanthene-3-carboxylic acid diethylamide, 10b The title compound was prepared starting from compound 1b, following procedure 11, substituting allyl bromide with 2-iodo-ethanol. MS m / z (MH +) 407.0; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 1.7 (m, 2H), 2.8 (m, 2H), 3.1 (m, 2H), 3.2-3.8 (m, 8H), 4.0 (m, 2H), 4.8 (m, 1 H), 7. 15-7.3 (m, 7H). Process 13 9- (1-t-fluorophenyl-piperidin-4-ylidene) -9H-xanthene-3-carboxylic acid diethylamide. 11b A sample of compound 1b (0.77 g, 2.1 mmol) was refluxed in 2 mL of toluene with N, N-dimethyl-thioformamide (0.36 mL, 4.24 mmol) for 5 h. The crude product was purified on a chromatography column Instant vaporization through silica gel, eluting with 45% ethyl acetate in hexane, to yield 0.66 g (1.6 mmol) of compound 11 b. Two rotamers were observed by 1 H-NMR. MS m / z (MH +) 406.9. 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 2.9 (m, 3 H), 3.3 (m, 2 H) 3.4-3.7 (m, 3 H), 3.9 (m, 2 H), 7.1-7.4 (m , 7H), 9.3 (s, 1 H). Method 14 9- (1-Phenyliminomethyl-piperidin-4-ylden) -9 / -xanthene-3-carboxylic acid diethylamide, 12b A sample of compound 1b (0.1 g, 0.25 mmol) in 1 mL of chloroform was put in a pressure tube and treated with methyl tosylate (0.037 mL, 0.25 mmol). The reaction was heated 1 h in a steam bath. At that time the reaction was cooled to room temperature and aniline (0.023 mL, 0.25 mmol) was added; the reaction was heated again in a steam bath for another 2 h. After 2 h, the reaction was cooled, washed with 1 N NaOH, and evaporated. The crude material was purified by flash chromatography on silica gel, eluting the product with 5% methanol / CH2Cl2, followed by conversion to its hydrochloride salt with ethereal hydrogen chloride. (0.004 g, 0.009 mmol). MS m / z (MH +) 466.3. 1 H NMR 300 MHz (CDCI3) d 1.2 (br s, 6H), 3.1 (m, 4H), 3.3 (d, 2H) 3.4-3.8 (m, 4H), 4.3 (s, 2H),) 7.1-7.4 (m, 10H), 7.7 (s, 2H), 8.0 (s, 1 H), 13.6 (s, 1 H). 9- (1-Allyl-pperidin-4-ylidene) -9 / - / - xanthene-3-carboxylic acid diethylamide. 13b Compound 1b was converted to the title compound 13b, following procedure 11 and substituting compound 10a with compound 1b. MS m / z (MH +) 403.3, 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 2.5 (m, 2 H), 3.1-3.7 (m, 12 H), 5.4 (m, 2 H),) 6.2 (m, 1H), 7.1-7.3 (m, 7H).

Example C Procedure 15 2- (3-Bromo-phenoxymethyl) -benzoic acid, 1c A solution of m-bromo-phenol (9.4 mL, 0.100 mmol) in 25 mL of THF was added dropwise to sodium hydride (4.0 g. , 0.10 mmol), which had been washed with hexane. When the bubbling ceased, the solvent was evaporated and phthalate (13 g, 0.1 mmol) was added. The reaction was heated to 200 ° C in an oil bath for 1 h. The reaction was cooled, diluted with water, washed with diethyl ether and acidified with HCl. The solid was collected and dried in air to yield 22.3 g (72.9 mmol) of compound 1c. MS m / z 305.31 (M-H). 3-Bromo-6H-dibenzo b.e1oxepin-11-one. 2c Compound 1c (22.3 g, 72.6 mmol) was converted to the title compound 2c (15.2 g, 52.3 mmol) using an adaptation of procedure 3. MS m / z (MH +) 289. 11-Oxo-1-methyl ester 6.11-dihydro-dibenzofb, eloxepine-3-carboxylic acid, 3c A sample of compound 2c (5.0 g, 17 mmol) was converted into the desired methyl ester (3.0 g, 11.2 mmol) using an adaptation of procedure 4. 11-oxo acid -6,11-dihydro-dibenzo-b, e-oxepin-3-carboxylic acid 4c A sample of compound 3c (6.0 g, 22 mmol) was converted into the corresponding carboxylic acid (5.5 g, 21.6 mmol) using an adaptation of the procedure 5.

L-Oxo-e-diethylamide I-dihydro-dibenzofb.eloxepine-S-carboxyliGQ, 5c A sample of compound 4c (5.5 g, 21.6 mmol) was converted to its corresponding diethylamide (4.28 g, 13.8 mmol) following an adaptation of the process 6. 11- (1-methyl-piperidin-4-ylidene) -6,11-dihydro-dibenzo ["b, e-oxopene-3-carboxylic acid, 0.5 fumarate, 6c A sample of compound 5c was converted to the title compound by following procedure 7, substituting compound 6a with compound 5c (3.85 g, 12.5 mmol), and substituting N-carbetoxinortropinone with N-methyl-piperidone The reaction yielded 2.5 g (6.4 mmol) of compound 6c MS m / z (MH +) 391.28; 1 H NMR 300 MHz (DMSO) d 1.0 (br s, 6H), 2.5 (m, 2H), 3.1-3.7 (m, 12H), 5.4 (m, 2H ),) 6.2 (m, 1 H), 7.1-7.3 (, 7H) Procedure 16 4- (3-Diethylcarbamoyl-6H-dibenzoic acid) 2,2,2-trichloro-ethyl ester, e1oxepin-11- Liden) -peridin-1-carboxylic acid, 7c A sample of compound 6c (2.58 g, 6.41 mmol) l), Trichloroethyl cioroformate (1.33 mL, 9.7 mmol) and potassium carbonate (3.34 g, 24.2 mmol) were refluxed for 3.5 h in benzene. An additional 4 mL of trichloroethyl chloroformate was added and the reaction was refluxed for another hour. Dimethylaminopropylamine (5 mL) was added and the reaction was terminated. The mixture was extracted with 2N HCl and washed with brine; the organic phase was dried over magnesium sulfate, filtered and then evaporated.

The crude product was recrystallized from acetone / hexane to give 2 g (3.6 mmol) of compound 7c. MS m / z (MH +) 551.31. Procedure 17 11-pyridin-4-ylidene-6 acid diethylamide, 11-dihydro-dibenzo-r? .eloxepin-1-ylidene-piperidine-1-carboxylic acid, 8c A sample of compound 7c (1.75 g, 3.17 mmol) and zinc (1.51 g, 23.1 mmol) was stirred in acetic acid (17.5 mL) at room temperature. The resulting solid was collected by filtration and washed with more acetic acid. The filtrate was concentrated and partitioned between NaOH and CH2Cl2. The organic phase was collected, dried over potassium carbonate and evaporated. The crude product was recrystallized from acetonitrile to give compound 8c (1.2 g, 3.2 mmol). MS m / z (MH +) 377.28; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 2.3 (m, 2 H), 2.4-3.1 (m, 6 H), 3.4 (br d, 4 H), 4.8 (d, 1 H), 5.8 ( d, 1 H), 6.8 (d, 1 H), 7.0 (m, 1 H), 7.1 (d, 1 H), 7.2-7.4 (m, 4H). 11- (1-Benzof1.31-dioxol-5-ylmethyl-D-peridin-4-ylidene-6,11-dihydro-dibenzo [b, e-oxepyne-3-carboxylic acid, 9c] -hydrochloride The title compound was prepared following procedure 9, substituting 3-furaldehyde with benzo [1, 3] dioxol-5-carbaldehyde and compound 10a with compound 8c The crude product was converted to its HCl salt using ethereal hydrogen chloride MS m / z (MH +) 511.34; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 2.3-2.7 (m, 12 H), 2.4-3.1 (m, 6 H), 4.05 (s, 2 H), 4.8 (d, 1 H), 5.7 ( d, 1H), 6.8-7.4 (m, 10H). 11- (1-Phenylethylpiperidin-4-yldenden-6,11-dihydro-dibenzof ?,> e-oxepin-3-carboxylic acid diethylamide, 10c Compound 8c was converted to the title compound following procedure 9, substituting 3-furaldehyde with phenylacetaldehyde and compound 10a with compound 8c The crude product was converted to its HCl salt using ethereal hydrogen chloride MS m / z (MH +) 481.35; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6H), 2.3-2.7 (m, 12H), 2.4-3.7 (m, 16H), 4.8 (d, 1H), 5.7 (d, 1H), 6.8-7.4 (m, 12H). 11-oxo-6, 11-dihydro-dibenzor), e-oxepin-3-carboxylic acid, 11c Compound 4c was converted to its monoethylamide following an adaptation of process 6, substituting diethylamine with ethylamine. 11- (8-phenethyl-8-aza-bicichlor3.2.poct-3-ylidene) -6,11-dihydro-dibenzoic acid, e1oxepine-3-carboxylic acid ethylamide, 12c A sample of compound 1c converted to the title compound following procedure 7, substituting compound 6a with compound 11c, and substituting N-carbetoxinortropinone with N-phenethyl-4-tropinone. The title compound was isolated as its TFA salt. MS m / z 479.1 (M + 1); 1 H NMR 300 MHz (DMSO-d 6) d 1.1 (t, 3 H), 1.35 (m, 1 H), 1.8 (m, 1 H), 2.2 (m, 2 H), 2.5 (m, 2 H), 2.8 (dd, 2 H) ), 3.1 (m, 2H), 3.3 (m, 2H), 3.75 (m, 2H), 4.1 (m, 2H), 5.0 (m, 1 H), 5.7 (m, 1H), 7.0-7.7 (m , 11 H), 8.4 (7, 1 H), 10.0 (br s, 1 H). 11- (1-Allyl-piperidin-4-ylidene) -6,11-dihydro-dibenzo [o, e] oxepine-3-carboxylic acid diethylamide, 13c The title compound was prepared following procedure 11, substituting the compound 10a with compound 8c. MS m / z (MH +) 417.33; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br d, 6 H), 2.4 (m, 1 H), 2.6 (n, 1 H), 2.8 (m, 2 H), 3.0-3.8 (m, 10 H), 4.8 (d, 1 H), 5.3-5.7 (m, 3H), 6.2 (m, 1H), 6.8-7.4 (m, 7H).

Example D (Grignard method) Method 18 3-Bromo-11-d-methyl-piperidin-4-yl) -6,11-dihydro-dibenzo [ib, e1-oxepin-11-ol, 1d A sample of the hydrochloride salt of 4-chloro- 1-metii-pperidine was basified with KOH and extracted with CH2Cl2. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was distilled from CaH2 at 50 ° C and 1 mm Hg.

Magnesium chips (3.42 g, 143 mmol) were suspended in 15 mL of dry THF under nitrogen. To this was added CH2Br2 (1.25 mL, 14.5 mmol) and a vigorous reaction was observed. The reaction was heated to reflux and 4-chloro-1-methyl-piperidine (21 mL, 128 mmol) was added. The reaction was refluxed 1 h. The reaction was allowed to cool and the supernatant was transferred via a cannula to a stirred solution of compound 2c (8 g, 128 mmol) in THF at room temperature. The suspension was rinsed with 2 x 20 mL of THF and the supernatant was transferred. At that time all the initial ketone had been consumed. Saturated sodium bicarbonate solution was added to the reaction and the mixture was extracted with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product, compound 1d, was used without further purification. MS m / z (MH +) 388.14. Procedure 19 4- (3-Bromo-6 - / - dibenzor? > e1oxepin-11-yldene) -1-methyl-piperidine, 2d A solution of compound 1d (9.53 g, 24.6 mmol) in 50 mL of formic acid was heated to reflux for 5 h. The reaction was concentrated and diluted with ethyl acetate; it was washed with 3 N HCl and then with 3 N KOH, to give compound 2d (9.0 g). MS m / z (MH +) 370.0. 11- (1-Methyl-piperidin-4-ylidene) -6,11-dihydro-dibenzo [D, e-oxepyne-3-carboxylic acid methyl ester, 3d The title compound 3d was synthesized using an adaptation of procedure 4. MS m / z (MH +) 350.2. Acid 11 - (1-methyl-piperidin-4-ylidene) -6,12-dihydro-dibenzorb.-oxepin-3-carboxylic acid, 4d The title compound 4d was synthesized starting from the 3d compound, using an adaptation of the process Etholamide of 11- (1-methylpperidin-4-ylidene) -6,11-dihydro-dibenzofep, e-oxepin-3-carboxylic acid, 5d The title compound was synthesized from compound 4d, using an adaptation of method 6, substituting diethylamine with ethylamine. MS m / z (MH +) 363.0. 4- (3-Ethylcarbamoyl-6 / - / - dibenzoyl.eloxepin-11-ylidenepiperidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester. The title compound was synthesized starting from compound 5d, using a procedure adaptation 16. MS m / z (MH +) 523.0 11-pperidin-4-ylidene-6,11-dihydro-d-benzo-r-α-oxoepine-3-carboxylic acid ethylamide, 7d Compound 6d was converted to the title compound using an adaptation of method 17. MS m / z (MH +) 349.0 Following procedure 9, compound 7d was converted to the next series of compounds, substituting 3-furaldehyde for the aldehyde appropriate: Ex. # Aldehyde R3 MS m / z (MH +) 8d 4-Methyl-but-3-enal 2-Methyl-but-2-ene 417.1 9d Thiophene-2-carbaldehyde Thiophen-2-yl-methyl 445.1 10d 2-Methyl-propene 2-Methyl-allyl 403.1 11d Cyclopropanecarbaldehyde Cyclopropylmethyl 403.1 12d 2-Pyridinecarboxaldehyde Pyridin-2-yl-methyl 440.1 13d 1W-lmidazol-4- 1 / - / - lidazol-4-ylmethyl 429.1 carbaldehyde 14d 4-H id roxy-3-methoxy- 4-Hydroxy-3- methoxy- 485.1 benzaldehyde phenylmethyl 15d Phenyl-acetaldehyde phenethyl 453.2 11- (1-Allyl-piperidin-4-ylidene) -6,11-dihydro-dibenzofo.eloxepine-S-carboxylic acid ethylamide, 16d The title compound 16d was prepared following procedure 11, substituting compound 10a with the compound 7d. MS m / z (MH +) 389.1.

