NOVEL THIO-AMINOTETRALIN COMPOUNDS USEFUL IN PAIN MANAGEMENT

Abstract: The present invention relates to novel thio-aminotetralin compounds of formula (I) wherein Z, X, R1, R2, R3, R4, R5, and R6 are defined herein. The compounds are useful in pain management.

Description: NOVEL THIO-AMINOTETRALIN COMPOUNDS USEFUL IN PAIN MANAGEMENT FIELD OF THE INVENTION The present invention is related to compounds that exhibit analgesic activity and in particular compounds exhibiting analgesia due to their opioid receptor affinity. BACKGROUND OF THE INVENTION Many natural alkaloids and related analogs bind to specific opioid receptors and elicit an analgesic response similar to classic narcotic opiates. Many different types of opioid receptors have been shown to coexist in higher animals. For example, see W. Martin et al., J. Pharmacol. Exp. Ther.. 197. p. 517 (1975) ; and J. Lord et al., Nature (London). 257. p.495 (1977). Three different types of opioid receptors have been identified. The first, δ, shows a differentiating affinity for enkephalin-like peptides. The second, μ, shows enhanced selectivity for morphine and other polycyclic alkaloids. The third, K, exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin. In general, the μ receptors seem to be more involved with analgesic effects. The δ receptors appear to deal with behavioral effects, although the δ and the K receptors may also mediate analgesia. Each opioid receptor, when coupled with an opiate, causes a specific biological response unique to that type of receptor. When an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects. The less specific and selective an opiate may be, the greater the chance of causing increased side effects by the administration of the opiate. Opiates can cause serious and potentially fatal side effects. Side effects such as respiratory depression, tolerance, physical dependence capacity, and precipitated withdrawal syndrome are caused by nonspecific interactions with central nervous system receptors. See K. Budd, In International Encyclopedia of Pharmacology and Therapeutics ; N.E. Williams and H. Wilkinson, Eds., Pergammon : (Oxford), 1 12, p.51 ( 1983). It is therefore an object of the present invention to provide compounds having analgesic effects but having as few side- effects as possible. DESCRIPTION OF THE INVENTION In one aspect, the present invention provides novel thio aminotetralin compounds represented by formula (I): and pharmaceutically acceptable derivatives thereof; wherein; Z is S, SO or SO 2 , X is selected from anyone of (i) a bond; (ii) -CR 7 Rs- wherein R 7 and R» are independently selected from the group consisting of H , OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- 6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N; and COOR c wherein R e is C 2- 6alkenyl or C 2- 6alkynyl; R and Rg can also be connected to form C 3-8 cycloalkyl, a C 3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms; Ri is selected from the group consisting of H, Cι.ι alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ι 2 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ι 2 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6- i2 aryl> C 6 .i 2 aralkyl, C 6 -i 2 aryloxy, C M ? acyl, heteroaryl having from 6 to 12 atoms, and phosphoryl; R 2 and R 3 are independently selected from the group consisting of Cι. 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C -6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6 -i 2 aryl, C 6- i 2 aralkyl, heteroaryl having from 6 to 12 atoms, and H; or R 2 and R 3 may together form a saturated heterocycle of from 3 to 8 atoms; R and R 5 are independently selected from the group consisting of Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H; R 4 and Rs can also be connected to form C 3-8 cycloalkyl, a C 3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms; Re is hydrogen, OH, Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O- . 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O-C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O-C 2- 6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, halogen, CN, COOH, CONH 2 , amino, nitro, or SH; with the provisos that: 1) not both R 4 and R 5 are H; and 2) at least one of R 2 and R 3 is H or Cι -6 alkyl. The compounds of the present invention are useful in therapy, in particular as analgesics. In another aspect, there is provided a method of treating pain in a mammal, comprising administering to said mammal an analgesic amount of a compound or composition of the invention. Still another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the treatment of pain. In another aspect, there is provided pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers, diluents or adjuvants. X is preferably -CR 7 Rβ- wherein R 7 and Rs are independently selected from the group consisting of OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, Cι. 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, H, and COORc wherein R e is Cι -6 alkyl; R and Rg can also be connected to form a C 3 . 8 cycloalkyl. X is more preferably -CR Rs- wherein R 7 and Rg are independently selected from the group consisting of -β alkyl, and H. X is most preferably -CH 2 -. Ri is preferably selected from the group consisting of H, Ci.i ∑ alkyi, C 6 -ι 2 aryl, and C 6- i2 aralkyl. Ri is more preferably selected from the group consisting of Cι. 6 alkyl, C 6- i 2 aryl, and C 6- i2 aralkyl. Ri is most preferably Cι. 6 alkyl. Ri can also be , wherein n is an integer between 1 to 5, Rx and Rxi are independently H, Cι -6 alkyl, C 2-6 alkenyl or C 2 . 6 alkynyl. More preferably, n is 1 or 2 and Rx and Rxi are Cι -6 alkyl. Most preferably, Rx and R i are methyl or ethyl. In an alternative embodiment, Ri is selected from the group consisting of CH 3 , -(CH 2 )π-CH 3 , and -(CH 2 )„-O-CH 3 wherein n is an integer selected between 1 and 5. In an alternative preferred embodiment Ri is C 6-12 aryl or heteroaryl having from 6 to 12 atoms. In a further preferred embodiment, Ri is selected from the group consisting of wherein A is selected from the group consisting of Cι -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O-Cι -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, , S-C 1-6 alkyl, S-C 2-6 alkenyl, S-C 2-6 alkynyl, N- .6 alkyl, N-C 2 . 6 alkenyl, N-C 2-6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is Cι -6 alkyl, C 2-6 alkenyl or C -6 alkynyl. In an alternative embodiment, Ri is C 6 -ι 2 aralkyl or heteroaryl having from 6 to 12 atoms. More preferably, Ri is selected from the group consisting of wherein A is selected from the group consisting of Cι -6 alkyl, Q^alkyl, C 2- 6alkenyl, C 2-6 alkynyl, O-C, -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, , S-Cι -6 alkyl, S-C 2-6 alkenyl, S-C 2-6 alkynyl, N-C 1-6 alkyl, N-C 2-6 alkenyl, N-C 2-6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is Cι -6 alkyl, C 2- 6alkenyl or C 2- 6alkynyl and Y is -(CH 2 ) m - wherein m is an integer selected between 1 and 5. Ri is preferably or wherein A and Y are as defined above. A is preferably selected from the group consisting of Cι -6 alkyl, O-Cι -6 alkyl, S-Ci-β alkyl, OH, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR a wherein R a is Cι -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl. A is more preferably selected from the group consisting of Cι -6 alkyl, OH, nitro, amino, aminoamidino, amidino, guanido, and COOH. A is most preferably selected from the group consisting of amidino, guanido, and OH. R 2 and R 3 are preferably H. R 4 and R 5 are preferably Cμ alkyl substituted by a hydroxyl. R» and Rs are preferably C )- alkyl. In a further preferred embodiment, R 4 and R 5 are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl. R 4 and R 5 are preferably ethyl. R 4 and R 5 are preferably methyl. R_ can be substituted at any position on the aromatic ring. More preferably Re is adjacent to the carbon bearing the OH. In an alternative embodiment, the present invention provides compounds of the formula (II) or (D ) (ID (ffl) and pharmaceutically acceptable derivative; wherein each of X, Z, Ri, R 2 , R3, R 4 , R 5 , and R^ are defined above. R is preferably, H, methyl, halogen or OR b wherein R b is Cι -6 alkyl, Cι. 6 alkenyl or Cι -6 alkynyl. Re is most preferably H. The compounds of the present invention contains at least 2 chiral centers which are marked by an asterik (*) on the general formula (I). The compounds of formula (I) thus exist in the form of different geometric( i.e. trans and cis) and optical isomers (i.e. (+) or (-) enantiomers). When there is 2 chiral centers at the position marked by the asteriks, the compounds may therefore be in the form of cis isomers or trans isomers. Each cis or trans isomers also exists as a (+) and (-) enantiomer. