NOVEL OXO-AMINOTETRALIN COMPOUNDS USEFUL IN PAIN MANAGEMENT

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

Description: NOVEL OXO-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, 6, 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 6 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 Encvclopedia of Pharmacologv 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 oxo-aminotetralin compounds which are represented by formula (I): and pharmaceutically acceptable derivative thereof; wherein; X is selected from anyone of (i) a bond; (ii) -CR7R8- wherein R 7 and Re 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 ^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 COORc wherein R« is C 2 _6alkenyl or C 2- 6alkynyl; R 7 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. t2 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 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, Cβ-1 2 aralkyl, C 6- ι 2 aryloxy, Cι.ι 2 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 - δ 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 -i 2 aryl, C 6 -ι 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 R5 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; R4 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; 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 . 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-Cι- 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 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 present 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 Rg- wherein R 7 and Re 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 COOR c wherein R e is Cι. 6 alkyl; R 7 and Rg can also be connected to form a C 3 . 8 cycloalkyl. X is more preferably -CR 7 Rs- wherein R 7 and Rg are independently selected from the group consisting of Cι_ 6 alkyl, and H. X is most preferably -CH 2 -. Ri is preferably selected from the group consisting of H, C 6 -i 2 aryl, and C 6- i2 aralkyl. Ri is more preferably selected from the group consisting of C 1-6 alkyl, C 6 -i2 aryl, and C 6- i 2 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 independentiy H, C 2-ό alkenyl or C 2 - 6 alkynyl. More preferably, n is 1 or 2 and Rx and Rxi are C h alky!. Most preferably, Rx and R i are methyl or ethyl. In an alternative embodiment, Ri is selected from the group consisting of CH , -(CH2) n - CH 3 , and -(CH 2 ) n -O-CH 3 wherein n is an integer selected between 1 and 5 In an alternative preferred embodiment Ri is C 6 .i2 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, Cι. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O-C 1-6 alkyl, O-C 2 - 6 alkenyl, O-C 2- 6alkynyl, , 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- 6alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 lkynyl. In an alternative embodiment, Ri is C 6- i 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 C^ alkyl, Cι.6alkyl, C 2 ^alkenyl, C 2-6 alkynyl, O-C 2-6 alkynyl, , S-d -6 alkyl, S-C 2- 6alkenyl, S-C 2 ^alkynyl, N-C^ alkyl, N-C ∑ -βalkenyl, N-C - 6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is 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-Cι.6 