Example E (McMurrv Bromide) 4- (3-Bromo-xanten-9-ylidene) -1-methyl-piperidine, 1e The compound 3a was converted to the title compound 1e following an adaptation of process 7, substituting compound 6a with compound 3a, and substituting the N-carbetoxinortropinone with N-methyl-piperidone. MS m / z (MH +) 356. 9- (1-methylpperidin-4-ylden) -9- / - xanthene-3-carboxylic acid methyl ester, 2e Compound 1e became in its methyl ester 2e by an adaptation of procedure 4. MS m / z (MH +) 336.1. 9- (1-methyl-piperidin-1-ylidene-VQH-xanthene-S-carboxylic acid, 3e The compound 2e was converted to the corresponding carboxylic acid, compound 3e, by an adaptation of procedure 5. MS m / z (MH +) 321.1 9- (1-Methyl-p-pperidin-4-ylidene) -9- / - xanthene-3-carboxylic acid dietilamide, 7 b Compound 3e was converted to the title diethylamide, compound 7b, using an adaptation of the procedure 6.

Example F N- [4- (5-Bromo-2-cyano-phenoxy-phenyl-1-acetamide, 1f) Compound 1f was synthesized as described in the synthesis of compound 1a in procedure 1, substituting phenol with N- (4-hydroxyphenyl) ) -acetamide 2- (4-Amino-phenoxy-4-bromo-benzoic acid, 2f The title compound 2f was synthesized in quantitative yield using the method described in procedure 2, substituting the compound 1a with compound 1f. CIMS m / z = 307 (M + 1). Procedure 20 2- (4-Acetylamino-phenoxy-4-bromo-benzoic acid, 3f Compound 2f (500 mg, 1.6 mmol) in 10 mL of THF was treated with acetyl chloride (0.15 mL, 2.08 mmol) and triethylamine (0.22 mL, 2.08 mmol) After stirring for 2.5 h, the solid was collected The filtrate was evaporated in vacuo to give 0.48 g of compound 3f MS m / z = 331 (M + 1). - (6-Bromo-9-oxo-9H-xanten-2-yl) -acetamide, 4f The title compound was synthesized using an adaptation of procedure 3, substituting compound 2a with compound 3f. acetylamino-9-oxo-9H-xanthene-3-carboxylic acid, 5f The title compound was synthesized using an adaptation of procedure 4, substituting compound 3a with compound 4f: 7-acetylamino-9-oxo-9H-xantho- 3-carboxylic acid, 6f The title compound was synthesized using an adaptation of process 5, substituting compound 4a with compound 5f .. Procedure 21 7-Acetylamino acid diethylamide -9-oxo-9H-xanthene-3-carboxylic acid, 7f Compound 6f (2 g, 6.7 mmol) in 35 mL of DMF was treated with HATU (2.5 g, 6.7 mmol), diethylamine (0.2 mL, 8.7 mmol) and diisopropylethylamine (4.75 mL, 26.8 mmol). After stirring for 3 h, the reaction was emptied in water and the solid was collected to give the product, compound 7f. The filtrate was extracted with diethyl ether / THF (1: 1). The combined organic phase was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and combined with the above solid, to give 1.5 g of compound 7f in total. MS m / z = 353 (M + 1). 7-Acetylamino-9-hydroxy-9- (1-methyl-piperidin-4-yl) -9? T - / - xanthene-3-carboxylic acid diethylamide, 8f The title compound was synthesized by an adaptation of the process 18, substituting compound 2c with compound 7f. Method 22 7-Acetylamino-9- (1-methyl-piperidin-4-ylide ') - 9 - / - xanthene-3-carboxylic acid diethylamide, 9f Compound 8f (0.3 g, 0.66 mmol) and trifluoromethanesulfonic acid (2 mL) were placed in a flask. After heating in a steam bath for 1 h, the reaction was poured into 3 N NaOH and ice. The aqueous solution was extracted with CH2Cl2 and dried over sodium sulfate. The solvent was evaporated in vacuo and the resulting residue was passed through a flash chromatography column (silica gel; CH 2 Cl 2: CH 3 OH: NH 4 OH, 90: 10: 1), to give 0.01 g of compound 9f. MS m / z ~ 435 (M + 1). 7-Acetylamino-9-piperidin-4-liden-9H-xanthene-3-carboxylic acid diethylamide, 10f Compound 10f was synthesized by an adaptation of method 7, substituting compound 6a with compound 7f, and substituting the N-carbetoxinortropinone with N-Boc-piperidone. MS m / z = 420.3 (M + 1).

Example G Method 23 9-Piperidin-4-yl-9H-xanthene-3-carboxylic acid diethylamide hydrochloride A sample of the hydrochloride salt of compound 1b (0.19 g, 0.52 mmol) was dissolved in 3 mL of CHCl3, treated with iodotrimethylsilane (0.15 mL), sealed in a pressure tube and heated in a steam bath for 2 h.

The mixture was cooled and the tube opened. A second portion of iodotrimethylsilane (0.15 mL) was added and the tube was reclosed; the vessel was heated 3 more hours in the steam bath. The reaction was cooled and 3 mL of MeOH was added. The reaction mixture was divided between CH2Cl2 and NaOH The organic layer was washed with sodium dithionite solution. The solvent was evaporated and the residue was subjected to flash chromatography: CH2Cl2, 90%: NH3 2N in MeOH, 10%, to give the title compound. An Et20 / HCl hydrochloride salt was prepared. MS m / z (MH +) 364.9; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br s, 6 H), 1.5 (m, 2 H), 1.7 (m, 2 H), 2.8 (m, 2 H), 3. 2-3.4 (m, 4H), 3.5 (br s, 2H), 3.7 (d, 1 H), 7.1-7.3 (m, 7H). 9- (1-Methylpiperidin-4-iQ-9H-xanthene-3-carboxylic acid diethylamide hydrochloride The title compound was obtained following the protocol of procedure 23 and substituting the hydrochloride salt of compound 1b with the hydrochloride salt of compound 7b MS m / z (MH +) 364.9; 1 H NMR 300 MHz (CDCl 3) d 1.2 (br s, 6 H), 1.4 (m, 1 H), 1.7 (m, 2 H), 2.05 (q, 2 H), 2.7 ( s, 3H), 3.1-3.5 (m, 6H), 3.7 (d, 1H), 7.1-7.3 (m, 7H), 12.2 (s, 1H).

Example H Method 24 4-Bromo-2-phenylsulfanyl-benzonitrile, 1 h In a flask, sodium hydride (2.40 g, 60 mmol) (60% by weight) was weighed and washed with several hexane rinses. The hexane was decanted and discarded and 20 mL of DMF was added to the flask. To the NaH mixture, a DMF solution of benzenethiol (5.1 mL, 50 mmol in 50 mL DMF) was added dropwise and stirred at room temperature. To 4-bromo-2-fluoro-benzonitrile (10.0 g, 50 mmol) in 40 mL DMF was added dropwise, for 30 minutes, benzenethiophene oxide (described above). Upon completion of the addition, the reaction was stirred at room temperature for 20 min. At that time, the mixture was poured into cold 1 N NaOH. A precipitate formed and was collected by vacuum filtration to give 14.0 g (48.4 mmol) of compound 1h. 4-Bromo-2-phenylsulfanyl-benzoic acid, 2h The compound 2h was obtained following procedure 2, substituting compound 1a with compound 1h. 3-Bromo-thioxanten-9-one, 3h The compound 3h was obtained following procedure 3, substituting compound 2a with compound 2h. Methyl ester of 9-oxo-9 / - / - thioxanthene-3-carboxylic acid, 4h. Compound 4h was obtained following procedure 4, substituting compound 3a with compound 3h. 9-Oxo-9 / - / - thioxanthene-3-carboxylic acid, 5h The compound 5h was obtained following the procedure 5, substituting the compound 4a with the compound 4h. 9-Oxo-9H-thioxanthene-3-carboxylic acid diethylamide, 6h. Compound 6h was obtained following procedure 6, substituting compound 5a with compound 5h. 9-Oxo-9H-thioxanthene-3-carboxylic acid ethylamide, 7h The compound 7h was obtained following procedure 6, substituting diethylamine with ethylamine and compound 5a with compound 5h. 3- (3-Dimethylcarbamoyl-thioxanten-9-ylidene) -8-aza-bicyclo [3.2.11octane-8-carboxylic acid ethyl ester, 8h. Compound 8h was obtained following the procedure described in the procedure , substituting compound 6a with compound 6h. MS m / z = 477? (MH +). 9- (8-aza-bicichlor3.2.11oct-3-lidenV9 / 7-thioxanthene-3-carboxylic acid diethylamide, 9h. Compound 9h was obtained following procedure 8, substituting compound 8a with compound 8h. the product was converted to its fumarate salt MS m / z (MH +) = 405.4 1H NMR 300 MHz (CDCl 3) d 1.05-1.3 (m, 6H), 1.40 (m, 2H), 1.9 (m, 2H), 2.75 (m, 2H), 3.1 (, 2H), 3.3 (m, 2H), 3.6 (m , 2H), 3.90 (br s, 2H), 7.2 (m, 5H), 7.5 (m, 2H). 9- (8-Benzop, 31-dioxol-5-ylmethyl-8-aza-biciclof3.2.noct-3-ylidTnV9H-thioxanthene-3-carboxylic acid diethylamide, 10h The compound 10h was obtained following procedure 9, substituting compound 10a with compound 9h, and substituting 3-furaldehyde with piperonal. Afterwards, the product became its salt fumarate. MS m / z (MH +) = 439.4. Salt fumarate: 1 H NMR 300 MHz (DMSO-d6) d 0.9-1.2 (m, 8H), 1.90 (m, 2H), 2.55 (m, 2H), 2.95 (m, 2H), 3.19 (m, 2H), 3.4 (m, 4H), 3.80 (br s, 2H), 6.05 (s, 2H), 6.65 (s, 2H), 6.9 (m, 2H), 7.2 (s, 1 H), 7. 35 (m, 5H), 7.6 (m, 2H). 9- (R3-8-aza-bicichlor3.2.11oct-3-ylidene) -9H-thioxanthene-3-carboxylic acid diethylamide, 11h-12h The following compounds were prepared following procedure 9, substituting 3-furancarboxaldehyde with The appropriate aldehyde: Ex. # Aldehyde R3 MS m / z (MH +) 11h Cyclopropane-Cyclopropylmethyl 459.7 carboxaldehyde 12h 3- (Metithium) -3- Methanesulfanyl-propyl 493.5 propionaldehyde 9-R8- (2-Hydroxy-ethyl) -8-aza-bicichlor3.2.1loct-3-ylidene-9-thioxanthene-3-carboxylic acid diethylamide, 13h Compound 13h was obtained following procedure 11, substituting compound 10a with compound 9h, and substituting the allyl bromide with 2-iodoethanol. MS m / z (MH +) = 449.2. H NMR 300 MHz (CDCI3) d 1.05-1.4 (m, 8H), 1.8 (m, 2H), 2.6-2.8 (m, 4H), 3.0 (m, 2H), 3.5 (m, 4H), 3.80 (m, 2H), 4.8 (br s, 1 H), 7.2 (m, 5H), 7.5 (, 2H).

Procedure 25 The (+) and (-) enantiomers of compound 24 (compounds 52 and 53 of Table 1 hereof) were separated on a preparative chiralpak AD column (500 grams of 20 micron material, 5 x 41 cm), using eluent hexane / methanol / ethanol (50/25/25). The analytes were monitored using a wavelength of 220 nm. For analytical work, the same column material was used (chiralpak AD, 4.6 x 50 mm), and the same solvents, but in an 80/10/10 ratio. The (+) and (-) enantiomers of compound 54 (compounds 55 and 56 of Table 1 hereof) were separated on a preparative chiralpak AD column (500 grams of 20 micron material, 5 x 41 cm), using as eluent heptane / ethanol (85/15). The analytes were monitored using a wavelength of 220 nm.