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. Preferably the compounds of the present invention are in the form of the trans isomers. More preferably the compounds of the present invention are present in the form of trans (+) and trans (-) enantiomers. Preferred compounds of the invention include:Trans-7-Amino-8,8-dimethyl-6- methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol (compound #l);Cis-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen- 2-ol (compound #2); Trans-7-Amino-8,8-diethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen- 2-ol (compound #3);Trans-7-Amino-8,8-dimethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2- ol (compound #4); Trans-7-Amino-8,8-dimethyl-6-(pyridin-2-ylsulfanyl)-5,6J,8-tetrahydro- naphthalen-2-ol (Compound #5); Trans-7-Amino-8,8-dimethyl-6-(pyrimidin-2-ylsulfanyl)-5,6J,8-tetrahydro-naphthalen-2-ol (Compound #6); Trans-7-Amino-6-(3-amino-phenylsulfanyl)-8,8 dimethyl-5,6,7,8-tetrahydro-naphthalen-2- ol (Compound #7); Trans-7-Amino-8,8-dimethyl-6-(4-methylsulfanyl-phenylsulfanyl)-5,6,7,8-tetrahydro- naphthalen-2-ol (Compound #8); Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-diethyl-5,6,7,8-tetrahydro- naphthalen-2-ol (Compound #9); Trans-2-(3-Amino-4,4-diethyl-6-hydroxy- 1 ,2,3 ,4-tetrahydro-naphthalen-2-ylsulfanyl)- acetamide (Compound #10); Trans-(3-Amino-4,4-diethyl-6-hydroxy-l,2,3,4-tetrahydro-naphthalen-2-ylsulfanylmethyl)- phosphonic acid diethyl ester (Compound #11); Trans-7-Amino-8,8-diethyl-6-(2-hydroxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #12); Trans-7-Amino-6-(5-amino-2H-[lJ,4]triazol-3-ylsulfanyl)-8,8-diethyl-5,6J,8-tetrahydro- naphthalen-2-ol (Compound #13); Trans-7-Amino-6-(2-amino-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #14); Trans-7-Amino-6-(5-amino-2H-[l,2,4]triazol-3-ylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydro-naphthalen-2-ol (Compound #15); Trans-7-Amino-8,8-dimethyl-6-propylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #16); Trans-7-Amino-6-isopropylsulfanyl-8,8-dimethyl-5,6J,8-tetrahydro-naphthalen-2-ol (Compound #17); Trans-7-Amino-6-(2-hydroxy-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2- ol (Compound #18); Trans-2-(3-Amino-6-hydroxy-4,4-dimethyl-lJ,3,4-tetrahydro-naphthalen-2-ylsulfanyl)- acetamide (Compound #19); Trans-7-Dimethylamino-8,8-dimethyl-6-methylsulfanyl-5,6J,8-tetrahydro-naphthalen-2-ol (Compound #20); 8,8-dimethyl-trans-7-methylamino-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #21); Trans-7-Amino-8,8-diethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #22); 8,8-dimethyl-trans-6-phenylsulfanyl-7-propylamino-5,6J,8-tetrahydro-nahthalen-2-ol (Compound #23); Trans-7-Amino-6-(2-amino-phenylsulfanyl)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #24; Trans-7-Amino-8,8-dimethyl-6-(2J,2-trifluoro-ethylsulfanyl)-5,6J,8-tetrahydro- naphthalen-2-ol Compound #25); Trans-4-(3-Amino-6-hydroxy-4,4-dimethyl-l,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)- butyric acid ethyl ester (Compound #26); Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-dimethyl-5,6J,8-tetrahydro- naphthalen-2-ol (Compound #27); Trans-7-Amino-8,8-dimethyl-6-(3-phenyl-allylsulfanyl)-5,6J,8-tetrahydro- naphthalen-2- ol (Compound #28); Trans-7-Amino-6-isobutylsulfanyl-8,8-dimethyl-5,6J,8-tetrahydro-naphthalen-2-ol (Compound #29); Trans-7-Amino-8,8-dimethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2- ol (Compound #30); Trans-7-Amino-8,8-diethyl-6-(2-phenoxy-ethylsulfanyl)-5,6J,8-tetrahydro-naphthalen-2-ol (Compound #31); (-)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #32); (+)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #33);Trans-7-amino-6-(4-bromo-phenylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydronaphthalen-2-ol (Compound #34); Trans-7-amino-8,8-dimethyl-6-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2- ol (Compound #35);Trans7-Amino-6-(4-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydro-naphthalen-2-ol (Compound #36);Trans-7-amino-6-(4-amino-phenylsulfanyl)- 8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #37);Trans-7-amino-6-(3- hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6J,8-tetrahydro-naphthalen-2-ol (Compound #38);Trans-3-(3-Amino-6-hydroxy-4,4-dimethyl- 1 ,2,3 ,4-tetrahydro-naphthalen-2- ylsulfanyl)-propionic acid ethyl ester (Compound #39);Trans-7-amino-8,8-dimethyl-6- phenethylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #40) ;Trans-2-(3-amino- 6-hydroxy-4,4-dimethyllJJ,4-tetrahydronaphthalen-2-ylsulfanyl)-propionamide (Compound #41);Trans-3-(3-amino-6-hydroxy-4,4-dimethyl- 1 ,2,3,4-tetrahydro- naphthalen-2-ylsulfanyl)-propionic acid (Compound #42);Trans-2-[3-(3-Amino-6- hydroxy-4,4-dimethyl- 1 JJ,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionylamino]-3-(4- hydroxy-phenyl)-propionamide (Compound #43); 3-trans-(2-ethoxycarbonyl-ethylsulfanyl)- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3,4-tetrahydro- naphthalen-2-yl (Compound #44); 3-trans-(2-carboxy-ethylsulfanyl)- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3 ,4-tetrahydro-naphthalen-2-yl (Compound #45); and pharmaceutically acceptable derivatives thereof; wherein said compound is in the form of the (+) enantiomer, the (-) enantiomer and mixture of the (+) and (-) enantiomer including racemic mixture. More preferably the compound of the present invention is selected from the group consisting of compound#l, compound#3, compound#4, compound#5, compound#9, compound#ll, compound#15, compound#31, compound#32, compound#33, compound#36, compound#37, compound#39 compound#41, compound#43, compound #44 and compound #45. Most preferably the compound of the present invention is selected from the group consisting of compound#l, compound#3, compound#5, compound#32, compound#33, compound#36, compound #44 and compound #45. As used in the present application the term "pain" represents "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. The term "pain" also includes "acute pain" and chronic pain. Acute pain is usually immediate and of a short duration. Acute pain can be present further to an injury, short-term illness, or surgical/medical procedure. Examples of acute pain include a burn, a fracture, an overused muscle, or pain after surgery. Cancer pain may be long-lasting but acute due to ongoing tissue damage. Some chronic pain is due to damage or injury to nerve fibers themselves (neuropathic pain). Chronic pain can result from diseases, such as shingles and diabetes, or from trauma, surgery or amputation (phantom pain). It can also occur without a known injury or disease. The present invention s directed to the treatment of all type of pain, including acute and chronic pain. As used in this application, the term "alkyl" represents an unsubstituted or substituted (by a halogen, nitro, aminoamidino, amidino, guanido, CONH 2 , COOH, O-Cι -6 alkyl, O-C -6 alkenyl, O-C 2 . 6 alkynyl, amino, hydroxyl or COOQ, wherein Q is Ci-β alkyl, C -6 alkenyl, a C -6 alkynyl) straight chain, branched chain, or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, flurohexyl or cyclopropyl). The term alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably, the halogen is fluoro (e.g., CF 3 -, or CF 3 CH 2 -). The term "saturated heterocycle" represents a carbocyclic ring in which one or more of the from 3 to 8 atoms of the ring are elements other than carbon, such as N, S and O; The term "aryl" represents an aromatic ring having from 6 to 12 carbon atoms, which may be substituted by a Cι -6 alkyl, C 2 . 6 alkenyl, a C 2-6 alkynyl, halogen, nitro, aminoamidino, amidino, guanido, CONH 2 , COOH, O-Cι -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, amino, hydroxyl or COOQ, wherein Q is Cι -6 alkyl, C 2-6 alkenyl, a C 2-6 alkynyl, such as phenyl and naphthyl. The term "aralkyl" represents an aryl group attached to the adjacent atom by a Ci-βalkyl, Ci-βalkenyl, or Cι. 6 alkynyl(e.g., benzyl). The term "aryloxy" represents an aryl or aralkyl moiety covalently bonded through an oxygen atom (e.g., phenoxy). The term "heteroaryl" represents an aromatic ring in which one or more of the from 6 to 12 atoms in the ring are elements other than carbon, such as O, N, and S (e.g pyridine, isoquinoline, or benzothiophene). The term "acyl" refers to a radical derived from a carboxylic acid, substituted (by halogen(F, Cl, Br, I), C 6-2 o aryl or Cι -6 alkyl) or unsubstituted, by replacement of the OH group. Like the acid to which it is related, an acyl radical may be aliphatic or aromatic, substituted (by halogen, . 5 alkoxyalkyl, nitro or OH) or unsubstituted, and whatever the structure of the rest of the molecule may be, the properties of the functional group remain essentially the same (e.g., acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, trifluoroacetyl, chloroacetyl, and cyclohexanoyl). The term "phosphoryl" represents a radical derived from a phosphono moeity in which the hydrogen atom of at least one of the -OH can be replaced by Cι -6 alkyl, C 2 - 6 alkenyl, C 2- 6alkynyl, Cι.6heteroalkyl, C 6 -i2 aryl, C 6- i2 aralkyl, and C 6 -ι 2 heteroaryl(e.g., diethoxyphosphorylmethyl). The term "halogen" encompasses chloro, fluoro, bromo and iodo; In the present application the following abbreviations are used: AcOEt ethyl acetate Boc t-butyloxycarbonyl DMAP 4-dimethylaminopyridine DME ethylene glycol dimethylether DMF dimethylformamide Et 2 O ether Hex hexane HPLC high performance liquid chromatography LAH lithium aluminium hydride LHMDS lithium bis(trimethylsilyl)amide NHMDS sodium bis(trimethylsilyl)amide Ph phenyl PPTS pyridium / oluenesulfonate PTSA /7-toluenesulfonic acid r.t. room temperature sat. saturated TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography When there is a sulfur atom present, the sulfur atom can be at different oxydation level, S, SO, or SO 2 . All such oxydation level are within the scope of the present invention. In yet another aspect of the invention, there is provided a process for preparing compounds of formula (I). The process is described in scheme 1 wherein each of X, Ri, R 2 , R3, R4, R 5 and Re are as defined above and P, PI, P2, and P3 are protecting groups. If desired, the sulfur of the compound of formula la can be oxydized to S=O or SO 2 by methods well known in the art. SCHEME 1 ( la) Step 1 The starting ketone AA was dissolved in a suitable solvent such as DMF, acetonitrile, THF, DME and was treated with sodium hydride or any other base such as potassium t- butoxide, sodium bis(trimethylsilyl)amide. The resulting mixture was then treated with ethyl iodide or any other alkyl halide such as methyl iodide, allyl bromide, diiodobutane to produce the compound A. Step 2 The compound A was dissolved in a suitable solvent such as pyridine, DMF, ethanol and was treated with hydroxylamine hydrochloride or any other hydroxylamine salt such as hydroxylamine sulfate, hydroxylamine bromide to produce the compound B. Step 3 The compound B was dissolved in a suitable solvent as THF, dioxane, DME, and was treated with LAH or any other reducing agent such as red-Al in presence of diethylamine or any other amine such as methylbutylamine, dipropylamine. The mixture was then heated to 50°C or at any higher temperature to produce the compound C. Step 4 The compound C in was dissolved in a suitable solvent as dichloromethane (CH 2 C1 2 ) or in any other solvent such as dichloroethane, and was treated with BBr 3 or any other demethylating agent such as BC1 3 , HBr, to produce the compound D. Step 5 The amino or hydroxyl groups of the compound D were protected with Boc or with any other protecting group, to produce the compound E. Protective groups are described in Protective Groups in Organic Synthesis. 