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 C M alkyl substituted by a hydroxyl. R4 and R 5 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. R4 and R 5 are preferably ethyl. R4 and R 5 are preferably methyl. R can be substituted at any position on the aromatic ring. More preferably R$ is adjacent to the carbon bearing the OH. In an alternative embodiment, the present invention provides compounds of the formula (II) or (HI) (H) flu) and pharmaceutically acceptable derivative; wherein each of X, Ri, R 2 , R3, R». Rs, and R are defined above. R is preferably, H, methyl, halogen or OR b wherein R t , is Cι. 6 alkyl, C2- 6 alkenyl or C2 -6 alkynyl. R« 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 be 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 (between the centers marked by an asteriks on the general formula (I)). More preferably the compounds of the present invention are present in the form of trans- (+) enantiomers and trans (-) enantiomers. Preferred compounds of the invention include: Trans-7-Amino-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#l);Trans-7-Amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2- ol (compound#2); Trans-7- Amino-8 ,8-dimethyl-6-phenoxy-5 ,6,7 ,8-tetrahydro-naphthalen-2-ol (compound#3); Trans-7-Amino-6-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#4); Trans-7-Amino-8,8-dimethyl-6-propoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#5); Trans-7-Amino-8,8-dimethyl-6-(2-phenoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#6); Trans-7- Amino-6-ethoxy-8 ,8-dimethyl-5 ,6,7 ,8-tetrahydro-naphthalen-2-ol (compound#7) ; Trans-7-Amino-8,8-diethyl-6-(2-methoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#8); Trans-7-Amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#9); Trans-7-Amino-8,8-diethyl-6-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#10); Trans-7-Amino-8,8-spiropentanyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#ll); Trans-7-Amino-6-methoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#12); Trans-7-Amino-6-ethoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#13); Trans-7-Amino-6-(2-phenoxy-ethoxy)-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#14); Trans-3-Amino-4,4-diethyl-l,2,3,4-tetrahydro-naphthalene-2,6-diol (compound#15) (-)Trans-3-Ethoxy- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride (compound #16); (+)Trans-3-Ethoxy- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride (compound #17); 1 , 1 -diethyl-7-hydroxy-3-trans-(3-hydroxy-propoxy)- 1 ,2,3 ,4-tetrahydro-naphthalen-2-yl- ammonium; chloride (compound#18); 7-Amino-6-(2-amino-ethoxy)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2- ol; BIS- trifluoroacetic acid salt (compound#19); 3-(3-Amino-4,4-diethyl-6-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-2-yloxy)-propionic acid; trifluoroacetic acid salt (compound#20); and pharmaceutically acceptable derivative thereof; wherein said compound in the form of the (+) enantiomer, the (-) enantiomer and mixture of the (+) and (-) enantiomer including racemic mixture More Preferred compounds of this invention are selected from the group consisting of: compound#l, compound#2, compound#3, compound#4, compound#5, compound#6, compound#7, compound#8, compound#9, compound#12, compound#16, compound#17, compound#18 and compound#19. Most preferred compounds of the present invention are selected from the group consisting of compound#l, compound#2, compound#5, compound#8, compound#9, compound#16, compound#17, compound#18 and compound#19. 