Example I Procedure 26 (2,4-D-fluoro-phenylH 2 -hydroxy-4-methoxy-phenyl) -methanone, 3i Aluminum chloride (2.03 g, 15.2 mmol) was added portionwise to a solution of 1,3-dimethoxybenzene (1.86 mL, 15.2 mmol) and 2,4-difluorobenzoyl chloride (1.86 mL, 15.2 mmol) in 1,2-dichloroethane, at 0 ° C. The mixture was allowed to warm to room temperature for 3 h and then was heated to reflux for 6 h. The resulting mixture was allowed to cool to room temperature, then was poured into a mixture of ice (-100 g) and concentrated hydrochloric acid (-20 mL). The organic layer was separated. The aqueous solution was stirred overnight at room temperature and extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the crude product. A portion of the product was purified by flash column chromatography Flash over silica gel, using as eluent a gradient of 1% -10% EtOAc / heptane, to give the title compound 3i (1.8 g). MS: m / z 264.9 (MH +). 1 H NMR (CDCl 3): d 3.90 (s, 3 H), 6.42 (d of d, 1 H, J = 9.0 and 2.5 Hz), 6.50 (d, 1 H, J = 2.5 Hz), 6.91-7.04 (m, 2H), 7.27-7.29 (m, 1 H), 7.44-7.50 (m, 1H) and 12.44 (s, 1H). Procedure 27 3-Fluoro-6-methoxy-xanten-9-one, 4i A mixture of potassium carbonate (2.13 g, 15.4 mmol) and (2,4-difluoro-phenyl) - (2-hydroxy-4-) methoxy-phenyl) -methanone (3.4 g, 12.9 mmol) in N, N-dimethylformamide (50 mL), was heated at 100 ° C for 2 h. The mixture was cooled and poured into water (-150 mL). A solid was collected by filtration, which was washed with water and dried under vacuum, to give the title compound (2.8 g), which was used without further purification in the subsequent step. MS: m / z 244.9 (MH +). 1 H NMR (CDCl 3): d 3.94 (s, 1 H), 6.88 (d, 1 H, J = 2.4 Hz), 6.96 (d of d, 1 H, J = 2.4 and 8.9 Hz), 7.07 (m, 2H ), 8.24 (d, 1 H, 8.9 Hz) and 8.34 (d of d, 1 H, J = 6.5 and 8.8 Hz). Method 28 6-Methoxy-9-oxo-9H-xanthene-3-carbonitrile, 5i A mixture of finely ground sodium cyanide (1.3 g, 26.5 mmol) and 3-fIuoro-6-methoxy-xanthen-9-one (2.3 g, 9.42 mmol) in N, N-dimethylformamide (30 mL), was heated at 100 ° C for 4 hours. Sodium cyanide (0.7 g, 14.3 mmol) was added and the heating was continued for an additional hour. The mixture was allowed to cool to room temperature and then emptied in ice water (-150 mL). The product was collected by filtration, washed with water and dried in air, to give compound 5i, 1.42 g (60%). MS: m / z 251.9 (MH +). 1 H NMR (CDCl 3): d 3.96 (s, 3 H), 6.91 (d, 1 H, J = 2.3 Hz), 7.00 (d of d, 1 H, J = 2.3 and 8.9 Hz), 7.61 (d of d, 1 H, J = 1 and 8.1 Hz), 7.79 (d, 1H, J = 1 Hz), 8.24 (d, 1 H, J = 8.9 Hz) and 8.42 (d, 1 H, J = 8.1 Hz). 6-Methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 6i The title compound was prepared (0.75 g) using the method described in procedure 2, substituting compound 1a with compound 5i. MS: m / z 270.9 (MH +). 1 H NMR (DMSO-d 6): d 3.95 (s, 3 H), 7.06 (d of d, 1 H, 2.4 and 8.9 Hz), 7.17 (d, 1 H, J = 2.4 Hz), 7.94 (d of d, 1 H , J = 1.4 and 8.2 Hz), 8.03 (d, 1 H, J = 1.4 Hz), 8.10 (d, 1 H, J = 8.9 Hz), 8.24 (d, 1 H, J = 8.2 Hz) and 13.65 ( br s, 1 H). Method 29 6-Methoxy-9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 7 \ A mixture of compound 6i (0.707 g, 2.62 mmol) and 0-benzotriazole-yl-α / V hexafluorophosphate, ? / '? - tetramethyluronyl (HBTU, 1.05 g, 2.74 mmol) in / V, / V-dimethylformamide (10 mL), treated with N, N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and left stirring 15 min at room temperature. Diethylamine (0.541 mL, 5.23 mL) was added and the resulting mixture was stirred 2 h. The mixture was poured into ice water. A solid was collected by filtration, which was washed with water and dried in the air to give the title compound (0.445 g). MS: m / z 326.0 (MH +). 1 H NMR (DMSO-d 6): d 1.07 (br t, 3 H), 1.19 (br t, 3 H), 3.20 (br q, 2 H), 3.48 (br t, 2 H), 3.95 (s, 3 H), 7.08 (m, 1 H), 7.17 (d , 1 H, J = 2.1 Hz), 7.40 (d of d, 1H, J = 1.3 and 8.1 Hz), 7.59 (d, 1 H, J = 1.2 Hz), 8.12 (d of d, 1 H, J = 1.3 and 8.9 Hz) and 8.21 (d, 1 H, J = 8.1 Hz). Procedure 30 9- (8-aza-bicyclo [3.2.11oct-3-liden) -6-methoxy-9H-xanthene-3-carboxylic acid dietilamide, 8i A suspension of zinc powder (0.626 g, 9.60 mmol) in THF (20 mL), at 0 ° C, treated with titanium (IV) chloride (0.525 mL, 4.79 mmol), by dropwise addition. The resulting mixture was heated to reflux for 2 h. The resulting solution was cooled to room temperature and 3-oxo-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert -butyl ester (0.270 g, 1.20 mmol) and compound 7i (0.390, 1.20 mmol); the solution was heated to reflux for 2 h. Sodium potassium tartrate (2.98 g, 10.5 mmol), dissolved in a minimal amount of water, was added to the reaction mixture and was allowed to stir overnight at room temperature. The inorganic solid was removed by filtration and washed generously with THF. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and 10% aqueous ammonium hydroxide. The organic layer was separated and dried over sodium sulfate. The solvent was evaporated in vacuo. The residue was taken in DMSO and purified by reverse phase preparative HPLC (C? 8), using an acetonitrile gradient (10% to 90%) in water with TFA (0.1%), to give the title compound as its salt of trifluoroacetic acid (0.50 g). MS: m / z 419.1 (MH +). 1 H NMR (DMSO-d 6): d 1.0-1.2 (br m, 6H), 1.32 (br d, 2H), 1.78 (br m, 2H), 2.85-3.02 (br m, 4H), 3.2-3.55 (br m, 4H), 3.80 (s, 3H), 3.96-4.05 (brs, 2H) ), 6.81 (d of d, 1 H, J = 2.5 and 8.6), 6.88 (d, 1 H, J = 2.5 Hz), 7.15 (d of d, 1 H, J = 1.4 and 7.8 Hz), 7.20 ( d, 1 H, J = 1.4 Hz), 7.31 (d, 1 H, J = 8.6 Hz), 7.41 (d, 1 H, J = 7.8 Hz), 8.81 (br s, 1 H) and 9.12 (br d , 1 HOUR). Procedure 31 9- (8-aza-bicylchlorof.2.2oct-3-ylidene) -6-hydroxyl-9H-xanthene-3-carboxylic acid diethylamide, 9i A 1.0 M solution of boron tribromide in dichloromethane (2.14 mL, 2.14 mmol) was added to a solution of the trifluoroacetic acid salt of 9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -6-methoxy-9H-xanthene diethylamide. -3-carboxylic acid (0.285 g, 0.535 mmol) in dichloromethane (10 mL), at 0 ° C.

The resulting mixture was stirred at room temperature for 2 h. The mixture was cooled to 0 ° C and treated with 10% aqueous ammonium hydroxide (-20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in DMSO and applied to a reverse phase C-β8 column for HPLC purification., using as eluent an acetonitrile gradient (10% to 90%) in water with trifluoroacetic acid (0.1%). Fractions containing the title compound were combined and the product was further purified by HPLC to give the pure title compound (0.035 g). MS: m / z 405.1 (MH +). 1 H NMR (DMSO-d 6): d 1.0-1.2 (br m, 6H), 1.29 (d, 12H, J = 8.1 Hz), 1.7-1.8 (br m, 2H), 2.8-3.0 (br m, 4H) , 3.1-3.5 (br m, 4H), 3.99 (br s, 2H), 6.63-6.65 (m, 2H), 7.13 (d, 1 H, J = 7.9 Hz), 7.18-7.21 (m, 3H), 7.41 (d, 1 H, J = 7.9 Hz), 8.70 (br s, 1 H), 9.01 br d, 1 H) and 9.93 (br s 1H).