2nd ed., Greene and Wuts, John Wiley & Sons, New York, 1991 which is herein incorparated by reference. Step 6 The compound E was dissolved in a suitable solvent such as ethanol or in any other alcohol such as methanol, propanol, butanol and was treated with pyridinium p-toluenesulfonate (PPTS) or any other acid or Lewis acid such as HC1, BF 3 .OEt 2 , PTSA, to produce the compound F. Alternatively, a non alcoholic solvent can be used in combination with an appropriate amount of an alcohol and a suitable Lewis acid such as ytterbium triflate see for example Tetrahedron Letters, Vol. 37, No.43, pp7717-7720, 1996 which is herein incorparated by reference. Step 7 The protecting groups of the compound F were removed under appropriate conditions e.g. with TFA or with any other acid such as HC1, PTSA, to produce the compound la. It will be appreciated that certain substituents require protection during the course of the synthesis and subsequent deprotection. For example, it may be necessary to protect an hydroxyl group by converion to an alkoxy or an ester and subsequently deprotected. Protective groups for other substituents are described in Protective Groups in Organic Synthesis. 2nd ed., Greene and Wuts, John Wiley & Sons, New York, 1991. In another aspect, there is provided a method of agonizing or activating opioid receptors in a mammal comprising administering to said mammal an opioid receptor agonizing or activating amount of a compound or composition of the invention. There is also provided pharmaceutically acceptable compositions comprising compounds of the present invention and derivatives thereof, in combination with pharmaceutically acceptable carriers diluents or adjuvants. By "pharmaceutically acceptable derivatives" is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compounds of formula (I) or (II) or any other compound such as a prodrug which, upon administration to the recipient, is capable of providing (directly or indirectly) compounds of formula (I) or (U) or an active metabolite or residue thereof. The present invention also provides pharmaceutical compositions which comprise a pharmaceutically effective amount of a compound of the invention, or pharmaceutically acceptable salts thereof, and preferably, a pharmaceutically acceptable carrier, diluent or adjuvant. The term "pharmaceutically effective amount" is the amount of compound required upon administration to a mammal in order to induce analgesia. Also, the term "opioid receptor agonizing amount" refers to the amount of compound administered to a mammal necessary to bind and/or activate opioid receptors in vivo. Therapeutic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions. Such compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions. In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. The unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients. For example, binding agents, such as acacia, gelatin, sorbitol, or polyvinylpyrolidone; fillers, such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants, such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. The compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Liquid oral preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may or may not contain conventional additives. For example suspending agents, such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents, such as sorbitan monooleate or acaci; non-aqueous vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives, for instance methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, n- propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and, if desired, conventional flavoring or coloring agents. The compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. For parenteral administration, fluid unit dosage forms may be prepared by utilizing the compound and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle. Once in solution, the compound may be injected and filter sterilized before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package. Adjuvants, such as a local anesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use. Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum, (e.g., freeze drying the composition). Parenteral suspensions may be prepared in substantially the same manner, except that the compound should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration. The compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle. A surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound. The pharmaceutical compositions of this invention comprise a pharmaceutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Typically, they contain from about 0.01% to about 99% by weight, preferably from about 10% to about 60% by weight, of a compound of this invention, depending on which method of administration is employed. The compounds of the present invention can be administered in combination with one or more further therapeutic agents. Preferably, the one or more further therapeutic agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, narcotics, antidepressants, anticonvulsants, corticosteroid, tramadol, sumatriptan, and capsaicin. Without limitations, NSAIDs include aspirin (Anacin, Bayer, Bufferin), ibuprofen (Motrin, Advil, Nuprin), naproxen sodium (Aleve) and ketoprofen (Orudis KT) Without limitations, narcotics include drugs derived from opium (opiates), such as morphine and codeine, and synthetic narcotics (opioids), such as oxycodone, methadone and meperidine (Demerol). Without limitations, antidepressants include amitriptyline (Elavil), trazodone (Desyrel) and imipramine (Tofranil) may be used with other analgesics. These drugs are especially useful for neuropathic, head and cancer pain. Without limitations, anticonvulsants include drugs developed for epilepsy, these drugs, such as phonation (Dilantin) and carbamazepine (Tegretol), can also help control chronic nerve pain. Tramadol (Ultram) is a synthetic analgesic used primarily for chronic pain, but is also prescribed for acute pain. Sumatriptan (Imitrex),may reduce pain from migraine headache by constricting blood vessels. Capsaicin (Zostrix), a topical cream made from an extract of red peppers, can help relieve skin sensitivity resulting from shingles. Capsaicin can also be used to treat pain from arthritis, cluster headaches, diabetic neuropathy and pain after mastectomy. In another aspect of the invention, compounds may be used to identify opioid receptors from non-opioid receptors. For such use, compounds of the invention are radiolabeled e.g. by incorporating 3H or 14C within its structure or by conjugation to 1251. Such radiolabeled forms can be used directly to identify the presence of opioid receptors and in particular μ opioid receptors in a receptor population. This can be achieved by incubating membrane preparations with a radiolabeled compound of the invention. The presence and or amount of opioid receptors in the preparation is determined from the difference in membrane-bound radioactivity against a control preparation devoid of opioid receptors. Furthermore, radiolabeled forms of the present compounds can be exploited to screen for more potent opioid ligands, by determining the ability of the test ligand to displace the radiolabeled compound of the present invention. To further assist in understanding the present invention, the following non-limiting examples are provided. Certain abbreviations used throughout the examples can be found in the Aldrich Chemical Company and Bachem catalogues. EXAMPLE 1 Synthesis of trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-πaphthalen-2-ol, hydrochloride EXAMPLE 1 Synthesis of trans and cis-7-Amino-8,8-dimethyl-6-methylsulfanyI-5,6,7,8-dihydro- naphthalen-2-ol, hydrochloride Step 1 : 7-Methoxy-l,l-dimethyl-3,4-dihydro-lH-naphthalen-2-one (A) To a solution of 7-methoxy-l-methyl-3,4-dihydro-lH-naphthalen-2-one (1.95g, 10.3 mmol) in THF (30 ml) was added NHMDS (113 mmol, 11.3 ml, IM in THF) at 0°C under nitrogen. The resulted solution was stirred at 0°C for 1 hr. Iodomethane (7.29 g, 3J9 ml, 513 mmol) was added and stirred for an additional 3 hrs. 10% KHSO 4 aqueous solution was added to acidify the reaction mixture, diluted with brine, extracted with ethylacetate, washed with brine, dried over MgSO 4 , filtered. The filtrate was evaporated under vacuo. The residue was purified by chromatography using ethylacetate : hexane (0.9 : 9.5) as eluant to give the desired product as white solid. (1.77 g, 85%). 1H NMR (CDC1 3 ) δ: 7.08(d, 1H, J=83Hz), 6.88(d, 1H, J=2.7Hz), 6.74(dd, 1H, J=2.7 and 8.3Hz), 3.80(s, 3H), 3.03(t, 2H, J=6.6Hz), 2.65(t, 2H, J=6.6Hz), 1.42(s, 6H). 13 C NMR (CDC1 3 ) δ : 213J, 157.8, 143.9, 128J, 126.5, 111.3, 110.4, 54.4, 46.9, 36.5, 26.8, 25.8. Step 2 : 7-Methoxy-l,l-dimethyl-3-methylsulfanyI-3,4-dihydro-lH-naphthalen-2- one(B) To a solution of 7-methoxy-lJ-dimethyl-3,4-dihydro-lH-naphthalen-2-one (1.72 g, 8.40 mmol) in THF (20 ml) was added LHMDS (8.82 mmol, 8.82 ml, IM in THF) at -78°C under nitrogen, and then the temperature was raised to 0°C and stirred for 1 hr. The solution was cooled to -78°C and methylmethanathiosulfonate (0.87 ml, 1.06g, 8.40mmol) was added and stirring was continued for 4hr at 0°C, then room temperature for lhr. The reaction mixture was quenched with IN HC1 (2ml). Then, it was partitioned between ethylacetate and brine, washed with sat. NaHCO 3 aqueous solution, brine, then dried over MgSO 4 , filtered, and evaporated under vacuo. The crude product was purified by flash column chromatography using ethylacetate : hexane (0.5 : 9.5 V/V) as eluant to give the desired product as white solid (2.07 g, 89%). Η NMR (CDC1 3 ) δ: 7.06(d, IH, J=7.2Hz), 6.89(d, IH, J=2.5Hz), 6.73(dd, IH, 5=1.2 and 2.5Hz), 3.79(s, 3H), 3.43(m, IH), 3.40(m, IH), 3.05(m, IH), 2.05(s, 3H), 1.61(s, 3H), 137(s, 3H). 