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 is 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 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) 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 C 1-6 alkyl, C 2-6 alkenyl, a C2-6 alkynyl, halogen, nitro, aminoamidino, amidino, guanido, CONH 2 . COOH, O-Cι -6 alkyl, O-C2-6 alkenyl, O-C 2-6 alkynyl, amino, hydroxyl or COOQ, wherein Q is Cτ. 6 alkyl, C 2-6 alkenyl, a C 2 . alkynyl, such as phenyl and naphthyl. The term "aralkyl" represents an aryl group attached to the adjacent atom by a Cι -6 alkyl, 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 ό - 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, C 1 . 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, C 6- ι 2 aryl, C 6- ι 2 aralkyl, and C 6 .ι 2 heteroaryl(e.g., diethoxyphosphorylmethyl). The term "halogen" encompasses chloro, fluoro, bromo and iodo. 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 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 - WO QO/37426 PCT/SE99/02402 13 LAH lithium aluminium hydride LHMDS lithium bis(trimethylsilyl)amide NHMDS sodium bis(trimethylsilyl)amide Ph phenyl PPTS pyridium -toluenesulfonate PTSA / oluenesulfonic acid r.t. room temperature sat. saturated TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography 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, R t , R 2 , R 3 , Rj, Rs and Re are as defined above and P, PI, P2, and P3 are protecting groups. SCHEME 1 (I) Step l 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, 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 , PTS A, 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, PTS A, to produce the compound I. 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 a pharmaceutically acceptable compositions comprising compounds of the present invention and derivatives thereof, in combination with pharmaceutically acceptable carriers diluents or adjuvants. By "derivative" is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compounds of formula (I) or (II) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) compounds of formula (I) or (II) 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. 3 14 125 by incorporating H or C within its structure or by conjugation to I. 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 are used throughout the examples and can be found in the Aldrich Chemical Company and Bachem catalogues. 