Example J Method 32 2- (2-Bromo-phenoxy) -terephthalic acid dimethyl ester, 3j A mixture of 2-fluoro-terephthalic acid dimethyl ester 2j (10 g, 47.1 mmol), 2-bromophenol 1j (6.0 mL, 51.8 mmol ) and potassium carbonate (7.16 g, 51.8 mmol) in? /,? / - dimethylformamide (100 mL), warmed to 100 ° C for 36 h. The mixture was allowed to cool to room temperature, then it was drained in cold diluted hydrochloric acid (0.5 N, 350 mL). The product was extracted into EtOAc, it was washed with water (4x) and brine (1x) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel, using dichloromethane as eluent. The crude product was isolated (10.5 g) and used without further purification in the subsequent reaction. MS: m / z 365 (MH +). Procedure 33 5-Bromo-9-oxo-9H-xanthene-3-carboxylic acid, 5j (via 4j) 2- (2-Bromo-phenoxy) -terephthalic acid dimethyl ester (10 g) was added dropwise to a solution of hot polyphosphoric acid (100 ° C, 280 g) for 5 min. The solution was heated at 155 ° C for 2 h, after which the heating was continued at 180 ° C for 2 h more. The solution was mixed with a large amount of ice water. The resulting solid was collected by filtration, washed with water and purified by flash chromatography on silica gel, using a gradient of methanol (1% to 10%) in dichloromethane with acetic acid (0.1%), to give the compound 4j (1.25 g). The acid compound 5j was isolated from the last fractions (3.52 g). A solution of ester 4j (1.25 g, 3.75 mmol) and 3 N sodium hydroxide (1.37 mL, 4.12 mmol) in MeOH (30 mL) was heated to reflux for 2 h. The solution was cooled to t.a. and made acid with 2N hydrochloric acid (-2.5 mL). The mixture was concentrated in vacuo and then diluted with water. The resulting solid was collected by filtration, washed with water and air dried to yield 1.08 g more of compound 5j. MS: m / z 318.7 (MH +). 1 H NMR (DMSO-de): d 7.43 (t, 1H, J = 7.8 Hz), 7.98 (d of d, 1 H, J = 1.4 and 8.2), 8.09 (d., 1 H, J = 1.3 Hz), 8.17-8.23 (m, 2H) and 8.28 (d, 1 H, J = 8.2 Hz). 5-Bromo-9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 6i The title compound was prepared using the method described in procedure 29, substituting compound 6i with compound 5j. The subsequent purification by flash chromatography, using dichloromethane as eluent, gave compound 6j (4.4 g). MS: m / z 373. 8 (MH +). 1 H NMR (CDCl 3): d 1.16 (t, 3 H, J = 6.8 Hz), 1.30 (t, 3 H, J = 6.8 Hz), 3.28 (q, 2 H, J = 6.8 Hz), 3.60 (q, 2 H, J = 6.8 Hz), 7.30 (d, 1 H, J = 7.9 Hz), 7.40 (d of d, 1 H, J = 1.4 and 8.0 Hz), 7.64 (d, 1 H, J = 1.4 Hz), 7.98 ( d of d, 1 H, J = 1.6 and 7.9 Hz), 8.30 (d of d, 1 H, J = 1.6 and 8.0 Hz) and 8.36 (d, 1 H, J = 8.1 Hz). Method 34 9- (8-aza-bicichlor3.2.11oct-3-ylidene) -5-bromo-9H-xanthene-3-carboxylic acid dietilamide, 7i A suspension of zinc powder (5.59 g, 85.5 mmol) in tetrahydrofuran (THF, 100 mL) at 0 ° C, treated with titanium (IV) chloride (4.69 mL, 42.8 mmol) by dropwise addition. The resulting mixture was heated to reflux for 2 h. The resulting solution was cooled to 0 ° C. 3-Oxo-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert -butyl ester (2.4 g, 10.7 mmol) and 5-bromo-9-oxo-9H-xanthene diethylamide were added. -3-carboxylic acid (4.0 g, 10.7 mmol), and the solution was refluxed for 4 h. To the reaction mixture was added sodium potassium tartrate tetrahydrate (30 g, 106 mmol) and was left stirring overnight at room temperature. The inorganic solid was removed by filtration and washed successively with THF, EtOAc and dichloromethane. The solvent was evaporated in vacuo. Purification by flash chromatography using as eluent a gradient of 1% to 10% methanol (with 2N ammonia) in dichloromethane, gave compound 7j (3.65 g). The crude product was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%), to give the trifluoroacetic acid salt of compound 7j. MS: miz 467.0 (MH +). 1 H NMR (DMSO-d 6): d 1.0-1.2 (br m, 6H), 1.32 (d, 2H, J = 7.9 Hz), 1.75-1.85 (br m, 2H), 2.85-3.10 (m, 4H), 3.15-3.50 (br m, 4H), 4.01 (br s, 2H), 7.15-7.26 (m, 3H), 7.42 (d, 1 H, J = 6.7 Hz), 7.49 (d, 1 H, J = 7.9 Hz), 7.66 (d, 1 H, J = 7.9 Hz), 8.81 (br s, 1H) and 9.12 br d, 1H). Method 35 9- (8-aza-biciclof3.2.noct-3-ylidene) -5-phenyl-9H-xanthene-3-carboxylic acid diethylamide A mixture of 9- (8-aza-bicyclo) diethylamide [3.2.1] oct-3-ylidene) -5-bromo-9H-xanthene-3-carboxylic acid (0.170, 0.363 mmol), phenylboronic acid (0.049 g, 0.40 mmol) and cesium carbonate (0.236 g, 0.726 mmol) in dioxane (4 mL) and ethanol (1 mL), treated with an adduct of dichloro [1,1-bis (diphenylphosphine) ferrocene] palladium (II) in dichloromethane (13 mg), and the resulting mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the inorganic material was removed by filtration and washed successively with dioxane, ethanol and dichloromethane. The solvent was evaporated in vacuo. The residue was purified by preparative reverse phase HPLC (C? 8), using as eluent an acetonitrile gradient (10% to 90%) in water with trifluoroacetate (0.1%), to give the title compound (0.153 g) as a colorless solid. MS: m / z 465.3 (MH +). 1 H NMR (DMSO-d 6): d 1.05-1.20 (br m, 6 HO, 1.31 d, 2 H, J = 8.2 Hz), 1.75-1.85 (br m, 2 H), 2.90-3.10 (m, 4 H), 3.15 -3.50 (br m, 4H), 4.03 (br s, 2H), 7.10 (d, 1 H, J = 1.5 Hz), 7.20 (d of d, 1 H, J = 1.5 and 7.9 Hz), 7.32 (t , 1H, J = 7.5 Hz), 7.40-7.63 (m, 8H), 8.83 (br s, 1 HO) and 9.16 (br d, 1H). 9- (8-aza-bicyclo3.2.1loct-3-ylidene) -5-methoxy-9H-xanthene-3-caboxylic acid diethylamide The title compound was prepared following example J and substituting the 2- bromophenol with 2-methoxyphenol in procedure 32. MS: m / z 419.1 (MH +). 1 H NMR (DMSO-de): d 1.0-1.2 (m, 6H), 1.29 (br m, 1 H), 1.73-1.82 (m, 2H), 2.87-3.15 (m, 4H), 3.22 (br m, 2H), 3.42 (br m, 2H), 3.88 (s, 3H), 4.00 (br s, 2H), 6.95 (d, J = 7.5 Hz, 1 H), 7.07-7.19 (m, 3H), 7.22 ( d, J = 1.5 Hz, 1 H), 7.44 (d, J = 7.9 Hz, 1 H), 8.77 (br s, 1 H) and 9.08 (br s, 1 H). 9- (8-aza-bicyclo3.2.11oct-3-ylidene) -5-hydroxy-9H-xanthene-3-carboxylic acid diethylamide The title compound was prepared from 9- (8-aza- bicyclo [3.2.1] oct-3-ylidene) -5-methoxy-9H-xanthene-3-carboxylic acid, using an adaptation of procedure 31. MS: m / z 405.0 (MH +). H NMR (DMSO-de): d 1.0-1.2 (m, 6H), 1.29 (br m, 1H), 1.73-1.84 (m, 2H), 2.95-3.15 (m, 4H), 3.20 (br m, 2H ), 3.42 (br m, 2H), 4.00 (br s, 2H), 6.80 (d, J = 7.6 Hz, 1 H), 6.87 (d, J = 7.9 Hz, 1 H), 7.02 (t, J = 7.9 Hz, 1H), 7.15 (d of d, J = 1.5 and 7.9 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 8.78 (br s, 1H), 9.08 (br s, 1 H) and 9.67 (br s, 1H). 9- (8-aza-bicyclic3.2.noct-3-ylidene) -5-pyridin-4-yl-9H-xanthene-3-carboxylic acid diethylamide The title compound was prepared following the method described in Example J and substituting phenyl-boronic acid with pyridin-4-yl-boronic acid in procedure 35. MS: m / z 466.1 (MH +). 1 H NMR (DMSO-d 6): d 1.0-1.2 (m, 6H), 1.32 (br m, 2H), 1.80 (br m, 2H), 2.88-3.42 (br m, 8H), 4.03 (br s, 2H ), 7.22 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 1 H ), 7.58 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1 H), 8.06 (d, J = 6.1 Hz, 2H), 8.90 (br m, 3H) and 9.22 (br d, J = 9.4 Hz, 1H). 9- (8-aza-bicycloï3.2.noct-3-ylidene) -5-furan-3-yl-9H-xanthene-3-carboxylic acid diethylamide The title compound was prepared using the method described in Example J , substituting the phenyl boronic acid with furan-3-yl-boronic acid in the procedure 35. MS: m / z 455.1 (MH +). 1 H NMR (DMSO-d 6): 61.0-1.2 (m, 6H), 1.30 (br m, 2H), 1.78 (br m, 2H), 2.89-3.05 (m, 4H), 3.20 (br m, 2H), 3.44 (br m, 2H), 4.02 (br s, 2H), 7.15 (s, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.26-7.31 (m, 2H), 7.47 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 1.1 Hz, 1 H), 7.69-7.72 (m, 1 H), 7.82 (s, 1 H), 8.59 (s, 1 H), 8.83 (br , 1 H) and 9.15 (br d, J = 9.3 Hz, 1 H). 9- (8-aza-bicichlor3.2.noct-3-ylidene) -5-pyridin-3-yl-9H-xanthene-3-carboxylic acid diethylamide The title compound was prepared using the method described in Example J , substituting phenyl-boronic acid with pyridin-3-yl-boronic acid in the procedure 35. MS: m / z 466.1 (MH +). 1 H NMR (DMSO-d 6): d 1.0-1.2 (m, 6H), 1.32 (m, 2H), 1.80 (br m, 2H), 2.90-3.02 (m, 4H), 3.20 (br m, 2H), 3.42 (br m, 2H), 4.03 (br s, 2H), 7.16 (d, J = 1.5 Hz, 1 H), 7.20 (d of d, J = 1.5 and 7.8 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.49-7.56 (m, 3H), 7.76 (d of d, J = 5.0 and 7.9 Hz, 1 H), 8.31 (d, J = 8.0 Hz, 1 H), 8.74 ( d of d, J = 1.5 and 5.0 Hz, 1 H), 8.82 (br s, 1 H), 8.95 (s, 1 H) and 9.13 (br d, 1 H). 9- (8-aza-bicyclo [3.2.noct-3-ylidene] -5-thiophen-3-yl-9H-xanthene-3-carboxylic acid diethylamide The title compound was prepared using the method described in Example J , substituting the phenyl boronic acid with thiophene-3-yl-boronic acid in the procedure 35. MS: m / z 471.0 (MH +). 1 H NMR (DMSO-d 6): d 1.0-1.2 (m, 6H), 1.31 (m, 2H), 1.78 (br m, 2H), 2.95-3.05 (m, 4H), 3.21 (br m, 2H), 3.43 (br m, 2H), 4.02 (br s, 2H), 7.21 (d of d, J = 1.5 and 7.8 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.34 (d of d, J = 1.4 and 7.6 Hz, 1 H), 7.38 (d, J = 1.4 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.63-7.70 (m, 3H), 8.13 ( d of d, J = 1.4 and 2.8 Hz, 1 H), 8.80 (br s, 1 H) and 9.12 (br d, J = 10 Hz, 1 H). 6 Example K 9- (8-aza-bicichlor3.2.1loct-3-ylidene) -9H-xanthene-3-carboxylic acid isopropyl-methyl-amide Procedure 36 2-phenoxy-terephthalic acid dimethyl ester In a 1-L 3-neck round-bottom flask equipped with a mechanical stirrer, a reflux condenser and containing toluene (350 mL), 2-dimethyl ester was added. iodo-terephthalic (10 g, 31 mmol), phenol (3.23 g, 34 mmol), tetrakis-acetonitrile-copper hexafluorophosphate (2.9 g, 7.8 mmol) and cesium carbonate (10.2 g, 31 mmol). The reaction was refluxed 5 hours under nitrogen with stirring. After cooling, EtOAc (200 mL) was added and the mixture was filtered. The filtrate was concentrated to yield the crude title compound (9.2 g), which was used without further purification. The dimethyl ester of 2-phenoxy-terephthalic acid was converted to 9-oxo-9H-xanthene-3-carboxylic acid using an adaptation of the process 33. The N-isopropyl-N-methyl-amide of 9-oxo-9H- acid xanthene-3-carboxylic acid was prepared from 9-oxo-9H-xanthene-3-carboxylic acid using an adaptation of method 29, and substituting diethylamine with N-isopropyl-N-methyl-amine. The title compound of Example K was prepared by the method described in procedure 34, substituting compound 6j with N- 9-Oxo-9H-xanthene-3-carboxylic acid isopropyl-N-methylamide. The crude product was purified by preparative reverse phase chromatography on a C-18 column, eluting with water / acetonitrile / 0.1% TFA, to give the product as its trifluoroacetic acid salt. MS m / z (MH +) 389.2; 1 H NMR 300 MHz (DMSO-de) d 1.12 (s, 6H), 1.2-1.3 (m, 2H), 1.79 (m, 2H), 2.82 (m, 3H), 2.95 (q, 4H), 4.00 (s) , 2H), 7.18-7.21 (m, 1H), 7.24 (d, 2H), 7.30 (d, 1H), 7.36 (d, 1H), 7.40-7.46 (m, 2H), 8.77 (m, 1H), 9.09 (d, 1H). Compounds 1 to 102 of the following table were synthesized using the methods described above.