13 C NMR (CDC1 3 ) δ: 208.3, 159J, 144.6, 129.4, 124.0, 111.8, 110.9, 55.1, 50.2, 46.5, 32.7, 29.6, 27.2, 14.7. Step 3 : 7-Methoxy-l,l-dimethyl-3-methylsulfanyl-3,4-dihydro-lH-naphthalen-2-one oxime (C) To a solution of 7-methoxy-lJ-dimethyl-3-methylsulfanyl-3,4-dihydro-lH-naphthalen-2- one (0J65 g, 1.05 mmol ) in pyridine (5 ml) was added hydroxyamine hydrochloride (1.09 g, 15.7mmol). The mixture was stirred under nitrogen at 85°C overnight. The solution was cooled to room temperature, poured into water, extracted with ethylacetate, washed with 10% KHSO aqueous solution, brine, dried over MgSO 4 , filtered. The filtrate was evaporated under vacuo. The crude product was purified by flash column chromatography using ethylacetate :Hexane (1 :9) as eluant to give the desired product as white solid (0J77g, 63%). Η NMR (CDC1 3 ) δ: 8.80(br, IH), 7.05(d, IH, J=8.2Hz), 6.93(d, IH, J=2.5Hz), 6.73(dd, IH, J=8.2 and 2.5Hz), 4.91(t, IH, J=3.0Hz), 3.81(s, 3H), 3J6(dd, IH, J=15.6 and 5.0Hz), 2.96(dd, IH, J=15.6and 3.0Hz), 2J5(s, 3H), 1.76(s, 3H), 1.48(s, 3H). I3 C NMR (CDC1 3 ) 5: 164.5, 159J, 145.0, 129.6, 129.4, 111.8, 111.0, 553, 39.8, 35.9, 32.9, 32.4, 30.8, 15.1. Step 4 : 7-Methoxy-l,l-dimethyl-3-methylsulfanyl-3,4-dihydro-lH-naphthalen-2- ylamine (mixture of cis and trans) (D) To a solution of 7-methoxy- 1 , 1 -dimethyl-3-methylsulfanyl-3 ,4-dihydro- 1 H-naphthalen-2- one oxime (1.13g, 4J1 mmol ) and sodium borohydride (0.669g, 17.69mmol) in 1,2- dimethoxyethane (20 ml) was added titanium tetrachloride (8.84 ml, 8.84mmol, IM in dichloromethane) dropwise under nitrogen at 0°C. The mixture was refluxed for 3 hrs. Then it was cooled to room temperature. Water (5ml) was added slowly, then Sat.NaHCO 3 aqueous solution (100ml) was added. It was extracted with ethylacetate (3x100ml). The combined extractions were dried over MgSO 4 , filtered. The filtrate was evaporated under vacuo. The residue was purified by flash chromatography using ethylacetate as eluant to give the desired product as a mixture of cis :trans (1 : 1) (0.655g, 61%). The mixture was further separated by reverse HPLC with gradient condition (10 to 50% acetonitrile / water (0.1% TFA). The aqueous solution was basified with sat. NaHCO 3 aqueous solution, extracted with ethylacetate, dried over MgSO , filtered. The filtrate was evaporated under vacuo to give cis isomer (C-18 HPLC fast isomer, 0J30g, 21.5%) and trans isomer (C-18 HPLC slow isomer, 0J47g, 14%) as white solid. 1H NMR (CDC1 3 ) δ: cis isomer, 6.97(d, IH, J=8JHz), 6.84(d, IH, J=2.8Hz), 6.69(dd, IH, J=2.8 and 8JHz), 3.77(s, 3H), 3.67(oct, IH, J=14.57, 631, and 2.20Hz), 2.75-2.97(m, 3H), 2J5(s, 3H), 1.49(s, br, 2H), 1.47(s, 3H), 1.25(s, 3H). 13 C NMR (CDC1 3 ) δ: cis isomer, 158.40, 144.03, 129.57, 125.49, 112.37, 111.46, 57.22, 55.11, 44.41, 39.30, 32.53, 30.13, 26.48, 13.65. Η NMR (CDC1 3 ) δ: trans isomer, 6.95(d, IH, J=8.5Hz), 6.87(d, IH, J=2.4Hz), 6.70(dd, IH, J=8.5 and 2.4Hz), 3.79(s, 3H), 3J8(m, IH), 3.00-2.68(m, 3H), 2J5(s, 3H), l/75(s, br, 2H), 1.46(s, 3H), 1.18(s, 3H). 13 C NMR (CDC1 3 ) δ: trans isomer, 158J, 146.4, 129.3, 126J, 112.4, 111.6, 59.0, 55J, 46.0, 40J, 36.0, 27.9, 24.8, 12.1. Step 5 : (±)-Trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro- naphthalen-2-oI, hydrochloride (compound #1) To a solution of trans-7-methoxy- 1 , 1 -dimethyl-3-methylsulf anyl-3 ,4-dihydro- 1 H- naphthalen-2-ylamine (0J47g, 0.585mmol ) in dichloromethane (10 ml) was added borontribromide (1.76 ml, 1.76mmol, IM in dichloromethane) dropwise at -78°C under nitrogen. The mixture was slowly warmed to room temperature and stirred overnight. Sat. NaHCO 3 aqueous solution (5ml) was added and stirred for 30 min. Then it was extracted with ethylacetate, dried over MgSO 4 , filtered. The filtrate was evaporated under vacuo. The residue was dissolved in dichloromethane and HC1 (1.8ml, IM in diethylether) was added. The solvent was evaporated. The residue was redisolved in dichloromethane, then it was added to hexane to precipitate the product. The precipitate was filtered off to give the desired product as white solid (0J35g, 89%). 1H NMR (CD 3 OD) δ: 6.92(d, IH, J=8.2Hz), 6.80(d, IH, J=2.4Hz), 6.63(dd, IH, J=8J and 2.4Hz), 337(d, IH, J=l lJHz), 3J0-3.00(m, 3H), 2J0(s, 3H), 1.52(s, 3H), 1.29(s, 3H). 13 C NMR (CD 3 OD) δ: 157.0, 1473, 130.4, 126.0, 114.7, 114.0, 603, 47.0, 40.9, 37.0, 28.5, 25.4, 11.8. LRMS, m/z, M+l, 238.0. Step 6 : (±)-Cis-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen- 2-ol, hydrochloride (compound #2) To a solution of cis-7-methoxy-lJ-dimethyl-3-methylsulfanyl-3,4-dihydro-lH-naphthalen- 2-ylamine (0.230g, 0.905 mmol ) in dichloromethane (10 ml) was added borontribromide (2.71ml, 2.71mmol, IM in dichloromethane) dropwise at -78°C under nitrogen. The mixture was slowly warmed to room temperature and stirred overnight. Sat. NaHCO 3 aqueous solution (5ml) was added and stirred for 30 min. Then it was extracted with ethylacetate, dried over MgSO , filtered. The filtrate was evaporated under vacuo. The residue was dissolved in dichloromethane and HC1 (1.8ml, IM in diethylether) was addεd.Solvent was evaporated. The residue was redisolved in dichloromethane. Then it was added to hexane to precipitate the product. The precipitate was filtered off to give the desired product as white solid (OJOOg, 80%). 1H NMR (CD 3 OD) δ: 6.96(d, IH, J=83Hz), 6.81(d, IH, J=2.4Hz), 6.66(dd, IH, J=2.4 and 8.3Hz), 3.65(oct, IH, J=2.2, 8.0, and 14.6Hz), 3.47(d, IH, J=2.2Hz), 3J l(dd, IH, J=2J and 8.0Hz), 2.58(dd, IH, J=8.0 and 14.6Hz), 2.24(s, 3H), 1.54(s, 3H), 139(s, 3H). 13 C NMR (CD 3 OD) δ: 1573, 144.9, 130.8, 125.5, 114.7, 114.1, 57.9, 45.4, 39.9, 33.1, 31.2, 27.2, 13.5. LRMS, m/z, M+l, 238J. EXAMPLE 2 Synthesis of trans-7-Amino-8,8-diethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2- ol, hydrochloride (COMPOUND #3) t EXAMPLE 2 Synthesis of (±)-Trans-7-Amino-8,8-diethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol, hydrochloride (compound #3) Step 1 : l,l-Diethyl-7-methoxy-3,4-dihydro-lJ 1 7-naphthalen-2-one (A) To a solution of 7-methoxy-2-tetralone (4.26 g, 24.18 mmol) in DMF (100 mL) at 0° C was 1 eq of sodium hydride ( 60% in oil) (lg, 41.6 mmol). After 30 minutes, 1J5 eq of iodoethane was added ( 2.5 mL, 30.2 mmol), then after 30 min, the other equivalent of sodium hydride (lg ), after 30 min the iodoethane was added (2.5 mL, 30J mmol). The resulting purpule solution was stirred for lh at 0°C then stirred for over night at r.t.The mixtutre was quenched with water, then diluted with Et 2 0. The organic layer was then washed with H 2 O, brine, dried over MgSO , filtered then evaporated. The residu was purified by a flash chromatography (5%AcOEt/ Hex) (4.40g, 78%). Η NMR (CDC1 3 ) : 7.12 (IH, d, J=8.0Hz, H 5 ), 6.78 (2H, m, H 6 and H 8 ), 3.84 (3H, s, OCH 3 ), 2.97 (2H, t, J=6.0 Hz, PhCH 2 ), 2.6 (2H, t, J=6.0 Hz, CH 2 CO), 2.10 (2H, m, CH 2 ), 1.71 (2H, m, CH 2 ), 0.63 (6H, t, J=7.5 Hz, CH 3 ). Step 2 : l,l-Diethyl-7-methoxy-3,4-dihydro-l//-naphthalen-2-one oxi e (B) lJ-diethyl-7-methoxy-3,4-dihydro-lH-naphthalen-2-one (4.40g, 18.96 mmol) in dry pyridine (20 mL) with the hydroxylamine hydrochloride salt (10.54 g, 151.7 mmol) was heated to 80 °C for one day. The mixture was cooled down to r.t., then the pyridine was removed under vaccum. The green gum was dissolved with AcOEt, washed with Η 2 O, HCl 10%, H 2 O, brine , dried over MgSO and filtered through a small silica pad. The crude compound was used without any other purification (4.69g, 100%). IH NMR (CDC1 3 ) : 7.94 (IH, s, OH), 7.06 (IH, d, J=8 Hz, H 5 ), 6.84 (IH, d, J=2.5 Hz, H 8 ), 6.73 (IH, dd, J=2.5 and 8 Hz, H 6 ), 3.83 (3H, s, OCH 3 ), 2.80-2.75 (4H, m, PhCH 2 CH 2 ), 2.08 (2H, m, CH 2 ), 1.85 (2H, m, CH 2 ), 0.68 (6H, t, J=7.5 Hz, CH 3 ). Step 3 : 7,7-Diethyl-5-methoxy-la,2,7,7a-tetrahydro-l/7-l-aza- cyclopropa [b] naphthalene (C) To a solution of the 1 J -diethyl-7-methoxy-3 ,4-dihydro- 1 H-naphthalen-2-one oxime (4.68g, 18.96 mmol) in dry TΗF (100 mL) at 0°C was added the diethylamine (4.9 mL, 47.4 mmol) and the LAΗ (95% powder) (2J6g, 56.9 mmol). The mixture was stirred at 0° C for 15 min then heated to reflux for 3h. The gray solution was cooled down to 0°C , quenched with brine and diluted with AcOEt. The organic layer was decanted, washed with Η 2 O (2x), brine, dried over MgSO 4 , filtered then evaporated. The residu was purified by a flash chromatography (3% MeOH/ CH 2 C1 2 ) (3.889 g, 89%). 1H NMR (CDC1 3 ) : 6.99 (IH, d, J=8 Hz, H 5 ), 6.76 (2H, m, H 6 and H 8 ), 3J3 (2H, m, CHCH), 2.40 (IH, broad, NH), 2J0-2.05 (2H, m), 1.84 (IH, m), 1.62 (4H, m, CH 2 ), 1.02 (3H, t, J=7.5 Hz, CH 3 ), 0J5 (3H, t, J=7.5hz, CH 3 ). Step 4 : 7,7-Diethyl-la^,7,7a-tetrahydro-l /-l-aza-cyclopropa[6]naphthalen-5-oI (D) To a solution of 7,7-diethyl-5-methoxy-la,2,7,7a-tetrahydro-lH-l-aza- cyclopropa[b]naphthalene (3.889g, 16.81 mmol) in CΗ 2 C1 2 (170 mL) at -78°C was added the BBr 3 (IM in CH 2 C1 2 ) (33.6 mL, 33.62 mmol). The mixture was kept at -78°C for 30 min then to 0°C for 1.5h. The mixture was quenched by NaHCO 3 , diluted with AcOEt. The organic layer was washed with H 2 O, brine, dried over MgSO , filtered then evaporated. The residu was purified by a flash chromatography ( 3% MeOH /CH2C12) (2.917g, 80%). 1H NMR (CDCI3) : 6.93 (IH, d, J=8 Hz, H 5 ), 6.68 (IH, d, J=2.5 Hz, H 8 ), 6.64 (IH, dd, J=8 and 2.5 Hz, H 6 ), 3J2 (2H, m, CHCH), 2.42 (IH, broad, OH),2J4 91H, broad, NH), 2.04 (IH, m), 1.82 (IH, m), 1.65 (4H, m, CH 2 ), 1.02 (3H, t, J=7.5 Hz, CH 3 ), 0.75 (3H, t, j=7.5hz, CH 3 ). 5 Step 5 : 5-terf-Butoxycarbonyloxy-7,7-diethyI-la,2,7,7a-tetrahydro-l-aza- cyclopropa[6]naphthalene-l-carboxylic acid tert-butyl ester (D) To a solution of diethyl-la,2,7Ja-tetrahydro-lH-l-aza-cyclopropa[b]naphthalen-5-ol (1.5g, 0 6.90 mmol) in CΗ 2 C1 2 (30 mL) at r.t was added the (Boc)O (3.77g, 17.26 mmol) , the triethylamine (3.85 mL, 27.6 mmol) and DMAP (cat). The mixture was strirred at r.t for over night. The mixture was quenched by NFLC1, diluted with AcOEt. The organic layer was washed with H O, brine, dried over MgSO 4 , filtered then evaporated. The residu was purified by a flash chromatography ( 5% to 25% AcOEt/Hex) (2.44g, 84%). 