22 EXAMPLE 1 compound # 1 EXAMPLE 1 Synthesis of tr /ιy-7-Amino-8,8-diethyl-6-methylsulfanyl-5,6,7,8-dihvdro-naphthalen-2-ol hydrochloride Step 1 : l,l-DiethyI-7-methoxy-3,4-dihydro-lH-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, 1.25 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, 30.2 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 ether. The organic layer was then washed with H2O, brine, dried over MgSO4, filtered then evaporated. The residue was purified by a flash chromatography (5%AcOEt Hex) (4.40g, 78%). IH NMR (CDC13) : 7.12 (IH, d, J=8.0Hz), 6.78 (2H, m), 3.84 (3H, s), 2.97 (2H, t, J=6.0 Hz), 2.6 (2H, t, J=6.0 Hz), 2.10 (2H, m), 1.71 (2H, m), 0.63 (6H, t, J=7.5 Hz). Step 2 : l,l-Diethyl-7-methoxy-3,4-dihydro-lH-naphthalen-2-one oxime (B) 1,1 -Diethyl-7-methoxy-3 ,4-dihydro- 1 H-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 H2O, HC1 10%, H2O, brine , dried over MgSO4 and filtered through a small silica pad. The crude compound was used without any other purification (4.69g, 100%). IH NMR (CDC13) : 7.94 (IH, s), 7.06 (IH, d, J=8 Hz), 6.84 (IH, d, J=2.5 Hz), 6.73 (IH, dd, J=2.5 and 8 Hz), 3.83 (3H, s), 2.80-2.75 (4H, m), 2.08 (2H, m), 1.85 (2H, m), 0.68 (6H, t, J=7.5 Hz). Step 3 : 7,7-Diethyl-5-methoxy-la,2,7,7a-tetrahydro-lH-l-aza- cyclopropa[b]naphthalene (C) To a solution of l,l-Diethyl-7-methoxy-3,4-dihydro-lH-naphthalen-2-one oxime (4.68g, 18.96 mmol) in dry THF (100 mL) at 0°C was added the diethylamine (4.9 mL, 47.4 mmol) and the LAH (95% powder) (2.16g, 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 H2O (2x), brine, dried over MgSO4, filtered then evaporated. The residu was purified by a flash chromatography (3% MeOH/ CH2C12) (3.889 g, 89%). IH NMR (CDC13) : 6.99 (IH, d, J=8 Hz), 6.76 (2H, m), 3.13 (2H, m), 2.40 (IH, bs), 2.10- 2.05 (2H, m), 1.84 (IH, m), 1.62 (4H, m), 1.02 (3H, t, J=7.5 Hz), 0.75 (3H, t, J=7.5Hz). Step 4 : 7,7-DiethyI-la,2,7,7a-tetrahydro-lH-l-aza-cyclopropa[b]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 CH2C12 (170 mL) at -78°C was added the BBr3 (lM in CH2C12) (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 NaHCO3, diluted with AcOEt. The organic layer was washed with H2O, brine, dried over MgSO4, filtered then evaporated. The residu was purified by a flash chromatography ( 3% MeOH /CH2C12) (2.917g, 80%). IH NMR (CDC13) : 6.93 (IH, d, J=8.0 Hz), 6.68 (IH, d, J=2.5 Hz), 6.64 (IH, dd, J=8 and 2.5 Hz), 3.12 (2H, m), 2.42 (IH, bs), 2.14 (IH, bs), 2.04 (IH, m), 1.82 (IH, m), 1.65 (4H, m), 1.02 (3H, t, J=7.5 Hz), 0.75 (3H, t, J=7.5Hz). Step 5 : 5-tert-Butoxycarbonyloxy-7,7-diethyI-la,2,7,7a-tetrahydro-l-aza- cyclopropa[b]naphthalene-l-carboxylic acid tert-butyl ester (E) To a solution of 7,7-Diethyl-la,2,7,7a-tetrahydro-lH-l-aza-cyclopropa[b]naphthalen-5-ol (1.5g, 6.90 mmol) in CH2C12 (30 mL) at r.t was added the (Boc)2O (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 NH4C1, diluted with AcOEt. The organic layer was washed with H2O, brine, dried over MgSO4, filtered then evaporated. The residu was purified by a flash chromatography ( 5% to 25% AcOEt/Hex) (2.44g, 84%). IH NMR (CDC13) : 7.05-6.95 (3H, m), 3.29 (IH, d, J=17 Hz), 3.04 (IH, dd, J=2Hz and 17Hz), 2.94 (IH, m), 2.67 (IH, d, J=6.5 Hz), 2.05-1.95 (2H, m), 1.65-1.50 (11H, m), 1.43 (9H, s), 1.11 (3H, t, J=7.5 Hz), 0.72 (3H, t, J=7.5 Hz). Step 6 : Carbonic acid 7-tert-butoxycarbonyIamino-trans-6-ethoxy-8,8-diethyl- 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (F) 5-tert-Butoxycarbonyloxy-7,7-diethyl-la,2,7,7a-tetrahydro-l-aza- cyclopropa[b]naphthalene-l-carboxylic