TABLE 1 Comp. i R R3 R4 Rs A Y z 1 Et Et Me H H absent CH2O O 2 Et Et H H H absent CH2O O 3 Et Et H H H absent O O 4 Et Et Benzo [1, 3] dioxol-5 H H absent CH 2 O O ilmethyl 5 Et Et Fenetyl H H absent CH 2 O O 6 Et Et Alilo H H absent CH2O O 7 Et Et Me H H absent O O 8 Et Et Alilo H H absent O O 9 Et H Me H H absent CH2O O Et H 1, 1, 1-Trichloroethoxy-H H absent CH2O O carbonyl TABLE 1 (Continued) Comp. RT R2 R4 A Y 11 Et H H H H absent CH20 O 12 Et H 2-Methyl-but-2-enyl H H absent CH 2 O O 13 Et H Tiofen-2-ylmethyl H H absent CH2O O 14 Et H 2-Methyl-allyl H H absent CH 2 O O Et H Cyclopropylmethyl H H absent CH2O O 16 Et H Pyridin-2-ylmethyl H H absent CH 2 O O 17 Et H 1 -H-lmidazol-4-ylmethyl H H absent CH 2 O O 18 Et H 4-Hydroxy-3-methoxyphenyl-H H absent CH 2 O O methyl 10 19 Et H Allyl H H absent CH 2 O O Et H Fenethyl H H absent CH 2 O O 22 Et Et Fenetyl H H absent O O 23 Et Et Me H H CH 2 CH 2 O O 24 Et Et H H H CH 2 CH 2 O O 5 Et Et Furan-3-ylmethyl H H CH 2 CH 2 O O 26 Et H Phenethyl H H CH CH 2 CH 2 O O 27 Et H Fenethyl H H CH 2 CH O O 28 Et Et Furan-3-ylmethyl H H absent O O 29 Et Et Pyridin-2-ylmethyl H H absent O O Et Et 2-Hydroxyphenyl-methyl H H absent O O op 31 Et Et Carbamimidoyl H H absent O O 32 Et H H H H absent O O TABLE 1 (Continued) Comp. R-i R2 A Y 33 Et Et 1-Prop-2-iniio H H absent O O 34 Et Et H Acetyl absent O O amino 35 Et Et Hydroxy-ethyl H H absent O O 36 Et Et Phenyliminomethyl H H absent O O 37 Et Et Tioformil H H absent O O 38 Et Et Allyl H H CH Cp2 O O 39 Et Et 2-Methoxy-ethyl H H CH 2 CH 2 O O 40 Et Et Methylthioethyl H H CH 2 Cl 2 O 0 41 Et Et Methyl Acetyl Absent O O amino 42 Et Et H H H absent O O 43 Et Et Me H H absent O O 44 Et Et Pyridin-2-ylmethyl H H CH 2 CH 2 O O 45 Et Et Hydroxyethyl H H CH CH 2 O O 46 Et Et 1 - / - / - Imidazol-4-ylmethyl H H CH 2 CH 2 O O 47 Et Et Benzo [1, 3] dioxol-5-ylmethyl H H CH CH 2 s O 48 Et Et H H H CH CH 2 s O 49 Et Et Cyclopropylmethyl H H CH CH 2 s O 50 Et Et Metillthiopropyl H H CH 2 CH 2 s O 51 Et Et Hydroxy-ethyl H H CH2CH2 s O 52 Et Et H H H CH 2 CH 2 O O enantiomer (-) TABLE 1 (Continued) Comp. R-i R2 R3 R4 A Y 53 enanEt Et H H H CH2CH2 O thiomer (+) 54 Et H H H H CH2CH2 'O O 55 enanEt H H H H CH2CH2 O O thimer (-) 56 enanEt H H H CH2CH2 O thimer (+) 57 Me Me H H H CH2CH2 O O 58 i-Pr H H H H CH2CH O o 59 Me i-Bu H H H CH2CH2 O O 60 n-Pr n-Pr H H H CH 2, CH 2 O O 61 enanEt Et H H H CH2CH2 s O thimer (+) 62 enanEt Et H H H CH2CH2 S thimer (-) 63 n-Pr H H H H CH2Cp2 O O 64 Me H H H H CH2CH2 O O 65 H H H H H CH 2 CH 2 O O 66 Et Et H 6-methyl H CH 2 CH 2 O O 67 Et Et H 7-methyl H CH 2 CH 2 O O 68 Et Et H 5- H CH 2 CH 2 O O Methoxy 69 Et Et H 7 -fluoro H CH 2 CH 2 O O TABLE 1 (Continued) Comp. RT R2 R3 R5 A Y 70 Et Et H 6- H CH 2 CH 2 O O methoxy 71 Et Et 1-H-imidazol-5-ylmethyl H H CH 2 CH 2 O O enant. A 72 Et Et 1 H-imidazol-5-ylmethyl H H CH 2 Cl O O enant. B 73 Me n- H H H CH 2 CH 2 'O O Bu 74 Et Et 1-H-imidazol-4-yl-methyl H H CH 2 CH s O 75 Et Et 1-H-imidazol-4-ylmethyl H H CH2CH s O 76 Et Et H 6- H CH 2 Cl 2 O O hydroxy 77 Et Et H 7- H CH 2 CH 2 O O Methoxy 78 Et H Trifluoromethylcarbonyl H H CH CH s O 79 Et H Trifluoromethylcarbonyl H H CH2CH2 s O 80 Et H H H H CH 2 CH 2 s O 81 Et H H H H CH 2 CH s O 82 Et Et H 7- H CH 2 CH 2 O O id roxi 83 Et Et H 7- H CH 2 CH 2 O O Bromine 84 Et Et H 7 -phenyl H CH 2 CH 2 O O 85 Et Et H 7- H CH 2 CH 2 O O pyridin-4-yl 86 Et Et H 7 -furan-H CH 2 CH 2 O O 3 -yl TABLE 1 (Continued) Comp. R 2 R 3 Rs 87 Et Et H 7 -benzo-H CH 2 CH 2 OO thiophen-2-yl 88 Et Et H Nt-Butoxy- H CH 2 Cl 2 O O carbonyl pyrrol-2-yl 89 Et Et H 7 -pyridin-3 H CH2CH OO ilo 90 Et Et H 7-thiophen-3 H CH 2 CH 2 OO ilo 91 Et Et H 7- (3,5- H CH 2 CH OO dimethyl) -isoxazol-4-yl 92 Me i-Pr HHH CH 2 CH 2 OO 93 Et Et H 7-pyrrole-2 H CH 2 CH 2 O O ilo 94 Et Et H 5 -bromo H CH 2 CH O O 95 Et Et H 5-phenyl H CH 2 CH 2 O O 96 Et Et H 5-pyridin-4- H CH 2 CH 2 OO ilo 97 Et Et H 5 -furan-3 H CH 2 CH OO ilo 98 Et Et H 5-quinolin-H CH 2 CH 2 OO 3-yl 99 Et Et H 5-thiophen- 3- H CH2CH2 OO ilo 100 Et Et H 5 -hydroxy H CH2CH2 OO 101 Et Et H 5-pyridin-3 H CH 2 CH 2 O O ilo 102 Et Et H 5-fluoro H CH 2 CH 2 O O BIOLOGICAL EXAMPLES Mu-opioid receptor binding test in rat brain Procedure: Male Sprague Dawley rats (150-250 g, VAF, Charles River, Kingston, New York) are killed by CO2 and their brains are removed and immediately placed in cooled Tris HCl buffer on ice (50 mM, pH 7.4). The forebrains are separated from the rest of the brain by a coronal transection, starting dorsally in the colliculus and passing ventrally through the mesencephalon-bridge junction. After dissection, the forebrains are homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate is diluted to a concentration of 1 g of forebrain tissue for 80 mL of Tris, and centrifuged at 39,000 x g for 10 min. The pellet is resuspended in the same volume of Tris buffer, which contains 5 mM MgCl2, with several brief pulses from a Polytron homogenizer. This particulate preparation is used for mu-opioid binding assays. After incubation with the mu selective peptide ligand, in [3 H] DAMGO -0.8 nM at 25 ° C for 2.5 h, in a 96-well plate with 1 ml in total, the contents of the plate are filtered through Wallac filtermat B leaves in a 96-cavity Tomtec harvester. The filters are rinsed three times with 2 mL of 10 mM HEPES (pH7.4), and dried twice in a 650 W microwave oven for 1.75 min. To each sample area, 2 x 40 μL of scintillation fluid Betaplate Scint (LKB) is added and analyzed in a scintillation counter of liquids BetaPlate 1205 LKB (Wallac). Analysis: the scintillation counter data is used to calculate the% inhibition compared to the control binding (when evaluating only a concentration of test compound), or a value of K i (when a concentration scale is tested) ). The% inhibition is calculated as: [(total dpm - dpm of test compound) / (total dpm - nonspecific dpm)] * 100. The values of Kd and Ki are calculated using a GraphPad PRISM data analysis program. Binding test of [35S1GTPvS on membranes of CHO- cells Membrane preparation: Membranes of CHO-hμ cells are purchased from Receptor Biology, Inc. (Baltimore, Maryland). Approximately 10 mg / ml membrane protein is suspended in 10 mM TRIS-HC, pH 7.2, 2 mM EDTA, 10% sucrose. The membranes are maintained at 4-8 ° C. Add 1 ml of the membranes in 15 ml of cold binding test buffer. The test buffer contains 50 mM HEPES, pH 7.6, 5 mM MgCl 2, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membrane suspension is homogenized 2 times with a Polytron and centrifuged at 3000 rpm for 10 min. Then, the supernatant is centrifuged at 18,000 rpm for 20 min. The pellet is stored in a tube and 10 ml of test buffer are added to the tube. The pellet and the shock absorber are mixed with a Polytron.

Incubation procedure: Pellet membranes (20 μg / ml) are preincubated with SPA (10 mg / ml) at 25 ° C for 45 min in the test buffer. The SPA (5 mg / ml) coupled with the membranes (10 μg / ml) is then incubated with 0.5 nM [35S] GTPgS in the same HEPES buffer, containing 50 μM GDP in a total volume of 200 μl. Increasing concentrations of receptor agonists are used to stimulate the binding of [35S] GTPgS. The basal junction is tested in the absence of agonists and the specific binding is tested in the unlabeled GTPyS 10 μM present. The data is analyzed in a Top counter. Data: basal% = (stimulation - specific) * 100 / (baseline - non-specific). The values of% inhibition are calculated using a formula,% inhibition = (basal% of DAMGO 1 μM -% of basal compound) * 100 / (basal% of DAMGO 1 μM -100).

F35S1GTPvS binding test on membranes of CHO-hd cells Membrane preparation: CHO-hd cell membranes are purchased from Biology Receptor, Inc. (Baltimore, Maryland). 10 mg / ml membrane protein is suspended in 10 mM TRIS-HC, pH 7.2, 2 mM EDTA, 10% sucrose. The membranes are maintained at 4-8 ° C. Add 1 ml of the membranes in 15 ml of cold binding test buffer. The test buffer contains 50 mM HEPES, pH 7.6, 5 mM MgCl2, NaCl 100 mM, 1 mM DTT and 1 mM EDTA. The membrane suspension is homogenized 2 times with a Polytron and centrifuged at 3000 rpm for 10 min. Then, the supernatant is centrifuged at 18,000 rpm for 20 min.

The pellet is stored in a tube and 10 ml of test buffer are added to the tube. The pellet and the shock absorber are mixed with a Polytron. Incubation procedure: Pellet membranes (20 μg / ml) are preincubated with SPA (10 mg / ml) at 25 ° C for 45 min in the test buffer. The SPA (5 mg / ml) coupled with the membranes (10 μg / ml) is then incubated with 0.5 nM [35S] GTPgS in the same HEPES buffer, containing 50 μM GDP in a total volume of 200 μl. Increasing concentrations of receptor agonists are used to stimulate the binding of [35S] GTPgS. The basal junction is tested in the absence of agonists and the non-specific binding is tested in the presence of unlabeled GTP S 10 μM. The data is analyzed in a Top counter.

F35S1GTPyS binding test on membranes of NG 108-15 cells Membrane preparation: Membranes of NG108-15 cells were purchased from Applied Cell Sciences (Rockville, Maryland). A portion of 8 mg / mL protein membrane was suspended in 10 mM TRIS-HC, pH 7.2, 2 mM EDTA, 10% sucrose. The membranes are maintained at 4-8 ° C. A 1 ml portion of the membranes is added in 10 ml of cold binding test buffer. The test buffer contains 50 mM Tris, pH 7.6, 5 mM MgCl2, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. The membrane suspension is homogenized 2 times with a Polytron and centrifuged at 3000 rpm for 10 min. Then, the supernatant is centrifuged at 18,000 rpm for 20 min. The pellet is stored in a tube and 10 ml of test buffer are added to the tube. The pellet and the shock absorber are mixed with a Polytron. Incubation procedure: The pelleted membranes (75 μg / ml) are preincubated with SPA (10 mg / ml) at 25 ° C for 45 min in the test buffer. The SPA (5 mg / ml) coupled with the membranes (37.5 μg / ml) is then incubated with 0.1 nM [35S] GTP? S in the same Tris buffer, containing 100 μM GDP in a total volume of 200 μl. Increasing concentrations of receptor agonists are used to stimulate the binding of [35S] GTP? S. The basal junction is tested in the absence of agonists and the non-specific binding is tested in the Non-labeled GTPyS 10 μM present. The data is analyzed in a Top counter. Data: basal% = (stimulation - nonspecific) * 100 / (baseline - non-specific). CE5o values are calculated using a Prism program.

Mouse Abdominal Irritation Test (MAIO) The procedure used was that described by Collier et al. (1968), with minor modifications.Tirty minutes after the administration of the test drug, the animals received an ip injection of acetylcholine bromide 5.5 mg / kg Afterwards, the mice were placed in large glass animal containers and observed continuously to see the first occurrence of a characteristic behavioral response (torsion and stretching of the body extending to the hind legs) in the specified observation period. The percentage of inhibition of this response was calculated as follows:% inhibition = 100 x (number of animals that did not respond) / (number of animals in the group) The estimated ED50 value (the dose of agonist calculated to produce 50% antinociception) and the corresponding 95% confidence intervals, were determined using the prob analysis. it by Litchfield and Wilcoxon (1949). Data: Basal% = (stimulation - nonspecific) * 100 / (basal - specific). The EC50 values were calculated using a Prism program.

Radiant heat test of Zymosan in rat After an overnight fast, the rats were acclimatized in test chambers that have warm glass bottoms. Then he focused a radiant thermal stimulus (light beam) on the plantar surface of each hind paw in its turn, and an initial response time to a thermal stimulus was recorded for each animal. The light stimulus was automatically cut off by a photoelectric relay when the leg was moved or when the cut-off time was reached (20 seconds for radiant heat @ 5 Amp). Zymosan A (100 μL at 25 mg / mL) was injected subcutaneously into the subplantar tissue of the left hind paw of the rats to stimulate an acute inflammatory reaction. Three hours later, the response time of the animal to the thermal stimulus was evaluated and compared with the basal response time of the animals. Normally it was shorter and this was recorded as a percentage of hyperalgesia (% H). A cut-off value for% H (-75%) was used during the analysis to ensure that the animals were hyperalgesics. The test drug or vehicle was then dosed to the animals. In some points of time (normally 60 minutes) the response time of the animal to the thermal stimulus was re-evaluated.

Thermal hyperalgesia by CFA Intraplantar injection of complete Freund's adjuvant (CFA) in rodents produces a severe and prolonged inflammatory reaction, characterized by chronic hyperalgesia and pronounced thermal and mechanical stimuli. These effects reach a maximum between 24 and 72 hours after the injection and can last from several days until a few weeks. To determine the ability of the JNJ compounds to reverse thermal hyperalgesia, CFA (CFA: 1: 1 saline, 100 μL) was administered to the left hind paw of male Sprague-Dawley rats (200-350 g). After an incubation period of 24 hours, response latencies were obtained in the radiant heat leg (RH) stimulator apparatus, and compared with the baseline latencies (pre-CFA). The response is recorded automatically by the RH device when the rat raises its leg from the glass surface. Only rats that exhibited a reduction of at least 25% baseline response latency (ie, hyperalgesia) were included in further analysis. After the post-CFA latency determination, the test compound or vehicle (2.5 mL / kg) was orally administered to the rats. The percent reversion of hyperalgesia was calculated for each animal as (Response to treatment - Post-CFA response) / (Pre-CFA response - Post-CFA response) x 100. Therefore, a return to the normal pre-CFA thresholds was defined as 100% efficacy, while no change of the post-CFA thresholds was 0% efficacy. The average reversion% of hyperalgesia was then calculated for each treatment group (n = 6-8 rats / group). Subsequently, dose-response curves were obtained in the time of the maximum effect. DE5o values and associated statistics were calculated using PharmTools Plus software (The McCary Group).