5 1H NMR (CDCI3) : 7.05-6.95 (3H, m, Har), 3.29 (IH, d, J=17 Hz, PhCHH), 3.04 (IH, dd, J=2Hz and 17Hz, PhCHH), 2.94 (IH, m), 2.67 (IH, d, J=6.5 Hz), 2.05-1.95 (2H, m), 1.65- 1.50 (1 IH, m), 1.43 (9H, s, t-butyl), 1.11 (3H, t, j=7.5 Hz, CH 3 ), 0.72 (3H, t, J=7.5 Hz, CH 3 ). 0 Step 6 : Thioacetic acid S-(trans-3-tert-butoxycarbonylamino-6-tert- butoxycarbonyloxy-4,4-diethyl-l,2,3,4-tetrahydro-naphthalen-2-yl) ester (E) 5-te -Butoxycarbonyloxy-7,7-diethyl- 1 a,2,7,7a-tetrahydro- 1 -aza- 5 cyclopropa[b]naphthalene-l-carboxylic acid tert-butyl ester (218 mg, 0.52 mmol) and the thiolacetic acid (2 mL) was stirred at r.t for over night. The mixture was diluted with Et 2 O (50 mL), washed with H 2 O, NaHCO 3 (3x), H 2 O, brine, dried over MgSO . The residu was purified by a flash chromatrgraphy (10% AcOEt/Hex) (234 mg, 91%). Η NMR (CDCI3) : 7.05-6.95 (3H, m, Har), 4.80 (IH, d, J=10.5 Hz, NH), 4.15-4.00 (2H, o m, CHCH), 3.17 (IH, dd J=5 Hz and 17 Hz, PhCHH), 2.97 (IH, dd, J=12Hz and 17Hz, PhCHH), 2.40 (3H, s, SCOCH 3 ), 1.86 (IH, m), 1.70 (2H, m), 1.60-1.55 (1 IH, m), 1.47 (9H, s, t-butyl), 0.89 (3H, t, J=7.5 Hz, CH 3 ), 0.71 (3H, t, J=7.5 Hz, CH 3 ). Step 7 : Carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyI-trans-6-mercapto- 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (F) Thioacetic acid S-(trans-3-tert-butoxycarbonylamino-6-tert-butoxycarbonyloxy-4,4- diethyl-l,2,3,4-tetrahydro-naphthalen-2-yl) ester (234 mg, 0.47 mmol) in MeOH (5 mL) was added the sodium methoxide ( 54 μL, 0.95mmol) and stirred at 0°C for 30 min. The mixture was quenched with H 2 O, diluted with Et O (50 mL), washed with H 2 O, HCl (10%), H 2 O, brine, dried over MgSO 4 . The residu was used without any other purification (151 mg, 71%). Η NMR (CDC1 3 ) : 7J0-6.95 (3H, m, Har), 4.58 (IH, d, J=11.0 Hz, NH), 4.00 (IH, t, J=l 1Hz, CHNH), 3.40-3.25 (2H, m), 2.98 (IH, m), 1.80-1.45 (22H, m), 0.80-0.70 (6H, m, CH 3 ). Step 8 : Carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-trans-6- methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (G) To a solution of carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-trans-6-mercapto- 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (28J mg, 0.062 mmol) in acetone (2 mL) was added the iodomethane ( 20 μL, 0.31 mmol) and the potassium carbonate (26 mg, 0J8 mmol), and stirred at reflux for 4 h. The mixture was quenched with H 2 O, diluted with Et 2 O (50 mL), washed with H 2 O, brine, dried over MgSO 4 . The residu was purified by a flash chromatography ( 10% AcOEt/Hex) (21.2 mg, 73%) . l H NMR (CDCI3) : 7.08 (IH, d, J=8.5 Hz, H 5 ), 7.00-6.95 (2H, m, H 6 and H 8 ), 4.56 (IH, d, J=l 1 Hz, NH), 4.09 (IH, t, J=l 1.0 Hz, CHNH), 3.25-3.00 (3H, m), 2J5 ( 3H , broad, SCH 3 ), 1.76 (4H, m, CH 2 ), 1.57 (9H, s, t-butyl), 1.50 (9H, s, t-butyl), 0.73 (6H, m, CH 3 ). Step 9 : (±)-Trans-l,l-diethyl-7-hydroxy-3-methylsulfanyl-l,2,3,4-tetrahydro- naphthalen-trans-2-yl-ammonium; chloride (compound #3) To a solution of Carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-trans-6- methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester ( 21 J mg, 0.045 mmol), in CH 2 C1 2 (2 mL) was added the TFA ( 0.2 mL). The solution was stirred at r.t for 3h. The volatil was removed and co-evaporated with CH C1 2 . The final purety was verified by HPLC reversed phased ( 0% to 50 % of CH 3 CN +0.01% TFA in 25 min, λ= 215 nM Rt=l 1.28 min, 97%) (14.8 mg, 86%). Η NMR (CD 3 OD) : 6.99 (IH, d, J=8.5 Hz, H 5 ), 6.70-6.65 (2H, m, H 6 and H 8 ), 4.46 (IH, d, j=l 1 Hz,), 3.30-3.25 (2H, m), 2.98 (IH, dd, J=5.5 Hz and 11 Hz, PhCHH), 2.22 (3H, s, SCH 3 ), 2.15 (IH, m, CHHCH 3 ), 1.77 (2H, m, CH 2 CH 3 ), 1.64 (IH, m, CHHCH 3 ), 0.85 (3H, t, J=7.5 Hz, CH 3 ), 0.75 (3H, t, j=7.5 Hz, CH 3 ). EXAMPLE 3 - 1 ,1 -Dimethyl-7-hydroxy-3-phenylsulfanyl-1 ,2,3,4-tetrahydro-naphthalen-trans- 2-yl-ammonium; chloride trans EXAMPLE 3 - (±)-Trans-l,l-dimethyl-7-hydroxy-3-phenylsulfanyI-l,2,3,4- tetrahydro-naphthalen-trans-2-yl-ammonium; chloride (compound #4) Step 1 : 7-Methoxy-l,l-dimethyi-3,4-dihydro-lH-naphthalen-2-one oxime (A) 7-Methoxy-lJ-dimethyl-3,4-dihydro-lH-naphthalen-2-one (used as a crude from example 1, stepl, 128.8 g, 0.63 mol) and hydroxylamine hydrochloride (350g, 5.04mol ) in pyridine (360 ml) were heated up to 80°C. The reaction mixture was stirred for 15h at 80-90°C. Pyridine was removed under reduced pressure. The residue was partitioned between ethylacetate (2.51) and water (11). Water layer was separated and washed with ethyl acetate (11). Ethyl acetate solution was washed with 10% aq. KHSO (11), dried over Na 2 SO . Ethyl acetate was removed under reduced pressure and the residue was crystallized from acetone to give 101.2 g of target compound. Mother liquid was concentrated to dryness and crystallized from acetone to give second crop (11.4 g). 112.6g (82%) of the desired product was obtained. 1H NMR (CDC1 3 ), d 9J5 (s, IH), 7.06 (d, IH, J=7.4 Hz) 6.92 (IH, d, J=2.4Hz), 6.75 (dd, IH, J= 7.4 and 2.4Hz), 3.82 (s, 3H), 2.78-2.95 (m, 4H), 1.5 (s, 6H). Step 2: 5-Methoxy-7,7-dimethylmethyl-la,2,7,7a-tetrahydro-l -l-aza- cy clopropa [b] naphthalene(B) LiAlH (IM in THF ,1.431, 1.43 mol) was added dropwise to a solution of diethylamine (108 ml, 1.05 mol) and 7-Methoxy-lJ-dimethyl-3 ,4-dihydro- lH-naphthalen-2-one oxime ( 112.6g, 0.51 mol) in THF (700ml) at 0-8°C. The reaction mixture was brought to reflux and refluxed for lh. An excess of LiAlH 4 was quenched with water solids were filtered off and washed with 25% MeOH in acetone followed by 5% aq ammonia in MeOH . The solution was concentrated to dryness and the crude was purified by flash chromatography using ethylacetate/methanol (1 to 4%) with 0.2% of ammonia hydroxide. Fraction containing desired product were concentrated to dryness and the residue was crystallized from hexane to give 58g (56%) of the target compound. The mother liquid was purified by flash chromatography using hexane/ethyl acetate (1/1) followed by ethyl acetate to give lOg (10%) of the target compound. Η NMR (CDC1 3 ), d 6.98(d, IH, J=7.8Hz) 6.85 IH, d, J=2.4Hz), 6.70(dd, IH, J= 7.8 and 2.4Hz), 3.15 ( br s, 2H), 2.51( br s, IH), 2.15 ( br s, IH), 1.75 (s, 3H), 1.22 (s, 3H). Step 3: 7-Methoxy-l,l-dimethyl-3-phenylsulfanyl-l,2,3 » 4-tetrahydro-naphthalen- trans-2-yl-amine(C) 4-Methoxy-2,2-dimethyl- 1 a,2,7,7a-tetrahydro- 1 H- 1 -aza-cyclopropa(b)naphthalene (0352g, 1.73 mmoles) was dissolved in 2 ml of ethyl alcohol. To the stirred solution, triethylamine (0.88ml, 6.3 mmoles) and thiophenol (0.53 ml, 5J6 mmoles) were added subsequently. The reaction mixture was stirred for 24 hours at room temperature until TLC shows complete reaction. The solvent was removed by vacuum distillation. Resulting dark yellow oil, was dissolved in minimum quantity of dichloromethane and applied on Mega-Bond Elut cartridge. The desired product was isolated by elution with ethyl acetate and hexane mixture (1 3), (0373g, 65%). Η NMR (CDCI3) d : 7.5 l(d, 2H), 730(m, 3H), 6.89(m, 2H), 6.68(m, IH), 3.79(s, 3H), 3.44(m, IH), 3J l(dd, IH), 2.88(dd, 2H), 1.66(br, 2H), 1.48(s, 3H), 1.20(s. 3H) ; ppm. Step 4 l,l-Dimethyl-7-hydroxy-3-phenylsulfanyl-1^3 ? 4-tetrahydro-naphthalen-trans-2-yl- ammonium; chloride (D) Trans-7-Methoxy- 1 , 1 -dimethyl-3-phenylsulfanyl- 1 ,2,3 ,4-tetrahydro-naphthalen-yl-amine (0373g, 1.19 mmoles) was dissolved at 0°C in dichloromethane (30ml). Solution of boron tribromide in dichloromethane (3.57 ml of IM soln.) was slowly added. It was stirred for and allowed to reach room temperature within 2 hours. Stirring was continued for overnight. Saturated sodium bicarbonate was added to quench reaction. The product was extracted using dichloromethane (4x 30ml). Crude mixture was purified on Mega Bond Elut cartridge eluting with ethyl acetate. Fractions containing pure product were combined, evaporated and evacuated under high vacuum. The resulting solid was dissolved in warm methanol (10 ml) place in an ice bath and treated with 1.2 ml of IM HCl in Et O. It was stirred for 25 min, evaporated to dryness, redissolved in 30 ml of water and freeze dried to give 0J927 g (48 %)of white solid. Η NMR (CD 3 OD) d : 7.62(d, 2H, J=6.46Hz), 7.4 l(d, 3H, J=73Hz), 7.79(dd, 2H, J=2Hz, J=7Hz), 6.59(dd, IH, J=2Hz, J=7Hz), 3.54(m, IH), 335(d, IH), 3J l(dd, IH, J=4.8Hz, J=16Hz), 2.84(dd, IH, J=16Hz, J=12Hz, 1.52(s, 3H), 132(s, 3H) ; ppm. EXAMPLE 4 Step 3 Step 3a Step 1. (-)-Trans-[Carbonic acid 2-(S)-isopropyl-5-(R)-methyl-cyclohex-(R)-yl ester 7- (R)-(2-(S)-isopropyl-5-(R)-methyl-cycIohex-(R)-yloxycarbonyl-(R)-amino)-8,8- dimethyl-6-methylsulfanyI-5,6,7,8-tetrahydronaphthalen-2-yl ester]. Trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (0J50g, 0.6 mmoles), was dissolved in 30 ml of dichloromethane at 0°C. To a stirred solution, pyridine (0.240ml, 3mmoles), and (L)-(-)-menthyl chloroformate (0.320ml, 1.5 mmoles) were added. The mixture was allowed to reach room temperature and it was further stirred for 2 hours.Aqueous sodium bicarbonate was added and stirred for 20 minutes. Organic phase was separated and aqueous layer was extracted with three portions of dichloromethane. Organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. Remaining oil was applied on preparative TLC plate and eluted three times with mixture of ethylacetate and hexane, 1 :20. Less polar fraction contains (+) diastereomer (0J2 g), more polar fraction contains (-) diastereomer (0.09g). 