acid tert-butyl ester (224.0mg ; 0.54mmol) placed under Argon at room temperature was dissolved in anhydrous ethanol (8.0 mL). To this solution was added a catalytic amount of pyridinium p-toluene sulfonate. The reaction mixture was stirred overnight. The next day, the reaction mixture was poured into an aqueous solution of sodium bicarbonate and it was extracted using dichloromethane. The combined organic layers were dried over sodium sulfate, filtered , and the solvent was removed. The crude was purified by flash chromatography using ; hexanes : ethyl acetate (9 :1) then (8 :2) as the eluent. The isolated product is a solid (129mg, 55%). Step 7 : Carbonic acid 7-tert-butoxycarbonyIamino-trans-6-ethoxy-8,8-diethyU 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester 5-tert-Butoxycarbonyloxy-7,7-diethyl- 1 a,2,7,7a-tetrahydro- 1 -aza- cyclopropa[b]naphthalene-l-carboxylic acid tert-butyl ester (346.0mg ; O.83mmol) placed under Nitrogen was dissolved using anhydrous chloroform (15.0mL) followed by 0.5 equivalents of Ytterbium trifluoromethanesulfonate (257.0 mg ;0.42mmol) were then added. The reaction mixture was allowed to stir at room temperature overnight. The next day, it was poured into an aqueous solution of sodium bicarbonate and extracted using dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered , and the solvent was removed by vacuo. The crude was purified by flash chromatography using ; hexanes : ethyl acetate (9 : 1) then (8 :2) as the eluent. The isolated product is a solid (275mg, 71%). IH NMR (400MHz) (CDC13; d; ppm): 7.06 (IH, d, J=8.3Hz), 6.93-6.99 (2H, m). 4.33 (IH, d, J=10.4Hz) ; 4.06 (IH, dd, Jl=J2=10.0Hz) ; 3.72 (IH, m) ; 3.64 (IH, m) ; 3.54 (IH, m), 3.22 (IH, dd, Jl=6.0Hz, J2=16.2Hz), 2.79 (IH, dd, Jl=9.5Hz, J2=16.0Hz), 1.72 (3H, m), 1.51 (IH, m), 1.55 (9H, s), 1.47 (9H, s), 1.22 (3H, t, J=7.0Hz) ; 0.74 (3H, t, J=7.5Hz) ; 0.69 (3H, t, J=7.3Hz). Step 8: Trans-3-Ethoxy-l,l-diethyI-7-hydroxy-1^2 ,4-tetrahydro-naphthalen-2-yl- ammonium chloride (compound #1) Carbonic acid 7-tert-butoxycarbonylamino-trans-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro- naphthalen-2-yl ester tert-butyl ester (200mg ; 0.43mmol) placed under nitrogen at room temperature was dissolved in tetrahydrofuran (5.0mL) and trifluoroacetic acid (3.0mL) was then added and the reaction mixture was stirred for about an hour. The solvents were then evaporated by vacuo and a solution of hydrochloric acid in ether (1.0M) (50mL) was then added. The reaction mixture thus obtained was then stirred for another hour. The solvents were removed by vacuo and the isolated solid washed several times with ether than dichloromethane. The isolated product is a yellow powder (145mg, >99%). IH NMR (400MHz) (CD3OD; d; ppm): 6.98 (IH, d, J=8.9Hz), 6.68 (2H, m). 