TABLE 2 Biological data and mass spectrum Comp. KITOR KRMOR CE50% l GTPyS CEso% l MAIT Max. MS No. (nM) (nM) GTPyS hMOR GTPyS @ 150 μmol calculated original hDOR (nM) @ 10 μM DOR (nM) obs. 1 25.5 6410 > 10,000 30.8 391.28 390.230 2 0.91 2630 58.6 100 377.24 376.215 3 0.95 6790 47.0 1.00 50 363.22 362,199 4 0.39 301 552 9.00 7.1 511.34 510.252 25.3 1290 > 10,000 40 481.35 480.278 6 4.25 7914.5 128 73.3 417.33 416.246 7 25.7 9190 1,400 1.00 76.9 377.26 376.215 8 2.1 2820 620 1.00 63.6 403.28 402.231 9 > 100000 > 100000 363.00 362,199 > 100000 92530 523.0 522.088 11 317.35 5659 349.0 348.184 12 271.25 1805.5 417.1 416.246 13 143.35 1902.5 445.1 444.187 14 432.45 4822.5 403.1 402.231 2043.5 4753 403.1 402.231 16 60.93 1145.5 440.1 439.226 17 218.5 2477 429.1 428.221 18 1997 2421.5 485.1 484.236 19 368.25 2873.5 389.1 388.215 23335 247.7 453.2 452,246 22 45.4 2130.0 > 10,000 2.00 467.33 466.262 TABLE 2 (Continued) Comp. Ki rMOR Ki rMOR CE50% l GTPyS CE50% l MAIT Max. MS No. (nM) (nM) GTPyS hMOR GTPyS @ 150 μmol calculated original hDOR (nM) @ 10 μM DOR (nM) obs. 23 48.38 5555.5 245 403.2 402.231 24 0.57 5692.5 10.2 1.00 389.3 388.215 0.01 879.4 1.39 74.00 30 (@ 30) 469.0 468.241 26 5479 15.62 41.00 479.1 478.262 27 209 189 465.1 464,246 28 0.07 811 70.3 24.00 40 443.1 442.226 29 0.05 362 31.6 34.00 30 454.5 453.242 10.89 912 2.480 24.00 469.2 468.241 31 29.8 564 253 14.00 405.1 404.221 32 72.99 1493.75 335.4 334.168 33 16.53 5423.75 401.4 400.215 34 > 10000 > 10000 420.3 419,221 7.01 > 10000 271 17.00 407.0 406,226 36 0.79 > 10000 42.5 14.00 466.3 465.242 37 2.02 > 10000 921 5.00 406.9 406.171 38 31.82 5518 342 429.0 428.246 39 8.43 1682.5 94.9 447.4 446.257 40 11.98 > 10000 267 463.8 462,234 41 5198.15 > 10000 435.0 433,236 42 14.67 8792 266 4.00 364.9 364.22 43 10000 > 10000 379.2 378.231 44 0.15 77.17 0.873 28.00 480.3 479.13 TABLE 2 (Continued) Comp. Ki rDOR Ki rMOR CEso% l GTPyS CEso% I MAIT Max. MS No. (nM) (nM) GTPyS hMOR GTPyS @ 150 μmol calculated original hDOR (nM) @ 10 μM D? R (nM) obs. 45 4.57 > 100.00 14.3 433.4 432.57 46 0.88 > 100.00 4.79 468.60 468.60 47 4.5 48.30 125 59.23 539.4 538.71 48 0.90 > 100.00 18.8 66.7 405.4 404.58 49 25.0 > 100.00 252 459.7 458.67 50 10.2 > 100.00 236 493.5 492.75 51 4.85 > 100.00 62.8 449.2 448.63 52 0.61 > 100.00 4.44 66 50 389.3 388.22 53 50.09 > 100.00 257 2059 60 389.3 388.22 54 68.45 715 20 361.2 360.46 55 66.48 1855 > 1000 20 361.2 360.46 56 161,375 711.95 40 361.2 360.46 57 396.67 5262 361.3 360.46 58 1160.2 2978 375.3 374.48 59 10.56 3336.5 403 402.54 60 4,621 835.8 416.9 416.57 61 133.3 7180 188 40 404.9 404.58 62 2,958 739.1 8.35 33.3 404.9 404.58 63 107.5 1729 375.2 374.48 64 117.635 711.4 347.1 346.43 65 197,345 857.7 333.1 332.40 66 3.1205 2954 403.2 402.54 TABLE 2 (Continued) Comp. Ki rMOR Ki rMOR CE50% l GTPyS CEso% l MAIT Max. MS No. (nM) (nM) GTPyS hMOR GTPyS @ 150 μmol calculated original hDOR (nM) @ 10 μM D? R (nM) obs. 67 54.39 10887 403.2 402.54 68 0.740 1294 22 419.1 418.54 69 4.99 5830 126 407.1 406.50 70 2.31 5742.5 419.1 418.54 71 enant. 5.43 2771.5 468.9 468.60 A 72 enant. 0.170 375.03 468.9 468.60 B 73 11.98 884 77.9 403.4 402.54 74 3.79 848.15 485.0 484.67 75 0.122 200.34 485.0 484.67 76 1.70 284.5 5.91 405.1 404.51 77 1023 > 10000 419.1 418.54 78 473 472.53 79 473.1 472.53 80 259.65 472.6 377.3 376.52 81 77,565 837.65 377.4 376.52 82 44.4 3098 405.0 404.51 83 138.56 17720 467 467.41 84 2890 37790 465.2 464.61 85 3004.5 10700 466.1 465.60 TABLE 2 (Continued) Comp. Ki rMOR Ki rMOR CE50% l GTPyS CEso% l MAIT Max. MS No. (nM) (nM) GTPyS hMOR GTPyS @ 150 μmol calculated original hDOR (nM) @ 10 μM DOR (nM) obs. 86 1755 12525 455.1 454.57 87 12060 29025 421.1 520.70 88 1082.5 15250 554.2 553.70 89 1953 18670 466.2 465.60 90 836.15 12360 471.1 470.64 91 1351.5 6702 484.1 483.61 92 2.0925 2.093 55.3 389.2 388.51 93 > 10000 > 10000 454.4 453.59 94 2,279 674.2 14.1 467 467.41 95 25.45 6516.5 465.3 464.61 96 1,692 4224 35.3 466.1 465.60 97 1.7785 1806 13.3 455.1 454.57 98 24.54 7355 516.2 515.66 99 19,335 3488 12.5 471.0 470.64 100 0.27385 5.854 0.452 405.0 404.51 101 9.14235 532.3 19.3 466 465.60 102 68.03 2860 407.1 406.50 Ki rDOR: Rat brain delta opioid receptor binding Ki rMOR: Rat brain opioid mu rat opioid receptor binding hDOR: GTPyS functional test on human delta opioid receptor GTP hMOR: Functional test of GTPyS on human mu opioid receptor GTP DOR: Functional test of GTPyS in delta opioid receptor MAIT: Abdominal Irritation Test in Mouse Compounds 1 and 5, at 10 μM, do not significantly stimulate GTP binding. However, at 10 μM they inhibited the binding of GTP induced with 1 μM DPDPE, in 61% and 19%, respectively. The results indicate that these two compounds can be delta opioid receptor antagonists.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula (I): Formula (I) wherein: Ri and R are substituents independently selected from the group consisting of hydrogen and alkanyl of C? -8; R3 is selected from the group consisting of hydrogen, C -? - 8 alkanyl, C? -? - 3-alkanyl, C2-8 alkenyl, C2-s alkynyl, C3-8 cycloalkanyl, cycloalkanyl -alcanyl of C?,. 8 > alkyloxy (C? -8) -alkanyl of C? -8, alkanylthio (C? -8) -alkanyl of C1-8, hydroxyalkanil of C-.8, alkanoyloxy (C? -8) -carbonyl, hal ??? 3-alkanyl (C? -8) carbonyl, formyl, thioformyl, carbamimidoyl, phenylimino-alkanyl of C? .8) phenyl-alkanyl of C? -8, phenyl-alkenyl of C? .8, phenyl-alkynyl of C? -8, C? -8-naphthyl-alkanyl and C-? -8-heteroaryl-alkanyl; wherein the phenyl, naphthyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of alkanoyl of d-6, alkenyl of C 2-6, alkanoyloxy of C 1-6, amino, alkanyl (C-6) - amino, di (alkanyl (C? -6)) -amino, (C-? 6) -carbonyl, (C? -6) -carbonyloxy, (C? -6) -carbonylamino (C? 6) alkanoyl, C 1-6 alkanthio, C? -6-alkylsulphonyl, halogen, hydroxy, cyano, fluoroalkanyl , thioureido and fluoroalkannoxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion; wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -0 (CH2)? -3-0-; R4 is one to three substituents independently selected from the group consisting of: hydrogen, C1-6 alkanyl, C2-6 alkenyl, CI.T alkanoyloxy, amino, (C? -6) -amino, di (alkanyl) (C 1-6)) - amino, alkane (C? -6) -carbonyl, alkanyl Ci-.beta.-carbonyloxy, alkynyloxy (C.sub.1-6) -carbonyl, C.sub.1-6.alkanyl-aminocarbonyl , di (alkanyl (C? -6)) -aminocarbonyl, Ci-eJ-carbonylamino, alkanoylthio of C? .6, C6-C6-alkylsulfonyl, halogen, hydroxy, cyano, hydroxycarbonyl, C? -io aryl, chromanyl , chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiophenyl , fluoroalkanyl and fluoroalkannyloxy; or optionally, when R4 are two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -0 (CH2 )? - 3-0-; R5 is one or two substituents independently selected from the group consisting of: hydrogen, C6-6 alkanyl, C2-6 alkenyl, C-? 6 alkanoyloxy, amino, (C6-6) alkanyl- amino, di (alkanyl (C? -6)) amino, alkanyl (C? -6) -carbonyl, alkanyl (C? -6) -carbonyloxy, alkanoxy (C?, .6) -carbonyl, alkanyl (C1) -6) -aminocarbonyl, alkanyl (C? 6) -carbonylamino, C 1-6 alkanthio, C-? 6 alkylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl and fluoroalkannoxy; A is - (CH2) m-, where m is 0, 2 or 3; Y is - (CH2) nX- or -X (CH2) n-; X is O, or S; n is 0 or 1; Z is O, or S; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, further characterized in that Ri and R2 are substituents independently selected from the group consisting of hydrogen and C? -4 alkanyl.
3. The compound according to claim 1, further characterized in that R1 and R2 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl and propyl.
4. The compound according to claim 1, further characterized in that R1 and R2 are substituents independently selected from the group consisting of hydrogen and ethyl.
5. The compound according to claim 1, further characterized in that R3 is selected from the group consisting of hydrogen, C? -8 alkanyl, C2-8 alkenyl, C2-8 alkynyl, alkanoyloxy (C? -8) ) -alkanyl of C? -8, alkanylthio (C? .8) -alkanyl of C? 8, hydroxyalkanyl of C? -8, thioformyl, phenylimino-alkanyl of Ci-β, phenyl-alkanyl of C? -8, and Ci-β heteroaryl-alkanyl; wherein the phenyl and the heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkynyloxy and hydroxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the portion is selected from 0 (CH2)? -3-0.
6. The compound according to claim 1, further characterized in that R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propinyl, hydroxyethyl, thioformyl, phenyliminomethyl, phenethyl and heteroaryl-alkanyl of Cis; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group.
7. The compound according to claim 1, further characterized in that R3 is hydrogen or methyl, allyl, heteroarylmethyl.
8. The compound according to claim 1, further characterized in that R4 is one to three substituents independently selected from the group consisting of hydrogen, C? -6 alkanyl, C? -6 alkanoyloxy, alkanol (C? 6) -aminocarbonyl, alkanol (C6-6) -carbonylamino, halogen, hydroxy, C6- or aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, siatyl , isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl and thiophenyl.
9. The compound according to claim 1, further characterized in that R 4 is one to two substituents independently selected from the group consisting of hydrogen, C 1-4 alkanoy, C 1-4 alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, soxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy.
10. The compound according to claim 1, further characterized in that R4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromine, fluorine, 5- or 6-phenyl, 5- or 6- pyridinyl, 5- or 6-furanyl, and hydroxy.
11. The compound according to claim 10, further characterized in that Y is O, or S.
12. The compound according to claim 1, further characterized in that R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen.
13. The compound according to claim 1, further characterized in that R5 is hydrogen.
14. The compound according to claim 1, further characterized in that A is (CH2) or-2- 15. The compound according to claim 1, further characterized in that A is - (CH2) 2-. 16. The compound according to claim 1, further characterized in that X is O, or S. 17. The compound according to claim 1, further characterized in that n is 0. 18. The compound according to claim 1, further characterized in that Z is O. 19. A compound of formula (I): Formula (I) wherein: R-i is alkanyl of C? -3; R2 is C3 -3 alkanyl or hydrogen; R3 is selected from the group consisting of hydrogen, C?-8 alkanyl, C 2-8 alkenyl, C 2-8 alkynyl, C 8 alkanoyloxy, C 8 alkanyl, alkanthio 8) -alkanyl of C? -8, hydroxyalkanyl of C-? -8, thioformyl, phenylimino-alkanyl of C-? -8, phenyl-alkanyl of C -8 and heteroaryl-alkanyl of C -8; wherein the phenyl and the heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C6-6 alkanoyloxy and hydroxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the portion is selected from -0 (CH2) -3-0-; R4 is one to three substituents independently selected from the group consisting of hydrogen, C alcan-6 alkanyl, C?-6-alkanoyloxy, C¡-C)-C6-aminocarbonyl, C (-C6-alkanoylamino, halogen, hydroxy, C6-aryl , chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl and thiophenyl; R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen; A does not exist or is CH2CH2; And it is O, S, CH20, or OCH2; Z is O; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. 20. The compound according to claim 19, further characterized in that R-i is ethyl; R2 is ethyl or hydrogen; and R3 is benzo [1,3] dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl-methyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl , 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-yl-methyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, or thiophen-2-ylmethyl. 21. The compound according to claim 19, further characterized in that R-i is ethyl; R2 is ethyl; and R3 is benzo [1,3] dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl , furan-3-ylmethyl, H, Me, methylthioethyl, or phenethyl. 22. The compound according to claim 19, further characterized in that R-i is ethyl; R2 is ethyl; and R3 is H, benzo [1,3] dioxol-5-ylmethyl, 1- - / - imidazol-4-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl, or phenyliminomethyl. 23. The compound according to claim 19, further characterized in that R3 is hydrogen, methyl, allyl, or heteroarylmethyl. 24. The compound according to claim 19, further characterized in that R3 is hydrogen, methyl, allyl, or heteroarylmethyl; and R 4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl and hydroxy; and R5 is hydrogen. 25. A compound of formula (I): Formula (I) wherein R-i is alkanyl of C1..3; R is C -? - 3 alkanyl or hydrogen; R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, thioformyl, phenyliminomethyl, phenethyl and heteroaryl-alkanyl of C- | 8; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group; R 4 is one to two substituents independently selected from the group consisting of hydrogen, C 4 alkanyl, C 1-4 alkanoyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy; R5 is hydrogen; A is CH2CH2; And it is O, or S; Z is O; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. 26. The compound according to claim 25, further characterized in that R3 is hydrogen, methyl, allyl, or heteroarylmethyl. 27. The compound according to claim 25, further characterized in that R3 is hydrogen, methyl, allyl, or heteroarylmethyl; and R 4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinyl, 5- or 6-furanyl, and hydroxy; and R5 is hydrogen. 28. A compound of formula (I): Formula (I) selected from the group consisting of: a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 2 O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is 1-benzo [1,3] dioxol-5-ylmethyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is phenethyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is allyl, R4 is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R ^ is ethyl, R2 is ethyl, R3 is allyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is phenethyl, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is furan-3-yl-methyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R2 is ethyl, R3 is furan-3-yl-methyl, R4 is H, R5 is H, A does not exist, Y is 0, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is pyridin-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is 2-hydroxyphenyl-methyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is 1 -carbamimidoyl, R 4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is 1-prop-2-inium, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is methylcarbonylamino, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is hydroxyethyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is phenyliminomethyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is thioformyl, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is allyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methoxyethyl, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is methylthioethyl, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) in where R1 is ethyl, R2 is ethyl, R3 is methyl, R is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is pyridin-2-yl-methyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is 2-hydroxy-ethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is 1- / -imidazol-4-yl-methyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is OR; a compound of formula (I) in where Ri is ethyl, R 2 is ethyl, R 3 is benzo [1,3] dioxol-5-ylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R1. is ethyl, R 2 is ethyl, R 3 is cyclopropylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is methylthiopropyl, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is 2-hydroxy-ethyl, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein Rt is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 1-H-imidazol-4-yl-methyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is OR; a compound of formula (I) wherein R1 is ethyl, R2 is H, R is 2-methyl-but-2-enyl, R is H, R5 is H, A does not exist, Y is CH2O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 2-methyl-allyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is 