1H NMR (400 MHz) (CDC1 3 ; d; ppm) : 7J2(m, IH), 7.05(m, IH), 6.98(m, IH), 4.6(m, 3H), 3.9(t, IH, J=6Hz), 3.25(m, IH), 3J5(m, IH), 3.0(m, IH), 2J-2.0(m, 5H), 1.7(m, 4H), 1.5(m, 3H), 1.4(, m, 3H), 1.2(m, 3H), 1.1 (m, 4H), 0.8-0.95(m, 21H). Step 2. (-)-Trans-7-Hydroxy-l,l-dimethyl-3-methylsulfanyl-l^Σ,3 » 4-tetrahydro- naphthalen-2-yl)-carbamic acid 2-isopropyl-5-methylcyclohexyl ester. (-)-Trans-[Carbonic acid 2-(S)-isopropyl-5-(R)-methyl-cyclohex-(R)-yl ester 7-(R)-(2-(S)- isopropyl-5-(R)-methyl-cyclohex-(R)-yloxycarbonyl-(R)-amino)-8,8-dimethyl-6- methylsulfanyl-5,6,7,8-tetrahydronaphthalen-2-yl ester], (0.09g, OJmmoles), was dissolved in 2 ml of methyl alcohol containing potassium carbonate (0.0 lg ). It was stirred for 5 hours at room temperature. Methyl alcohol was evaporated and the residue was applied on silicagel column. The product was eluted using ethylacetate : hexane mixture 1 : 5, (0.021g). Η NMR (400 MHz) (CD 3 OD; d; ppm) : 6.7(d, 0.8H, J=10Hz), 6.65(d, IH, J=8Hz), 6.5(d, IH, J=2Hz), 6.3(dd, IH, J=2Hz, J=8Hz), 4.6(s, 3H), 4.3(m, IH), 3.45(m, IH), 3J(m, 3H), 2.9(dd, IH, J=6Hz, J=12Hz), 2.8(m, IH), 2.7(m, IH), 1.9(s, 2H), 1.85(m, IH), 1.5(d, IH, J=10Hz), 13-lJ(m, 2H), l.l(s, 2H), 0.95(s, 2H), 0J(d, 3H, J=5Hz), 0.6(d, 3H, J=5Hz). Step 3. (-)-Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2-ol hydrochloride. (-)-Trans-7-Hydroxy- 1 , 1 -dimethyl-3-methylsulfanyl- 1 J,3,4-tetrahydro-naphthalen-2-yl)- carbamic acid 2-isopropyl-5-methylcyclohexyl ester (0.02 lg), was dissolved in a mixture of acetic acid solution of HBr (36%) 0.5ml, and formic acid (1ml). The flask was sealed and heated at 58-60°C for 4 hours. The liquids were evaporated to dryness under vacuum and the residue was alkalized with aqueous ammonia. Alkaline solution was extracted with dichloromethane. Organic extracts were dried over sodium sulfate, foltered and evaporated, The residue was dissolved in MeOH (0.5ml) and IM solution of HCl in ethyl ether (OJml) was added. It was stirred for 10 min., evaporated, dissolved in water (5ml) and freeze dried. Yield : 0.0125g of white solid ; a D = -65° (c=0.04, MeOH). Compound #32 Trans-(-)-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol hydrochloride 1H NMR (CD 3 OD; d; ppm) : 6.92(d, IH, J=10 Hz), 6.78(d, IH, J=3Hz), 6.63(dd, IH, J=10Hz, J=3Hz), 331(1H), 3J0(m, 3H), 2.2(s, 3H), 1.5(s, 3H). 13(s, 3H). Compound #33 Trans-(+)-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2-ol hydrochloride Η NMR (CD 3 OD; d; ppm) : 6.92(d, IH, J=10 Hz), 6J8(d, IH, J=3Hz), 6.63(dd, IH, J=10Hz, J=3Hz), 331(1H), 3J0(m, 3H), 2J(s, 3H), 1.5(s, 3H). 13(s, 3H). In a similar manner as described in examples 1 to 4, the following compounds were also obtained: Compound #5 (±)-Trans-7-hydroxy-l,l-dimethyl-3-(2-pyridylsulfanyl)-l,23-4- tetrahydronaphthalen-2-yl ammonium trifluoroacetate 1H NMR (CD 3 OD), d 8.49 (d, IH, J=5Hz), l.ll-1.13( , IH), 7.49 (IH, d, J=8JHz), 7J7- 7.24(m, IH), 6.92 (d, IH, J=8.4 Hz), 6.84 (IH, d, J=2.5Hz), 6.64 (dd, IH, J= 8.4 and 2.5Hz), 4J3-4J5 (m, IH), 3.60 (d, IH, J=11J Hz), 3J8 (dd, IH, J=18Hz and J=53 Hz), 3.05 (dd, IH, J=18Hz, J=5J Hz), 1.55 (s, 3H), 1.43 (s, 3H) Compound #6 (±)-Trans-7-hydroxy-l,l-dimethyl-3-(pyrimidyl-2-sulfanyl)-l, 2,3,4- tetrahydronaphthalen-2-yl ammonium chloride 1H NMR (CD 3 OD), d 8.28 (s, IH), 8.27 (s, IH), 6.87 (d, IH, J=8.3 Hz), 6.77 (d, IH, J=2.4Hz), 6.62-6.56. (m, 2H), 431 (d, IH, J=l 1.6 Hz), 3.40-3.47 (m, IH), 3.60 (d, IH, J=l 1.2 Hz), 3.28 (dd, IH, J=16.2Hz and J=5.3 Hz), 2.93 (dd, IH, J=16JHz, J=5.2 Hz), 1.30 (s, 3H), 1.23 (s, 3H) Compound #7 (±)-Trans-7-amino-6-(3-amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro- naphthalen-2-ol dihydrochloride 1HNMR 7.06 (dd, IH, J=7.9Hz, J=7.8Hz), 6.9 (dd, IH, J=1.9Hz, J=1.8Hz), 6.82 (d, IH, J=7.8 Hz), 6.77 (d, J=6.8Hz), 6.76 (s, 2H), 6.62-6.65 (m, IH), 6.53 (dd, IH, J=2.5, J=83 Hz), 3.86-33.94( m, IH), 3.06 (dd, IH J=5.3Hz, J=163Hz), 2.82 (s, IH), 2.72(s, IH), 1.41 (s, 3H), 1.18 (s, 3H) Compound #8 (±)-Trans-7-amino-6-(4-methylthio-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro- naphthalen-2-oI hydrochloride 'HNMR (CD 3 OD), d 7.46 (dd, 2H, J=1.8Hz, J=8.4Hz), 7.24 (dd, 2H, J=1.8Hz, J=8.4Hz), 6.74-6.76 (m, 2H), 6.52 (dd, IH, J=2.4Hz, J=8.3Hz). 3.29-3.36 (m, IH), 3.00 (dd, IH, J=53Hz, J=16JHz), 2J8-2J8 (m, 2H), 2.47 (s, 3H), 1.40 (s, 3H), 1.17 (s, 3H). Compound #9 (±)-Trans-3-benzenesuIfonylmethylsulfanyl-l,l-diethyl-7-hydroxy-l,23 > 4- tetrahydronaphthalen-2-yl-ammonium; chloride Η NMR (MeOD) : 8.02 (2H, d, j=8.0 Hz), 7.80 (IH, m), 7.70 (2H, t, j=8.0 Hz), 6.96 (IH, d, j=8.0 Hz), 6J0 (2H, m), 4.58 (2H, s), 3.72 (IH, m), 3.62 (IH, d, J=l 1.5 Hz), 2.93 (IH, dd, J=l 1.5 Hz and 16 Hz), 2.13 (IH, m), 1.85-1.65 (3H, m), 0.86 (3H, t, j=7.5 Hz), 0.73 (3H, t, j=7.5 Hz). Compound #10 (+)-Trans-3-carbamoylmethylsulfanyl-l,l-diethyl-7-hydroxy-l^,3,4-tetrahydro- naphthalen-2-yl-ammonium; trifluoro-acetate Η NMR (DMSO) : 9.23 (IH, s), 8.47 (3H, broad), 1.10-1.60 (2H, broad), 6.91 (IH, d, J=8.5 Hz), 6.61 (IH, s), 3.58 (2H, s), 3.11 (IH, m), 2.94 (IH, m), 1.93 (IH, m), 1.82 (IH, m), 1.65 (IH, m), 1.54 (IH, m), 0.71 (3H, t, J=7.5 Hz), 0.57 (3H, t, J=7.5 Hz). Compound #11 (±)-Trans-3-(diethoxy-phosphorylmethylsulfanyl)-l,l-diethyl-7-hydroxy-1^ ? 4- tetrahydro-naphthalen-2-yl-ammonium; chloride Η NMR (DMSO) :9.23 (IH, s), 8.22 (3H, broad), 6.92 (IH, d, J=8.5 Hz), 6.61 (2H, m), 4.12 (4H, m), 3.20-3.15 (2H, m), 2.97 (IH, m), 1.95 (IH, m), 1.83 (IH, m), 1.65 (IH, m), 1.51 (IH, m), 1.27 (6H, m), 0.71 (3H, t, J=7.5 Hz), 0.60 (3H, t, J=7.5 Hz). Compound #12 (±)-Trans-l,l-diethyl-7-hydroxy-3-(2-hydroxy-ethyIsulfanyl)-l,2,3,4-tetrahydro- naphthalen-2-yl-ammonium; chloride Η NMR (MeOD) : 6.97 (IH, d, J=8.0 Hz), 6J0-6.65 (2H, m), 3.82 (2H, m), 3.50-3.40 (2H, mm), 3.00-2.85 (2H, m), 2.12 (IH, m), 1.80-1.60 (3h, m), 0.83 (3H, t, J=7.5 Hz), 0J3 (3H, t, J=7.5 Hz). Compound #13 (±)-Trans-3-(5-amino-2 -[l,2,4]triazol-3-ylsulfanyl)-l,l-diethyI-7-hydroxy-l,2 ,4- tetrahydro-naphthalen-2-yl-ammonium; trifluoro-acetate 'H NMR (MeOD) : 6.97 (IH, d, J=8.5 Hz), 6J0-6.65 (2H, m), 3.90 (IH, qd, J=5.5 Hz and 12 Hz), 3.76 (IH, d, J=12 Hz), 3.29 (IH, dd, J=5.5 Hz and 16.5 Hz), 2.11 (IH, m), 1.85-1.65 (3H, m), 0.88 (3H, t, J=7.5 Hz), 0J0 (3H, t, J=7.5 Hz). Compound #14 (±)-Trans-3-(2-Ammonium-ethylsulfanyl)-7-hydroxy-l,l-dimethyl-l,2,3,4-tetrahydro- naphthalen-2-yl-ammonium dichloride (400MHz,CD 3 OD)δ : 6.8(3H, m), 3.8-2.5(8H, m), 1.5(3H, s), 132(3H, s). Compound #15 (±)-Trans-3-(5-Amino-2 -[l^,4]triazol-3-ylsulfanyl)-l,l-dimethyl-7-hydroxy-l,2 ,4- tetrahydro-naphthalen-2-yl-ammonium; chloride CIH (400MHz, DMSO-D 6 )δ : 93(3H, bs), 83(3H, bs), 6.75(3H, m), 3.9-3.0(4H, m), 1.45(3H, s), lJ5(3H,s). Compound #16 (±)-Trans-l,l-dimethyl-7-hydroxy-3-propylsulfanyl-l,2,3,4-tetrahydro-naphthalen-2- yl-ammonium; trifluoro-acetate 1H NMR (DMSO) : 9.22 (IH, s), 8.04 (3H, bs), 6.87 (IH, d, J=8.5 Hz), 6.74 (IH, d, J=2.0 Hz), 6.74 (IH, dd, J=2.0 Hz and 8.5 Hz), 3.28 (IH, m), 3.15-3.05 (2H, m), 2.91 (IH, m), 2.75-2.60 (2H, m), 1.60 (2H, m), 1.44 (3H, s), 1.19 (3H, s), 0.98 (3H, t, J=7.5 Hz). MS : 266 (MH+) Compound #17 (±)-Trans-l ,1 -dimethy l-7-hydroxy-3-isopropy lsulfanyl-1 ,23,4-tetrahydro-naphthalen- 2-yl-ammonium; chloride 1H NMR (DMSO) : 9.23 (IH, s), 8.14 (3H, bs), 6.87 (IH, d, J=8.5 Hz), 6.75 (IH, d, J=2.0 Hz), 6.59 (IH, dd, J=2.0 Hz and 8.5 Hz), 3.29 (IH, m), 3.25-3.10 (3H, m), 2.84 (IH, td, J=10.5 Hz and 6.5 Hz), 1.43 (3H, s), 1.30 (3H, d, J=6.5 hz), 1.27 (3H, d, J=6.5 Hz), 1.22 (3H, s). MS : 266 (MH+) Compound #18 (±)-Trans-l,l-dimethyl-7-hydroxy-3-(2-hydroxy-ethylsulfanyI)-l,23,4-tetrahydro- naphthalen-2-yl-ammonium; chloride Η NMR (DMSO) : 9J3 (IH, s), 8J4 (3H, bs), 6.87 (IH, d, J=8.5 Hz), 6J4 (IH, d, J=2.0 Hz), 6.58 (IH, dd, J=2.0 Hz and 8.5 Hz), 5.32 (IH, broad), 3.70-3.60 (2H, m), 3J0-3.05 (2H, m), 2.95-2J5 (3H, m), 1.44 (3H, s), 1.19 (3H, s). MS : 268 (MH+) Compound #19 (±)-Trans-3-arbamoylmethylsulfanyl-l,l-dimethyl-7-hydroxy-l,23,4-tetrahydro- naphthalen-2-yl-ammonium; trifluoro-acetate 1H NMR (DMSO) : 9.23 (IH, s), 8.48 (3H, bs), 7.98 (IH, s), 7.59 (IH, s), 6.86 (IH, d, j=8.0 Hz), 6.74 (IH, s), 6.58 (IH, dd, J=2.0 Hz and 8.0 Hz), 3.55 (IH, d, J=16.0 Hz), 3.50- 3.15 (3H, m), 2.99 (2H, d, J=8.0 Hz), 1.42 (3H, s), 1.17 (3H, s). Compound #20 (±)-Trans-7-dimethylamino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2-ol IH NMR (400MHz) (CDC1 3 ; d; ppm): 6.90 (IH, d), 6.78 (IH, d), 6.59 (IH, dd), 3.21 (IH, dd), 3.08 (IH, m), 2.93 (IH, dd), 2.64 (IH, d), 2.28 (6H, s) 2.21 (3H, s), 1.31 (3H, s), 1.30 (3H, s). Compound #21 (±)-Trans-8,8-dimethyl-7-methylamino-6-methylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2-oI *H NMR (400MHz) (CDC1 3 ; d; ppm): 6.90 (IH, d), 6.80 (IH, d), 6.61 (IH, dd), 3.05 (IH, m), 2.95 (IH, m), 2.67 (3H, s), 2.36 (IH, d), 2.19 (3H, s), 1.43 (3H, s, CH 3 ), 1.20 (3H, s, CH 3 ). Compound #22 (±)-Trans-7-Amino-8,8-diethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol *H NMR (400MHz) (CDC1 3 ; d; ppm): 7.51 (IH, d), 7.27-734 (4H, m), 6.85 (IH, d), 6.66 (IH, d), 6.60 (IH, dd), 3.62 (IH, m), 3.12 (IH, dd), 2.83(lH,dd), 2.75-3.12 (2H, bs, NH 2 ), 1.84 (2H, m), 1.79 (IH, m), 1.67 (IH, m), 0.75 (3H, t, J=7.5Hz, CH 3 ), 0.64 (3H, t, J=7.2Hz, CH 3 ). Compound #23 (±)-Trans-8,8-dimethyl-trans-6-phenylsulfanyl-7-propylamino-5,6,7,8-tetrahydro- nahthalen-2-ol iH NMR (400MHz) (CDC1 3 ; d; ppm): 7.50 (2H, m), 7.32 (2H, m), 7J7 (IH, m), 6.81 (2H, m), 6.59 (IH, m), 3.77 (IH, m), 3.11 (IH, m), 2.89-3.02 (2H, m),2.47-2.76 (2H, m), 1.56 (2H, bs), 1.44 (3H, s), 1.27 (3H, s), 0.94 (3H, t, J=7.2Hz). Compound #24 (±)-Trans-7-Amino-6-(2-amino-phenylsulfanyl)-8,8-diethyl-5,6,7,8-tetrahydro- naphthalen-2-ol !H NMR (400MHz) (CDC1 3 ; d; ppm): 7.44 (IH, m), 7.15 (IH, m), 6.84 (IH, m), 6.74 (IH, m), 6.70 (IH, m), 6.64 (IH, d), 6.57 (IH, m), 3.46 (IH, m), 3.07 (IH, d), 3.02 (IH, dd), 2.82 (IH, dd), 1.81 (2H, m), 1.73 (IH, m), 1.59 (IH, m), 0.71 (3H, t, J=7.5Hz), 0.65 (3H, t, J=73Hz). Compound #25 (±)-Trans-7-hydroxy-l,l-dimethyl-trans-3-(2,2,2-trifluoro-ethylsulfanyl)-l,2,3,4- tetrahydro-naphthalen-2-yl-ammonium chloride !H NMR (400MHz) (CD 3 OD; d; ppm): 6.93 (IH, d), 6.80 (IH, d), 6.64 (IH, dd), 3.57 (2H, m), 3.40 (IH, d), 3.25-3.33 (2H, m), 3.00 (IH, dd), 1.53 (3H, s), 1.31 (3H, s). Compound #26 (±)-Trans-3-(3-ethoxycarbonyl-propyIsulfanyl)-7-hydroxy-l,l-dimethyl-l,23,4- tetrahydro-naphthalen-2-yl-ammonium chloride ΪH NMR (400MHz) (CDC1 3 ; d; ppm): 6.91 (IH, m), 6.80 (IH, m), 6.62 (IH, m), 4.14 (2H, m), 3.23 (IH, m), 3.14 (IH, m), 2.98 (IH, m), 2.77 (2H, m), 2.51 (2H, m), 1.96 (2H, m), 1.52 (3H, s), 1.30 (3H, s), 1.26 (3H, t, J=7JHz). Compound #27 (±)-Trans-3-benzenesuIfonylmethylsulfanyl-7-hydroxy-l,l-dimethyl-l,23 > 4- tetrahydro-naphthalen-2-yl-ammonium chloride iH NMR (400MHz) (CD 3 OD; d; ppm): 8.03 (2H, m), 7.80 (IH, m), 7.70 (2H, m), 6.88 (IH, d), 6.80 (IH, d), 6.64 (IH, dd), 4.56 (2H, s), 3.48 (2H, m), 3.21 (IH, m), 2.95 (IH, m), 1.53 (3H, s), 132 (3H, s). Compound #28 (±)-Trans-7-hydroxy-l,l-dimethyl-trans-3-styrylsulfanyl-l,23 ? 