3.96 (IH, m), 3.87 (IH, m), 3.56 (IH, m), 3.39 (2H, m), 2.57 (IH, dd, Jl=10.0Hz, J2=15.5Hz), 2.07 (IH, m), 1.73 (IH, m), 1.66 (2H, m), 1.30 (3H, t, J=7.0Hz) 0.80 (3H, t, J=7.4Hz), 0.70 (3H, t, J=7.3Hz). EXAMPLE 2 chiral trans chiral trans Step 2 Step 2A chiral chiral (-) trans (+)trans Step l Trans-7-Amino-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (23 lmg ; 0.88mmol) is placed under nitrogen at room temperature and dissolved with anhydrous acetonitrile (20 mL). Triethylamine 0.25mL (1.75mmol) and the chiral auxiliary reagent 504mg (1.75mmol) are then added. The reaction mixture thus obtained was heated overnight at reflux. The following day, the reaction mixture is cooled back to room temperature and it is then poured into an aqueous solution of sodium bicarbonate and extracted using dichloromethane. The combined organic layers were washed with 0.1N HC1, brine, and were then dried over sodium sulfate. After filtration, the solvent was removed by vacuo. The crude was purified by flash chromatography using ; hexanes : ethyl acetate (9 : 1) then (8 :2) as the eluent. The isolated products are a colorless oils (72%). (less polar isomer): IH NMR (400MHz) (CDC13; d; ppm): 7.41 (10H, m) ; 7.03 (IH, m) ; 6.94 (2H, m) ; 5.84 (2H, m) ; 4.54 (IH, d) ; 4.10 (IH, m) ; 3.61 (2H, m) ; 3.39 (IH, m) ; 3.19 (IH, m) ; 2.72 (IH, m) ; 1.71 (2H, m) ; 1.64 (3H, d) ; 1.50-1.62 (2H, m) ; 1.57 (3H, d) ; 0.98 (3H, t, J=7.0Hz) ; 0.72 (6H, 2t). (more polar isomer): IH NMR (400MHz) (CDC13; d; ppm): 7.37 (10H, m) ; 7.03 (IH, m) ; 6.95 (2H, m) ; 5.82 (2H, m) ; 4.51 (IH, d) ; 4.10 (IH, m) ; 3.71 (2H, m) ; 3.55 (IH, m) ; 3.23 (IH, dd) ; 2.80 (IH, dd) ; 1.40-1.78 (4H, m) ; 1.67 (3H, d) ; 1.56 (3H, d) ; 1.22 (3H, t) ; 0.68 (6H, 2t). Step 2 (-)Trans-3-Ethoxy-l,l-diethyl-7-hydroxy-1^3,4-tetrahydro-naphthalen-2-yl- ammonium chloride (compound #16) Carbonic acid trans-6-ethoxy-8,8-diethyl-7-( l-phenyl-ethoxycarbonylamino)-5,6,7,8- tetrahydro-naphthalen-2-yl ester 1-phenyl-ethyl ester (less polar isomer) (3 lmg ; 0.055mmol) placed under nitrogen at room temperature was dissolved in dichloromethane (8.0mL) and trifluoroacetic acid (3.0mL) was then added and the reaction mixture was stirred for about an hour. The solvents were then evaporated by vacuo and a solution of hydrochloric acid in ether ( 1.0M) (7mL) was then added. The reaction mixture thus obtained was then stirred for another hour. The solvents were removed by vacuo and the isolated solid washed several times with ether, hexanes, than dichloromethane. The isolated product is a yellow powder (15.7mg, 95%). IH NMR (400MHz) (CD3OD; d; ppm): 6.98 (IH, d, J=8.9Hz, aromatic), 6.68 (2H, m, aromatics). 3.96 (IH, m, CH-NH2), 3.87 (IH, m), 3.56 (IH, m), 3.39 (2H, m), 2.57 (IH, dd, Jl=10.0Hz, J2=15.5Hz), 2.07 (IH, m), 1.73 (IH, m), 1.66 (2H, m), 1.30 (3H, t, J=7.0Hz) 0.80 (3H, t, J=7.4Hz), 0.70 (3H, t, J=7.3Hz). [α]D 443.00° c = 0.2 step 2A (+)Trans-3-Ethoxy-l,l-diethyl-7-hydroxy-1^3?4-tetrahydro-naphthaIen-2-yI-ammonium chloride (compound #16) Carbonic acid trans-6-ethoxy-8,8-diethyl-7-(l-phenyl-ethoxycarbonylamino)-5,6,7,8-tetrahydro- naphthalen-2-yl ester 1-phenyl-ethyl ester (more polar isomer) (32mg ; 0.057mmol) placed unde nitrogen at room temperature was dissolved in dichloromethane (5.0mL) and trifluoroacetic acid (3.0mL) was then added and the reaction mixture was stirred for about an hour. The solvents w then evaporated by vacuo and a solution of hydrochloric acid in ether (1.0M) (lOmL) was then added. The reaction mixture thus obtained was then stirred for another hour. The solvents were removed by vacuo and the isolated solid washed several times with pentane, hexanes, than dichloromethane. The isolated product is a yellow powder (10.3mg, 60%). IH NMR (400MHz) (CD3OD; d; ppm): 6.98 (IH, d, J=8.9Hz, aromatic), 6.68 (2H, m). 