4-hydroxy-3-methoxyphenyl-methyl, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is allyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is H, R 3 is 1,1,1-trichloroethoxycarbonyl, R 4 is H, R 5 is H, A does not exist, Y is CH 2 O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R2 is H, R3 is cyclopropylmethyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is H, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is phenethyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is phenethyl, R is H, R5 is H, A is CH2CH2, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is phenethyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is pyridin-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is thiophen-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R is H, R3 is H, R is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is methyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is sobutyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is n-propyl, R 2 is n-propyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is n-propyl, R2 is H, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is H, R 3 is H, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is H, R2 is H, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-methyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-methoxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-fluoro, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is 1-H-imidazol-5-ylmethyl, R4 is H, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is methyl, R 2 is n-butyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is 1-H-imidazol-4-ylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-hydroxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is trifluoromethylcarbonyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is H, R4 is H, R5 is H, A is CH2CH2, Y is S, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-hydroxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R is 7-bromo, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-phenyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-pyridin-4-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-furan-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-benzothiophen-2-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7- (N-α-butoxycarbonyl) pyrrol-2-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R is 7-pyridin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R is 7-thiophen-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 7- (3,5-dimethyl) isoxazol-4-yl, R5 is H, A is CH2CH2, Y is O , and Z is O; a compound of formula (I) wherein R 1 is methyl, R 2 is isopropyl, R 3 is H, R 4 is H, R 5 is H, A is CH CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 7-pyrrol-2-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-bromine, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-phenyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R is ethyl, R is ethyl, R3 is H, R4 is 5-pyridin-4-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-furan-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-quinolin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-thiophen-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R- is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-hydroxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-pyridin-3-yl, R 5 is H, A is CH CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-t is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-fluoro, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof. 29. A compound of formula (I): Formula (I) selected from the group consisting of: a compound of formula (I) in where R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; and a compound of formula (I) wherein Ri is ethyl, R 2 is H, R 3 is 1-H-imidazol-4-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z that; a compound of formula (I) wherein Ri is ethyl, R 2 is H, R 3 is 2-methyl-but-2-enyl, R 4 is H, R 5 is H, A does not exist, and is CH20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is 2-methyl-allyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is allyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is H, R4 is H, R is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is phenethyl, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is H, R 3 is pyridin-2-yl-methyl, R 4 is H, R 5 is H, A does not exist, Y is CH 20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is thiophen-2-yl-methyl, R4 is H, R5 is H, A does not exist, Y is CH20, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is H, R3 is H, R4 is H, R5 is H, A does not exist, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is 1H-imidazol-5-yl-methyl, R is H, R5 is H, A is CH2CH2, Y is O, and Z is OR; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-hydroxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is 1-H-imidazol-4-ylmethyl, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z that; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R is 5-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-pyridin-4-yl, R5 is H, A is CH2CH2, Y is 0, and Z is 0; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-furan-3-yl, R5 is H, A is CH2CH2, Y is O, and Z is 0; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 6-hydroxy, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is isopropyl, R 3 is H, R is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R ^ is ethyl, R2 is ethyl, R3 is H, R4 is 5-bromine, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is S, and Z is O; a compound of formula (I) wherein R-i is n-propyl, R 2 is n-propyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-fluoro, R 5 is H, A is CH 2 CH 2, Y is O, and Z is 0; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-pyridin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is isobutyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH, Y is O, and Z is O; a compound of formula (I) wherein R 1 is methyl, R 2 is n-butyl, R 3 is H, R 4 is H, R 5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-quinolin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-thiophen-3-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-phenyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-y is methyl, R 2 is isopropyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof. 30. A compound of formula (I): Formula (1) selected from the group consisting of: a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R is 5-hydroxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-methoxy, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-pyridin-4-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R is 5-furan-3-yl, R 5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R- is ethyl, R 2 is ethyl, R 3 is H, R 4 is 6-methyl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R 1 is ethyl, R 2 is ethyl, R 3 is H, R 4 is 7-fluoro, R 5 is H, A is CH CH 2, Y is O, and Z is O; a compound of formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is 5-pyridin-3-yl, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; a compound of formula (I) wherein R1 is ethyl, R2 is ethyl, R3 is H, R4 is 5-thiophen-3-yl, R5 is H, A is CH2CH2, Y is O, and Z is O; a compound of formula (I) wherein R-i is methyl, R 2 is isopropyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof. 31. A composition comprising the dextrorotatory enantiomer of a compound of formula (I): Formula (I) wherein R-i is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; wherein said composition is substantially free of the levorotatory isomer of said compound. 32. A composition comprising the enantiomer Levorotatory of a compound of formula (I): Formula (I) wherein Ri is ethyl, R 2 is ethyl, R 3 is H, R 4 is H, R 5 is H, A is CH 2 CH 2, Y is O, and Z is O; wherein said composition is substantially free of the dextrorotatory isomer of said compound. 33. A pharmaceutical composition comprising a compound, salt or solvate as defined in claim 1, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 34. A veterinary composition comprising a compound, salt or solvate as defined in claim 1, mixed with a veterinarily acceptable carrier, excipient or diluent. 35.- The use of a compound, salt or solvate as defined in claim 1, for preparing a medicament for the treatment or prevention of a disease or condition in a mammal, wherein said disease or condition is affected by the modulation of delta-opioid receptors. 36. The use claimed in claim 35, wherein said therapeutically effective amount comprises a dose scale of about 0.001 mg to about 1,000 mg. 37. The use claimed in claim 35, wherein said therapeutically effective amount comprises a dose scale of from about 0.1 mg to about 500 mg. 38. The use claimed in claim 35, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 39.- The use of a compound, salt or solvate as defined in claim 1, to prepare a medicament for the prevention or treatment of mild to severe pain in a mammal. 40.- The use claimed in claim 39, wherein the pain is selected from the group consisting of: inflammatory pain, centrally mediated pain, peripherally mediated pain, structure-related pain, cancer pain, pain related to injury of soft tissue, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic pain of headache, chronic pain of neuropathic conditions, chronic pain of conditions after stroke and pain chronic migraine 41.- The use claimed in claim 39, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, stinging snake, spider bite, insect bite, neurogenic bladder, hypertrophy benign prosthetics, interstitial cystitis, rhinitis, contact dermatitis / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain , postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome, postherpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache , peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, neuralgia migraineous, neur algia, diopatic, intercostal neuralgia, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinusitis headache, tension headache, labor, delivery, menstrual cramps and cancer. 42.- The use of a compound, salt or solvate as defined in claim 1, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease, and respiratory diseases in a mammal. 43. - The use claimed in claim 39, wherein said therapeutically effective amount comprises a dose scale of from about 0.001 mg to about 1,000 mg. 44. The use claimed in claim 39, wherein said therapeutically effective amount comprises a dose scale of about 0.1 mg to about 500 mg. 45. The use claimed in claim 39, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 46.- A device comprising, in one or more containers, an amount of the compound defined in claim 1, effective to treat or prevent mild to severe pain. 47. A pharmaceutical composition comprising a compound, salt or solvate as defined in claim 19, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 48. A veterinary composition comprising a compound, salt or solvate as defined in claim 19, mixed with a veterinarily acceptable carrier, excipient or diluent. 49.- The use of a compound, salt or solvate as defined in claim 19, for preparing a medicament for the prevention or treatment of mild to severe pain in a mammal. 50.- The use claimed in claim 49, wherein the pain is selected from the group consisting of: inflammatory pain, pain centrally mediated, peripherally mediated pain, structure-related pain, cancer pain, pain related to soft tissue injury, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic pain of headache, chronic pain of neuropathic conditions, chronic pain of post-stroke conditions and chronic migraine pain. 51.- The use claimed in claim 49, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, sting snake, spider bite, insect bite, neurogenic bladder, benign prosthetic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, pain phantom limb, postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome, postherpetic neuralgia, trigeminal neuralgia, cluster headache, headache of migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinusitis headache, tension headache, work of labor, delivery, menstrual cramps and cancer. 52.- The use of a compound, salt or solvate as defined in claim 19, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cancer pain, cardiovascular disease and respiratory diseases in a mammal. 53. The use claimed in claim 49, wherein said therapeutically effective amount comprises a dose scale of from about 0.001 mg to about 1,000 mg. 54. The use claimed in claim 49, wherein said therapeutically effective amount comprises a dose scale of about 0.1 mg to about 500 mg. 55. The use claimed in claim 49, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 56.- A device comprising, in one or more containers, an amount of the composition defined in claim 19, effective for Treat or prevent mild to severe pain. 57.- A pharmaceutical composition comprising a compound, salt or solvate as defined in claim 25, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 58.- A veterinary composition comprising a compound, salt or solvate as defined in claim 25, mixed with a veterinarily acceptable carrier, excipient or diluent. 59.- The use of a compound, salt or solvate as defined in claim 25, for preparing a medicament for the prevention or treatment of mild to severe pain in a mammal. 60.- The use claimed in claim 59, wherein the pain is selected from the group consisting of: inflammatory pain, centrally mediated pain, peripherally mediated pain, structure-related pain, cancer pain, pain related to injury of soft tissue, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic pain of headache, chronic pain of neuropathic conditions, chronic pain of conditions after stroke and pain chronic migraine 61.- The use claimed in claim 59, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, stinging snake, spider bite, insect bite, neurogenic bladder, hypertrophy benign prosthetics, interstitial cystitis, rhinitis, contact dermatitis / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain , postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome, postherpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache , peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, headache sinusitis, tension headache, labor, delivery, menstrual cramps and cancer. 62.- The use of a compound, salt or solvate as defined in claim 25, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease and respiratory diseases in a mammal. 63. - The use claimed in claim 59, wherein said therapeutically effective amount comprises a dose scale of from about 0.001 mg to about 1,000 mg. 64.- The use claimed in claim 59, wherein said therapeutically effective amount comprises a dose scale of about 0.1 mg to about 500 mg. 65. The use claimed in claim 59, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 66.- A device comprising, in one or more containers, an amount of the composition defined in claim 25, effective to treat or prevent mild to severe pain. 67.- A pharmaceutical composition comprising a compound, salt or solvate as defined in claim 28, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 68.- A veterinary composition comprising a compound, salt or solvate as defined in claim 28, mixed with a veterinarily acceptable vehicle, excipient or diluent. 69. The use of a compound, salt or solvate as defined in claim 28, for preparing a medicament for the prevention or treatment of mild to severe pain in a mammal. 70. The use claimed in claim 69, wherein the pain is selected from the group consisting of: inflammatory pain, pain centrally mediated, peripherally mediated pain, structure-related pain, cancer pain, pain related to soft tissue injury, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic pain of headache, chronic pain of neuropathic conditions, chronic pain of post-stroke conditions and chronic migraine pain. 71.