4-tetrahydro- naphthalen-2-yl-ammonium chloride *H NMR (400MHz) (CD 3 OD; d; ppm): 7.39 (2H, m), 7.30 (2H, m), 7J3 (IH, m), 6.88 (IH, d), 6.78 (IH, s), 6.60 (2H, m), 634 (IH, m), 3.59 (2H, d), 338 (IH, m), 3J7 (IH, m), 3J6 (IH, m), 3.00 (IH, m), 1.51 (3H, s), 1.28 (3H, s). Compound #29 (±)-Trans-7-hydroxy-TRANS-3-isobutylsulfanyl-l,l-dimethyl-l,23,4-tetrahydro- naphthalen-2-yl-ammonium chloride !H NMR (400MHz) (CD 3 OD; d; ppm): 6.91 (IH, d), 6.79 (IH, d), 6.62 (IH, dd), 330 (IH, m), 3.23 (IH, dd), 3.10 (IH, m), 2.97 (IH, dd), 2.64 (2H, m), 1.88 (IH, m), 1.52 (3H, s), 1.29 (3H, s), 1.06 (6H). Compound #30 (±)-Trans-7-hydroxy-l,l-dimethyl-trans-3-(2-phenoxy-ethylsulfanyl) -l,2,3,4- tetrahydro-naphthalen-2-yl-ammonium chloride iH NMR (400MHz) (CD 3 OD; d; ppm): 7.28 (2H, m), 6.89-6.97 (4H, m), 6.80 (IH, d), 6.63 (IH, dd), 4.27 (2H, m), 3.27-3.49 (3H, m), 3.15 (2H, m), 3.02 (IH, dd), 130 (3H, s), 1.26 (3H, s). Compound #31 (±)-Trans-l,l-diethyI-7-hydroxy-trans-3-(2-phenoxy-ethylsulfanyl) -1^3,4- tetrahydro-naphthalen-2-yl-ammonium chloride iH NMR (400MHz) (CD 3 OD; d; ppm): 7.26 (2H, m), 6.91 (4H, m), 6.67 (2H, m), 4.27 (2H, m), 3.53 (IH, m), 3.45 (IH, m), 337 (IH, dd, J,=53Hz, J 2 =16.5Hz), 3.15 (2H, m), 2.93 (IH, dd, J,=11.2Hz, J 2 =16.0Hz), 2.08 (IH, m), 1.75 (2H, m), 1.66 (IH, m), 0.81 (3H, t, J=73Hz), 0.69 (3H, t, J=7.0Hz). Compound #34 (±)-Trans-7-amino-6-(4-bromo-phenylsulfanyl)-8,8-dimethyI-5,6,7,8- tetrahydronaphthalen-2-ol hydrochloride 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 7.54(m, 4H), 6.8(m, 2H), 6.6(m, IH), 3.57(m, IH), 3.40(d, IH, J=12Hz), 3J4(dd, IH, J=53Hz, J=16Hz), 2.86(dd, IH, J=l 1Hz, 5Hz), 1.53(s, 3H), 132(s, 3H). Compound #35 (±)-Trans-7-amino-8,8-dimethyl-6-(naphthalen-2-ylsulfanyl)-5,6,7,8- tetrahydro-naphthalen-2-ol 1H NMR (400 MHz) (DMSO; d; ppm) : 9J0(s, IH), 8.04(d, IH, J=13Hz), 7.88(m, 3H), 7.59(dd, IH, J=1.8Hz, J=3Hz), 7.50(m, 2H), 6.7(m, 2H), 6.45(m, IH), 3.57( IH), 3.00(1H), 2.72(m, 2H), 1.98(br, 2H), 133(s, 3H), 1.13(s, 3H). Compound #36 (±)-Trans-7-amino-6-(4-hydroxyphenylsulfanyl)-8,8-diamino-5,6,7,8- tetrahydro-naphthalen-2-ol hydrochloride 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 7.49(m, 2H), 6.82(m, 4H), 6.58(m, IH), 33(m, 2H), 3.05(dd, IH, J=5Hz, J=8Hz), 2.75(dd, IH, J=9Hz, J=5Hz), 1.49(s, 3H), 1.29(s, 3H). Compound #37 (±)-Trans-7-amino-6-(4-amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydro-naphthalen-2-ol dihydrochloride 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 7.75(m, 2H), 738(m, 2H), 6.81(m, 2H), 6.61(m, IH), 3.61(m, IH), 3.43(d, IH, J=12Hz), 3J l(dd, IH, J=l lHz, J=5JHz), 2.87(dd, IH, J=l lHz, J=5Hz), 1.54(s, 3H), 134(s, 3H). Compound #38(±)-Trans-7-amino-6-(3-hydroxy-phenylsuIfanyl)-8,8-dimethyl-5,6,7,8- tetrahydro-naphthalen-2-ol; CIH 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 7.2 l(m, IH), 7.04(m, 2H), 6.8 l(m, 3H), 6.60(m, IH), 3.56(m, IH), 3.40(m, IH), 3J4(dd, IH, J=6Hz, J=l lHz), 2.86(dd, IH, J=l lHz, J=5Hz), 1.52(s, 3H), 1.31(s, 3H). Compound #39 (+)-Trans-3-(3-Aamino-6-hydroxy-4,4-dimethyl-l,23 > 4-tetrahydro- naphthalen-2-ylsu!fanyl)-propionic acid ethyl ester hydrochloride; 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 6.92(d, IH, J=8.4Hz), 6.80(d, IH, J=23Hz), 4.19(q, 2H, J=7Hz, J=7Hz), 3.42(d, IH, J=l 1Hz), 3J8(m, 2H), 2.98(m, 3H), 2.73(m, 2H), 1.52(s, 3H), 130(m, 6H). Compound #40 (±)-Trans-7-amino-8,8-dimethyl-6-phenethylsulfanyl-5,6,7,8- tetrahydro-naphthalen-2-ol hydrochloride; CIH 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 7.29(m, 4H), 7.23(m, IH), 6.88(m, IH), 6.78(m, IH), 6.61(m, IH), 3J8(m, 2H), 3.06(m, 6H), 1.49(s, 3H), 1.27(s, 3H). Compound #41 (±)-Trans-2-(3-amino-6-hydroxy-4,4-dimethyll,2,3,4- tetrahydronaphthalen-2-ylsuIfanyl)-propionamide hydrochloride: 1H NMR (400 MHz) (CD 3 OD; d; ppm) : 6.89(m, IH), 6.82(m, IH), 6.63(m, IH), 3.45(m, IH), 3J(m, 3H), 2.85(m, 2H), 2.7(m, IH), 2.55(m, IH), 1.5(s, 3H), 13(s, 3H). Compound #42 (±)-Trans-3-(3-amino-6-hydroxy-4,4-dimethyl-l,2,3 > 4-tetrahydro- naphthalen-2-ylsulfanyl)-propionic acid trifluoroacetate: Η NMR (400 MHz) (CD 3 OD; d; ppm) : 6.9(m, IH), 6.78(m, IH), 6.62(m, IH), 3.45(d, IH, J=l 1Hz), 3Jl(m, 2H), 2.98(m, 3H), 2.70(m, 2H), 1.53(s, 3H), 130(s, 3H). Compound #43 (+)-Trans-3-{2-[l-carbamoyI-2-(4-hydroxy-phenyl)-ethylcarbamoyl]- ethylsulfanyl}-7-hydroxy-l,l-dimethyl-l,2,3,4-tetrahydro-naphthalen-2-yl- ammonium; chloride: 1H NMR (400 MHz) (DMSO; d; ppm) : 9.2(br, IH), 8.0(br, 2H), 6.9(m, IH), 6.8(m, IH), 6.65(m, 2H), 6.6(m, IH), 6.5(m, 2H), 33-2.8(m, 11H), 1.45(s, 3H), 13(s, IH). Compound #44 3-trans-(2-ethoxycarbonyl-ethylsulfanyl)-l,l-diethyl-7-hydroxy-l,2,3,4-tetrahydro- naphthalen-2-yl-ammonium; chloride: NMR('H, MeOD) : δ = 6.95(m, IH), 6.7(m, IH), 6.6(m, IH), 4J(m, 2H), 3J(m, 2H), 2.95(m, 2H), 2.85(m, IH), 2.65(m, 2H), 1.95(m, IH), 1.8(m, 2H), 1.65(m, IH), 13(m, 3H), 0.75(m, 3H), 0.65(m, 3H) ppm. Compound #45 3-trans-(2-carboxy-ethylsulfanyl)-l,l-diethyl-7-hydroxy-l,23,4-tetrahydro- naphthalen-2-yl-ammonium; chloride IH NMR (CD 3 OD) δ 6.98 (d, IH, J 8Hz), 6.67-6.70 (m, 2H), 3.52 (d, 2H, J 11Hz), 3.27- 3.41 (m, 3H), , 2.92-2.99 (m, 2H), 2.67-2.75 (m, 2H), 2.10-2.16 (m, IH), 1.62-1.79 (m, 3H), 0.83 (m, 3H, J 8Hz), 0.72 (m, 3H, J 8Hz) BIOLOGICAL ASSAYS A. Receptor Affinity - Radioligand Binding Assay Affinity for μ opioid receptor was assessed in vitro using radioligand binding assay employing rat brain membrane preparations as described in Schiller et al., Biophys. Res. Commun., 85, pJ322 (1975) incorporated herein by reference. Male Sprague-Dawley rats weighing between 350-450g were sacrificed by inhalation of CO2. The rats were decapitated and the brains minus cerebellum were removed and place in ice-cold saline solution and then homogenized in ice-cold 50 mM Tris buffer pH 7.4 (lOml/brain). The membranes were centrifuged at 14000 rpm for 30 min. at 4°C. The pellets were re- suspended in approximately 6ml/brain of ice-cold Tris buffer 50mM pH 7.4 and stored at - 78°C until ready for use. Protein quantification of the brain homogenate was conducted according to protein assay kit purchased (Bio-Rad). (3H)- DAMGO was used as radioligands for the μ receptor. Radioligand 50 μl, membranes 100 μl and serially diluted test compound were incubated for 1 hr at room temperature or 22°C. Non specific binding was determined using 500 fold in the presence of tracer and membranes. Free ligand was separated from bound by filtration through Whatman GF/B paper (presoaked in polyethylenimine 1 % aqueous solution) and rinsing with ice-cold 50mM Tris pH 7.4 using a Brandel cell harvester. The filters were dried and radioactivity was counted in a 24 well microplate in the presence of 500 μl scintillant per well. Radioactivity was measured using a Wallac 1450 Microbeta counter. Inhibition constants (Ki) for the various compounds were determined from the IC50 according to the Cheng and Prusoff equation. B. Central and Peripheral Analgesia - PBQ Writhing Assay PBQ (phenyl-p-benzoquinone) induced writhing in mice was used to assess both central and peripheral analgesia of compounds of the invention according to the experimental protocol described in Sigmund et al., Proc. Soc. Exp. Biol. Med., 95, p. 729(1957) which is incorporated herein by reference. The test was performed on CD-I male mice weighing between 18 and 22g. The mice were weighed and marked and administered peritoneally with 03ml/20g by weight 0.02% solution of phenylbenzoquinone (PBQ) . The number of writhings was counting 5 minutes after PBQ injection and for a period of 20 minutes. ED50 values (dose of compound which induced a 50% reduction in the number of writhes observed compared to the control) was calculated using non linear regression of dose response curve. The PBQ was injected at time intervals of 5, 20 or 30 minutes after intravenous, subcutaneous or oral administration respectively of the compound (or medium, or standard). Aqueous solution of 0.02% PBQ was prepared by dissolving PBQ in 5% ethanol/saline 0.9% solution. C. Central analgesia tail flick assay The compounds of the present invention were evaluated for central analgesia as described in D'Amour et al. J.Pharmacol. 72:74-79, 1941 which is herein incorporated by reference. Male mice CD-I were weighed and marked on their tail. Tail is placed between two light beams at specific intensity using a Tail Flick Analgesia Meter, Columbus Instrument. Each mouse was tested at specific time points after compound or saline injection and latency period was noted. Cut off latency was settled at 10 seconds. ED 50 value was calculated from results obtained for different doses at 5 minutes for intravenous injection and at 30 minutes for oral and subcutaneous injection using non linear regression analysis of the dose response curve. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses or adaptations of the invention following, in general, the principles of the invention and including such departures from the present description as come within known or customary practice within the art to which the invention pertains, and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims: CLAIMS 1. A compound represented by formula (I) and pharmaceutically acceptable derivative thereof; wherein; Z is S, SO or SO 2 , X is selected from anyone of (i) a bond; (ii) -CR R«- wherein R 7 and Rg are independently selected from the group consisting of H , OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N; and COOR c wherein R, is Cι -6 alkyl, C 2-6 alkenyl or C 2 . 6 alkynyl; R 7 and R« can also be connected to form C3 -8 cycloalkyl, a C3 -8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms; Ri is selected from the group consisting of H, Cι-ι 2 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ι 2 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ι 2 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6 -ι 2 aryl, C 6- ι aralkyl, C 6- ι 2 aryloxy, C M acyl, heteroaryl having from 6 to 12 atoms, and phosphoryl; R 2 and R 3 are independently selected from the group consisting of Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C . 