3.96 (IH, m), 3.87 (IH, m), 3.56 (IH, m), 3.39 (2H, m), 2.57 (IH, dd, Jl=10.0Hz, J2=15.5Hz), 2.07 (IH, m, CH2), 1.73 (IH, m), 1.66 (2H, m), 1.30 (3H, t, J=7.0Hz) 0.80 (3H, t, J=7.4Hz), 0.70 (3H, t, J=7.3Hz). [α]D -43.68° c = 0.19 In a like manner, the following compounds were prepared: compound #2 (±)-TRANS-7-AMINO-6-METHOXY-8,8-DIMETHYL-5,6,7,8- TETRAHYDRO-NAPHTHALEN-2-OL HCL SALT IH NMR (400MHz) (DMSO-d6; d; ppm): 9.24 (IH, bs), 8.30 (3H, bs), 6.88 (IH, d, J=9.3Hz), 6.74 (IH, d, J=2.2Hz), 6.59 (IH, dd, J=2.2 and 9.3Hz), 3.65 (IH, m), 3.43 (3H, s), 3.40 (IH, m), 3.27 (IH, m), 3.13 (IH, m), 1.40 (3H, s), 1.17 (3H, s). compound #3 (±)-TRANS-7-AMINO-8,8-DIMETHYL-6-PHENOXY-5,6,7,8-TETRAHYDRO- NAPHTHALEN-2-OL TFA SALT IH NMR (400MHz) (DMSO-d6; d; ppm): 9.26 (IH, bs), 8.31 (3H, bs), 7.34 (2H, t, J=8.5Hz), 7.15 (2H, d, J=8.1Hz), 7.01 (IH, t, J=7.2Hz), 6.88 (IH, d, J=8.4Hz), 6.78 (IH, d, J=2.4Hz), 6.60 (IH, dd, J=2.4 and 8.4Hz), 4.74(lH,m), 3.51 (IH, m), 3.30 (IH, dd, J=5.4 and 10.3Hz), 2.72 (IH, dd, J=5.4 and 10.3Hz), 1.47 (3H, s), 1.24 (3H, s). compound #4 l,l-DIETHYL-7-HYDROXY-TRANS-3-ISOPROPOXY-l,2,3,4-TETRAHYDRO- NAPHTHALEN-2-YL-AMMONIUM CHLORIDE IH NMR (400MHz) (CD3OD; d; ppm): 6.98 (IH, d, J=9.0Hz), 6.67 (2H, m). 4.04 (IH, m), 3.97 (IH, m), 3.34 (IH, m), 3.32 (IH, m), 2.58 (IH, dd, Jl=10.0Hz, J2=15.6Hz), 2.05 (IH, m), 1.76 (IH, m), 1.68 (2H, dd, Jl=7.5Hz, J2=15.1Hz), 1.28 (3H, d, J=6.1Hz), 1.25 (3H, d, J=6.0Hz), 0.79 (3H, t, J=7.5Hz), 0.69 (3H, t, J=7.2Hz). compound #5 (±) l,l-DIETHYL-7-HYDROXY-TRANS-3-PROPOXY-l^,3,4-TETRAHYDRO- NAPHTHALEN-2-YL-AMMONIUM CHLORIDE IH NMR (400MHz) (CD3OD; d; ppm): 6.97 (IH, d, J=8.7Hz), 6.66 (2H, m). 3.94 (IH, m), 3.72 (IH, m), 3.48 (IH, dd, Jl=7.0Hz , J2=14.1Hz), 3.39 ( IH, m), 3.37 (IH, m), 2.55 (IH, dd, Jl=9.8Hz, J2=15.3Hz), 2.06 (IH, m), 1.67 (5H, m), 1.00 (3H, t, J=7.3Hz), 0.78 (3H, t, J=7.3Hz), 0.68 (3H, t, J=7.0Hz). compound #6 (±)l,l-DIETHYL-7-HYDROXY-TRANS-3-(2-PHENOXY-ETHOXY)- 1 ,23, 4-TETRAHYDRO-NAPHTHALEN-2-YL-AMMONIUM CHLORIDE IH NMR (400MHz) (CD3OD; d; ppm): 7.29 (2H, m), 6.96 (4H, m), 6.69 (2H, m), 4.23 (2H, m), 4.13 (2H, m), 3.93 (IH, m), 3.45 (2H, m), 2.64 (IH, dd, Jl=9.9Hz, J2=15.5Hz), 2.07 (IH, m), 1.72 (IH, m), 1.67 (2H, m), 0.80 (3H, t, J=7.5Hz), 0.70 (3H, t, J=7.2Hz). (±)compound #7 7-AMINO-TRANS-6-ETHOXY-8,8-DIMETHYL-5,6,7,8-TETRAHYDRO- NAPHTHALEN-2-OL HCL SALT IH NMR (400MHz) (CD3OD; d; ppm): 6.94 (IH, d, J=8.3Hz), 6.79 (IH, d, J=2.4Hz). 6.64 (IH, dd, Jl=2.4 Hz, J2=8.3Hz), 3.87 (IH, m), 3.77 (IH, m), 3.56 (IH, m), 3.35 (IH, m), 3.23 (IH, dd, Jl=0Hz, J2=10.8Hz), 2.63 (IH, dd, Jl=10.4Hz, J2=15.3Hz), 1.49 (3H, s), 1.31 (3H, t, J=7.0Hz), 1.28 (3H, s). compound #8 (±)l,l-DIETHYL-7-HYDROXY-TRANS-3-(2-METHOXY-ETHOXY)-l,2 ,4- TETRAHYDRO-NAPHTHALEN-2-YL-AMMONIUM CHLORIDE IH NMR (400MHz) (DMSO-d6; d; ppm): 9.24 (IH, bs), 7.97 (3H, bs), 6.91 (IH, d, J=8.2Hz), 6.60 (2H, m), 3.89 (IH, m), 3.79 (IH, m), 3.66 (IH, m), 3.54 (2H, m), 3.45 (2H, m), 3.28 (3H, s), 3.20 (IH, m), 1.84 (2H, m), 1.35 (2H,m), 0.66 (3H, t, J=7.3Hz), 0.56 (3H, t, J=7.1Hz). compound #9 (±)l,l-DIETHYL-7-HYDROXY-TRANS-3-METHOXY- 3,4- TETRAHYDRO-NAPHTHALEN-2-YL- AMMONIUM CHLORIDE IH NMR (400MHz) (CD3OD; d; ppm): 7.00 (IH, d, J=6,4Hz), 6.68 (2H, m). 