- The use claimed in claim 69, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, stinging of snake, spider bite, insect sting, neurogenic bladder, benign prosthetic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, joint neuralgia mandibular, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre, meralgia paresthetica, urethral mouth syndrome, postherpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinusitis headache, tension headache, work of labor, delivery, menstrual cramps and cancer. 72.- The use of a compound, salt or solvate as defined in claim 28, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease and respiratory diseases in a mammal. 73.- The use claimed in claim 69, wherein said therapeutically effective amount comprises a dose scale, from about 0.001 mg to about 1,000 mg. 74. The use claimed in claim 69, wherein said therapeutically effective amount comprises a dose scale of about 0.1 mg to about 500 mg. 75. The use claimed in claim 69, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 76.- A device comprising, in one or more containers, an amount of the composition defined in claim 28, effective to treat or prevent mild to severe pain. 77. - A pharmaceutical composition comprising a compound, salt or solvate as defined in claim 29, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 78.- A veterinary composition comprising a compound, salt or solvate as defined in claim 29, mixed with a veterinarily acceptable vehicle, excipient or diluent. 79. The use of a compound, salt or solvate as defined in claim 29, for preparing a medicament for the prevention or treatment of mild to severe pain in a mammal. 80.- The use claimed in claim 79, wherein the pain is selected from the group consisting of: inflammatory pain, centrally mediated pain, peripherally mediated pain, pain related to the structure, pain of cancer, pain related to injury of soft tissue, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic pain of headache, chronic pain of neuropathic conditions, chronic pain of conditions after stroke and pain chronic migraine 81.- The use claimed in claim 79, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, stinging of snake, spider bite, insect bite, neurogenic bladder, benign prosthetic hypertrophy, interstitial cystitis, rhinitis, dermatitis contact / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, neuralgia of the mandibular joint, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome, postherpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy , postherpetic neuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, neural Morton's gia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinusitis headache, tension headache, labor, delivery, menstrual cramps and cancer. 82.- The use of a compound, salt or solvate as defined in claim 29, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease and respiratory diseases in a mammal. 83.- The use claimed in claim 79, where said therapeutically effective amount comprises a dose scale of from about 0.001 mg to about 1,000 mg. 84. The use claimed in claim 79, wherein said therapeutically effective amount comprises a dose scale of from about 0.1 mg to about 500 mg. 85. The use claimed in claim 79, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 86.- A device comprising, in one or more containers, an amount of the composition defined in claim 29, effective to treat or prevent mild to severe pain. 87.- A pharmaceutical composition comprising a compound, salt or solvate as defined in claim 31, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 88.- A veterinary composition comprising a compound, salt or solvate as defined in claim 31, mixed with a veterinarily acceptable vehicle, excipient or diluent. 89.- The use of a compound, salt or solvate as defined in claim 31, for preparing a medicament for the prevention or treatment of mild to severe pain in a mammal. 90. The use claimed in claim 89, wherein the pain is selected from the group consisting of: inflammatory pain, centrally mediated pain, peripherally mediated pain, pain related to the structure, pain of cancer, pain related to soft tissue injury, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic headache pain, chronic pain of neuropathic conditions , chronic pain of post-stroke conditions and chronic migraine pain. 91.- The use claimed in claim 89, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, stinging of snake, spider bite, insect sting, neurogenic bladder, benign prosthetic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis / hypersenvity, itching, eczema, pharyngitis, mucos, enteritis, cellulitis, causalgia, sciatic neuritis, joint neuralgia mandibular, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome , postherpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, neur peripheral opathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, neuralgia intercostal, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinus headache, tension headache, labor, delivery, menstrual cramps and cancer. 92.- The use of a compound, salt or solvate as defined in claim 31, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease and respiratory diseases in a mammal. 93. The use claimed in claim 89, wherein said therapeutically effective amount comprises a dose scale of from about 0.001 mg to about 1,000 mg. 94. The use claimed in claim 89, wherein said therapeutically effective amount comprises a dose scale of about 0.1 mg to about 500 mg. 95. The use claimed in claim 89, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 96.- A device comprising, in one or more containers, an amount of the compoon defined in claim 31, effective to treat or prevent mild to severe pain. 97.- A pharmaceutical compoon comprising a compound, salt or solvate as defined in claim 32, mixed with a pharmaceutically acceptable carrier, excipient or diluent. 98.- A veterinary compoon comprising a compound, salt or solvate as defined in claim 32, mixed with a veterinarily acceptable vehicle, excipient or diluent. 99. - The use of a compound, salt or solvate as defined in claim 32, for preparing a medicament for the prevention or treatment of mild to severe pain in a mammal. 100.- The use claimed in claim 99, wherein the pain is selected from the group consisting of: inflammatory pain, centrally mediated pain, peripherally mediated pain, pain related to the structure, pain of cancer, pain related to soft tissue injury, pain related to progressive disease, neuropathic pain and acute pain of acute injury, acute pain of trauma, acute pain of surgery, chronic pain of headache, pain Chronic neuropathic conditions, chronic pain of post-stroke conditions and chronic migraine pain. 101. The use claimed in claim 99, wherein the pain is caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, dental pain, burns, sunburn, stinging of snake, spider bite, insect bite, neurogenic bladder, benign prosthetic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis / hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, neuritis sciatica, neuralgia of the mandibular joint, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot, reflex sympathetic dystrophy syndrome Guillain-Barre, meralgia paresthetica, mouth syndrome burning, postherpetic neuralgia, trigeminal neuralgia, headache, cluster migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, posfebril neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, neuralgia red, neural Sluder's syndrome, splenopalatine neuralgia, supraorbital neuralgia, vidial neuralgia, sinusitis headache, tension headache, labor, delivery, menstrual cramps and cancer. 102.- The use of a compound, salt or solvate as defined in claim 32, for preparing a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: depression, Parkinson's disease, abuse of drugs, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease and respiratory diseases in a mammal. 103.- The use claimed in claim 99, where 65 said therapeutically effective amount comprises a dose scale of from about 0.001 mg to about 1,000 mg. 104. - The use claimed in claim 99, wherein said therapeutically effective amount comprises a dose scale of about 0.1 mg to about 500 mg. 105. The use claimed in claim 99, wherein said therapeutically effective amount comprises a dose scale of about 1 mg to about 250 mg. 106.- A device comprising, in one or more containers, an amount of the composition defined in claim 32, effective to treat or prevent mild to severe pain. 107.- A compound of formula (I): Formula (I) wherein: Ri and R2 are substituents independently selected from the group consisting of hydrogen and alkanyl of C-i-s; R3 is selected from the group consisting of hydrogen, alkanyl C -8, halo? -? - 3-C aIcanilo -8, C2-8 alkenyl, C2-8 alkynyl, cycloalkanyl C3-8, cicloalcanil-? C -? - 8 alkanyl, C? -8 alkanoyloxy, C? -8 alkanyl, Cis-8-alkanoyl, Cis-alkenyl, hydroxyalkanyl of C1.8, alkanyloxy (C? -8) -alkoxycarbonyl, hal ??. 3-alkanyl (C? 8) alkoxycarbonyl, formyl, tioformilo, carbamimidoyl, phenylimino-alkanyl C?,. 8, phenyl-alkanyl C? -8, C? -8 phenyl-alkenyl, C? -8 phenyl-alkynyl, C? -8-naphthyl-alkanyl and C? -8-heteroaryl-alkanyl; wherein the phenyl, naphthyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of alkanyl C -? - 6, C2-6alkenyl, C -6 alkanyloxy, amino, alkanyl (C-? 6) -amino, di (aIcanl (C-? 6)) -amino, (C? -6) -carbonyl, (C-? 6) -carbonyloxy, alkanyl (C -? - 6) -carbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl, thioureido and fluoroalkannoxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the fused portion is selected from the group consisting of - (CH2) 3- 5- and -0 (CH2)? -3-0-; R is one to three substituents independently selected from the group consisting of hydrogen, C-i-β alkanyl, C 2-6 alkenyl, C-α-6 alkanoyloxy, amino, alkanyl (C? -6) -amino, di (alkanyl (C? -6)) -amino, (C1-6) alkanoylcarbonyl, (C1-6) alkanoylcarbonyl, alkanoyloxy (C? 6) -carbonyl, (C 1-6) alkane-aminocarbonyl, di (C 1-6) alkanoyl-aminocarbonyl, (C 6,6) -carbonylamino, C 1-6 alkanthio, C 1-6 alkylsulfonyl -6, halogen, hydroxy, cyano, hydroxycarbonyl, C6-aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiophenyl, fluoroalkanyl and fluoroalkanyloxy; or optionally, when R4 are two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the fused portion is selected from the group consisting of - (CH2) 3-5- and -0 (CH2 )? - 3-0-; R5 is one to two substituents independently selected from the group consisting of hydrogen, C1-6 alkanyl, C2-6 alkenyl, C1-6 alkanoyloxy, amino, (C6-6) -amino, d-alkylene ^ -amino, alkanyl (C? -6) -carbonyl, alkanol C? eJ-carbonyloxy, alkanoyloxy (C? -6) -carbonyl, alkanyl (C? -6) -aminocarbonyl, alkanyl (C? -6) -carbonylamino , C, 6 alkanthio, C, C6 alkylsulfonyl, halogen, hydroxy, cyano, fluoroalkanyl and fluoroalkanyloxy; A is - (CH2) m-, where m is 2 or 3; Y is - (CH2) nX- or -X (CH2) n-; X is O or S; n is 0 or 1; Z is O, or S; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof. 108. The compound according to claim 107, further characterized in that Ri and R2 are substituents independently selected from the group consisting of hydrogen and alkanyl of C-u. 109. The compound according to claim 107, further characterized in that Ri and R2 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl and propyl. 110.- The compound according to claim 107, further characterized in that R-i and R2 are selected substituents independently of the group consisting of hydrogen and ethyl. 111. The compound according to claim 107, further characterized in that R3 is selected from the group consisting of hydrogen, C-_ 8 alkanyl, C2.8 alkenyl, C2-8 alkynyl, alkynyloxy (C--8) ) -alkanyl of Ct-8, alkanylthio (C? -8) -alkanium of C 1-8, hydroxyalkanil of C? -8, thioformil, phenylimino-alkanyl of C 1-8, phenyl-alkanyl of C? -8, and heteroaryl -alkanyl of C? -8; wherein the phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C-i-β alkanoyloxy and hydroxy; or optionally, when the phenyl and the heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the portion is selected from 0 (CH2)? -3-0. The compound according to claim 107, further characterized in that R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methy1-allyl, propynyl, hydroxyethyl, thioformyl, phenyliminomethyl, phenethyl and heteroaryl-C-acyl. -? - 8; wherein the phenyl in any phenyl-containing substituent is optionally substituted with a hydroxyl group. 113. The compound according to claim 107, further characterized in that R3 is hydrogen or methyl, allyl, heteroarylmethyl. 114. The compound according to claim 107, further characterized in that R4 is one to three substituents independently selected from the group consisting of hydrogen, C1-6 alkanyl, C6 -6 alkanoyloxy, (C-? - 6) -alkyloxycarbonyl, C6-C5-alkanoylaminocarbonyl, halogen, hydroxy, C6-? oaryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl and thiophenyl. The compound according to claim 107, further characterized in that R4 is one to two substituents independently selected from the group consisting of hydrogen, C? -4 alkanyl, C? - alkanoyloxy, halogen, phenyl, furanyl, imidazolyl , indazolyl, indolyl, ndolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thiophenyl and hydroxy. The compound according to claim 107, further characterized in that R4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6- pyridinyl, 5- or 6-furanyl and hydroxy. 117. The compound according to claim 10, further characterized in that Y is O, or S. The compound according to claim 117, further characterized in that R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen. 119.- The compound according to claim 107, further characterized in that R5 is hydrogen. 120. The compound according to claim 107, further characterized in that A is (CH2) 0-2. 121. The compound according to claim 107, further characterized in that X is O, or S. 122. The compound according to claim 107, wherein n is 0. 123.- The compound according to the claim 107, wherein Z is O. 124.- A compound of formula (I): Formula (I) wherein R 1 is C 3 alkanyl; R 2 is C 4 alkanyl or hydrogen; R3 is selected from the group consisting of hydrogen, alkanoyl of C? -8, alkenyl of C2-8, alkynyl of C2-8, alkanoyloxy (C? -8) -alkanyl of C1-8, alkanoyl (C1-8) - C1-8 alkenyl, hydroxyalkanyl of C- | 8, thioformyl, phenylimino-alkanyl of C? -8, phenyl-alkanyl of C 1-8, and heteroaryl-alkanyl of C? -8; wherein the phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1.6 alkanoyloxy and hydroxy; or optionally, when phenyl and heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused portion, wherein the portion is selected from -0 (CH2)? -30-; R4 is one to three substituents independently selected from the group consisting of hydrogen, Ci-β alkanyl, C -6 alkanoyloxy, alkane (C- | ..6) -aminocarbonyl, (C6-6) -carbonylamino , halogen, hydroxy, C6-aryl, chromanyl, chromanyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolium, thiazolyl and thiophenyl; R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen; A is CH2CH2; And it is O, S, CH20, or OCH2; Z is O; and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof. 125. The compound according to claim 124, further characterized in that R-i is ethyl; R2 is ethyl or hydrogen; and R3 is benzo [1,3] dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl-methyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl , 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-yl-methyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, or thiophen-2-ylmethyl. 126. The compound according to claim 124, further characterized in that R-i is ethyl; R2 is ethyl; and R3 is benzo [1, 3] dioxol- 5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, or phenethyl. 127. The compound according to claim 124, further characterized in that R-i is ethyl; R2 is ethyl; and R3 is H, benzo [1, 3] dioxol-5-ylmethyl, 1-H-imidazol-4-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl, or phenyliminomethyl. 128. The compound according to claim 124, further characterized in that R3 is hydrogen, methyl, allyl, or heteroarylmethyl. 129. The compound according to claim 124, further characterized in that R3 is hydrogen, methyl, allyl, or heteroarylmethyl; and R 4 is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, bromo, fluoro, 5- or 6-phenyl, 5- or 6-pyridinium, 5- or 6-furanyl, and hydroxy; and R5 is hydrogen.