6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6- i2 aryl, C 6 .j 2 aralkyl, heteroaryl having from 6 to 12 atoms, and H; or R 2 and R 3 may together form a saturated heterocycle of from 3 to 8 atoms; R4 and Rs are independently selected from the group consisting of . 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H; R 4 and R5 can also be connected to form C 3-8 cycloalkyl, a C 3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms; R is hydrogen, OH, Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 - 6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O-Cι -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O-C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O-C 2-6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, halogen, CN, COOH, CONH 2 , amino, nitro, or SH; with the provisos that: 1) not both R4 and R 5 are H; and 2) at least one of R and R 3 is H or Cι- alkyl. 2. The compound of claim 1 wherein Z is S and X is -CH 2 -. 3. The compound of claim 2 wherein the geometric relation between the substituents of carbons marked by an * is trans. 4. The compound of claim 3 wherein R 2 and R 3 are H. 5. The compound of claim 3 wherein R is H. 6. The compound of claim 5 wherein R 4 and R 5 are Cμ alkyl. 7. The compound of claim 5 wherein R» and R s are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl. 8. The compound of claim 5 wherein R 4 and Rs are ethyl. 9. The compound of claim 5 wherein R 4 and R 5 are methyl. 10. The compound of claim 5 wherein Ri is selected from the group consisting of H, Cι_ι 2 alkyl, Cό-12 aryl, and C 6- i2 aralkyl. 11. The compound of claim 5 wherein Ri is selected from the group consisting of Cι -6 alkyl, C 6 -i2 aryl, and C 6- i2 aralkyl. 12. The compound of claim 5 wherein Ri is Cι -6 alkyl. 13. The compound of claim 5 wherein Ri is selected from the group consisting of CH 3 , -(CH 2 ) n -CH 3 , and -(CH 2 ) n -O-CH 3 wherein n is an integer selected between l and 5. 14. The compound of claim 5 wherein Ri is C 6 -i 2 aryl. 15. The compound of claim 14 wherein Ri is selected from the group consisting of wherein A is selected from the group consisting of Cι. 6 alkyl, Cι -6 alkyl, C 2- 6alkenyl, C 2-6 alkynyl, O-Cι -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, , S-C 1-6 alkyl, S-C -6 alkenyl, S-C 2-6 alkynyl, N-Cι -6 alkyl, N-C 2-6 alkenyl, N-C 2 . 6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is Cι- alkyl, C 2 . 6 alkenyl or C 2-6 alkynyl. 16. The compound of claim 5 wherein Ri is C 6 -i 2 aralkyl. 17. The compound of claim 5 wherein Ri is selected from the group consisting of wherein A is selected from the group consisting of C t . 6 alkyl, Ci^alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, O-Cι -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, , S-Cι -6 alkyl, S-C 2-6 alkenyl, S-C 2-6 alkynyl, N-Cι -6 alkyl, N-C 2 . 6 alkenyl, N-C 2-6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is -βalkyl, C 1-6 alkenyl or Cι. 6 alkynyl and Y is -(CH 2 ) m - wherein m is an integer selected between 1 and 5. 18. The compound of claim 1 wherein said compound selected from the group consisting of:Trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol, (compound #l);Trans and cis-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6J,8- dihydro-naphthalen-2-ol, (compound #2); Trans-7-Amino-8,8-diethyl-6- methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol, (compound #3);Trans-7-Amino-8,8- dimethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol(compound #4); Trans-7-Amino-8,8-dimethyl-6-(pyridin-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #5; Trans-7-Amino-8,8-dimethyl-6-(pyrimidin-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #6; Trans-7-Amino-6-(3-amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2- ol Compound #7; Trans-7-Amino-8,8-dimethyl-6-(4-methylsulfanyl-phenylsulfanyl)-5,6,7,8-tetrahydro- naphthalen-2-ol Compound #8; Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-diethyl-5,6,7,8-tetrahydro- naphthalen-2-ol Compound #9; Trans-2-(3-Amino-4,4-diethyl-6-hydroxy-l,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)- acetamide Compound #10; Trans-(3-Amino-4,4-diethyl-6-hydroxy-l,2,3,4-tetrahydro-naphthalen-2-ylsulfanylmethyl)- phosphonic acid diethyl ester Compound #11; Trans-7-Amino-8,8-diethyl-6-(2-hydroxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #12; Trans-7-Amino-6-(5-amino-2H-[lJ,4]triazol-3-ylsulfanyl)-8,8-diethyl-5,6J,8-tetrahydro- naphthalen-2-ol Compound #13; Trans-7-Amino-6-(2-amino-ethylsulfanyl)-8,8-dimethyl-5,6J,8-tetrahydro-naphthalen-2-ol Compound #14; Trans-7-Amino-6-(5-amino-2H-[lJ,4]triazol-3-ylsulfanyl)-8,8-dimethyl-5,6J,8- tetrahydro-naphthalen-2-ol Compound #15; Trans-7-Amino-8,8-dimethyl-6-propylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #16; Trans-7-Amino-6-isopropylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #17; Trans-7-Amino-6-(2-hydroxy-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2- ol Compound #18; Trans- 2-(3-Amino-6-hydroxy-4,4-dimethyl- 1 ,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)- acetamide Compound #19; Trans-7-Dimethylamino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #20; 8,8-dimethyl-trans-7-methylamino-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #21; Trans-7-Amino-8,8-diethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #22; 8,8-dimethyl-trans-6-phenylsulfanyl-7-propylamino-5,6,7,8-tetrahydro-nahthalen-2-ol Compound #23; Trans-7-Amino-6-(2-amino-phenylsulfanyl)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #24; Trans-7-Amino-8,8-dimethyl-6-(2,2,2-trifluoro-ethylsulfanyl)-5,6,7,8-tetrahydro- naphthalen-2-ol Compound #25; Trans-4-(3-Amino-6-hydroxy-4,4-dimethyl-l,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)- butyric acid ethyl ester Compound #26; Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro- naphthalen-2-olcompound #27; Trans-7-Amino-8,8-dimethyl-6-(3-phenyl-allylsulfanyl)-5,6J,8-tetrahydro-naphthalen-2-ol Compound #28; Trans-7-Amino-6-isobutylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #29; Trans-7-Amino-8,8-dimethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2- ol Compound #30; Trans-7-Amino-8,8-diethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #31; (-)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #32;(+)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2-ol Compound #33;Trans-7-amino-6-(4-bromo-phenylsulfanyl)-8,8- dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol Compound #34; Trans-7-amino-8,8-dimethyl-6-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2- ol Compound #35;Trans7-Arrrino-6-(4-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydro-naphthalen-2-ol Compound #36;Trans-7-amino-6-(4-amino- phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #37;Trans-7-amino-6-(3-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro- naphthalen-2-ol Compound #38;Trans-3-(3-Amino-6-hydroxy-4,4-dimethyl- 1 ,2,3,4- tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid ethyl ester Compound #39;Trans-7- amino-8,8-dimethyl-6-phenethylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #40;Trans-2-(3-amino-6-hydroxy-4,4-dimethyll ,2,3,4- tetrahydronaphthalen-2-ylsulfanyl)-propionamide Compound #41 ;Trans-3-(3-amino-6- hydroxy-4,4-dimethyl- 1 ,2,3 ,4-tetrahydro-naphthalen-2-ylsulf anyl)-propionic acid Compound #42;Trans-2-[3-(3-Amino-6-hydroxy-4,4-dimethyl- 1 ,2,3,4-tetrahydro- naphthalen-2-ylsulfanyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionamide Compound #43; 3-trans-(2-ethoxycarbonyl-ethylsulfanyl)- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3 ,4-tetrahydro- naphthalen-2-yl Compound #44; 3-trans-(2-carboxy-ethylsulfanyl)- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-2-yl Compound #45; and pharmaceutically acceptable derivatives thereof. 19. The compound of claim 18 wherein said compound is selected from the group consisting of compound#l, compound#3, compound#4, compound#5, compound#9, compound#ll, compound#15, compound#31, compound#36, compound#37, compound#39 compound#41, compound#43, compound#44 and compound#45. 20. The compound of claim 19 wherein said compound is selected from the group consisting of compound#l, compound#3, compound#5, compound#36, compound#44 and compound#45. 21. The compound of claim 19 wherein said compound is selected from the group consisting of compound#32 and compound#33. 22. A compound according to any one of claims 1 to 20 wherein said compound is in the form of the (+) enantiomer, the (-) enantiomer and mixture of the (+) and (-) enantiomer including racemic mixture. 23. A compound according to any one of claims 1 to 20 wherein said compound is in the form of the (+) enantiomer. 24. A compound according to any one of claims 1 to 20 wherein said compound is in the form of the (-) enantiomer. 25. A compound according to any one of claims 1 to claim 24 for use in therapy. 26. A method of treating pain in a mammal comprising administering to said mammal an analgesic amount of a compound as defined in any one of claims 1 to 24. 27. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 24 and pharmaceutically acceptable carriers, diluents or adjuvants. 28. Use of a compound according to any one of claims 1-24, for the manufacture of a medicament for the treatment of pain.

Inventors: BEDNARSKI KRZYSZTOF, DIXIT DILIP, LI TIECHAO, ROBERTS EDWARD, STORER RICHARD, WANG WUYI, BEDNARSKI, KRZYSZTOF, DIXIT, DILIP, LI, TIECHAO, ROBERTS, EDWARD, STORER, RICHARD, WANG, WUYI
Applicants: ASTRA AB, ASTRA PHARMA INC, BEDNARSKI KRZYSZTOF, DIXIT DILIP, LI TIECHAO, ROBERTS EDWARD, STORER RICHARD, WANG WUYI, ASTRA AKTIEBOLAG, ASTRA PHARMA INC., BEDNARSKI, KRZYSZTOF, DIXIT, DILIP, LI, TIECHAO, ROBERTS, EDWARD, STORER, RICHARD, WANG, WUYI
Application year: 1999
Main classification: C07C323
IPC codes: A61K31, A61P25, C07B53, C07B55, C07C53, C07C323, C07D213, C07D239, C07D249, C07F9