3.87 (IH, m), 3.53 (3H, s), 3.41 (2H, m), 2.54 (IH, dd, Jl=10Hz, J2=16Hz), 2.07 (IH, m), 1.71 (IH, m), 1.66 (2H, m), 0.80 (3H, t, J=7.5H), 0.70 (3H, t, J=7.3Hz). compound #10 (±)l,l-DIETHYL-7-HYDROXY-TRANS-3-(2-HYDROXY-ETHOXY)-l,2,3,4- TETRAHYDRO-NAPHTHALEN-2-YL-AMMONIUM CHLORIDE IH NMR (400MHz) (DMSO-d6; d; ppm): 9.22 (IH, bs), 7.96 (3H, bs), 6.91 (IH, d, J=8.2Hz), 6.60 (2H, m), 4.70 (lH,bs), 3.89 (IH, m), 3.79 (IH, m), 3.66 (IH, m), 3.54 (2H, m), 3.45 (2H, m), 3.20 (IH, m), 1.83 (2H, m), 1.58 (2H,m), 0.66 (3H, t, J=7.3Hz), 0.57 (3H, t, J=7.1Hz). compound #11 (±)-l,l-spiropentanyl trans-7-hydroxy-3-methoxy-l^ 3 » 4-tetrahydro-naphthalen-2-yI- ammonium; trifluoro-acetate IH NMR (MeOD) : 6.95 (IH, d, J=8.5 Hz), 6.73 (IH, d, J=2.5 Hz), 6.63 (IH, dd, J=2.5 Hz and 8.5 Hz), 3.66 (IH, m), 3.53 (3H, s), 3.45-3.35 (2H, m), 2.65 (IH, dd, J=10 Hz and 16 Hz), 2.20 (IH, m), 2.15-1.95 (5H, m), 1.80-1.65 (2H,m). compound #12 (±)7-Hydroxy-3-methoxy-l,l-dipropyl-l,2,3,4-tetrahydro-naphthalen-2-yl- ammonium; trifluoro-acetate IH NMR (MeOD) : 6.99 (IH, d, J=8.0 Hz), 6.70-6.65 (2H, m), 3.84 (IH, qd, J=6.0 hz and 10.0 Hz), 3.53 (3H. s), 3.45-3.35 (2H, m), 2.54 (IH, dd, J=10.0 Hz and 15.5 Hz), 1.95 (IH, m), 1.73 (IH, m), 1.65-1.45 (2H, m), 1.30-1.05 (3H, m), 0.95-0.90 (4H, m), 0.86 (3H, t, J=7.0 Hz). compound #13 (±)3-Ethoxy-7-hydroxy-l,l-dipropyl-1^ ? 4-tetrahydro-naphthalen-2-yl-ammonium; trifluoro-acetate IH NMR (MeOD) : 6.98 (IH, d, J=8.0 Hz), 6.70-6.65 (2H, m), 4.00-3.85 (2H, m), 3.57 (IH. m), 3.39 (2H, m), 2.57 (IH, dd, J=10.0 Hz and 15.5 Hz), 1.95 (IH, m), 1.77 (IH, m), 1.65-1.50 (2H, m), 1.31 (3H, t, J=7.0 Hz), 1.30-1.05 (3H, m), 0.95-0.90 (4H, m), 0.86 (3H, t, J=7.0 Hz). compound #14 (±)7-Hydroxy-3-(2-phenoxy-ethoxy)-l,l-dipropyl-l,2,3,4-tetrahydro- naphthalen-2-yl-ammonium; trifluoro-acetate IH NMR (MeOD) : 7.31 (2H, t, J=8.0 Hz), 7.05-6.95 (4H, m), 6.70-6.65 (2H, m), 4.25 (2H, t, J=5.0 Hz), 4.20-4.05 (2H, m), 3.95 (IH. m), 3.50-3.45 (2H, m), 2.64 (IH, dd, J=10.0 Hz and 15.5 Hz), 1.95 (IH, m), 1.80-1.50 (3H, m), 1.30-1.05 (4H, m), 0.95-0.90 (4H, m), 0.86 (3H, t, J=7.0 Hz). compound #16 (-)Trans-3-Ethoxy-l,l-diethyI-7-hydroxy-l,2,3,4-tetrahydro-naphthalen-2-yI- ammonium chloride compound#17 (+)Trans-3-Ethoxy-l,l-diethyI-7-hydroxy-l,23 . 4-tetrahydro-naphthaIen-2-yI- ammonium chloride compound #18 l,l-diethyl-7-hydroxy-3-trans-(3-hydroxy-propoxy)-l,2,3,4-tetrahydro-naphthaIen-2- yl-ammonium; chloride NMR (1H, DMSO): 9.22(bs, IH), 7.96 (s, 3H), 6.91(m,lH), 6.59 (m, 2H), 4.65 (m, 1 H), 4.00-3.00 (m, 8H), 2.10-1.70 (m, 4H), 1.54 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H), 0.57 (t, J = 6.9 Hz, 3H). compound #19 7-Amino-6-(2-amino-ethoxy)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2- ol; BIS- trifluoroacetic acid salt Η NMR (DMSO) : 9.28 (IH, s), 7.91 (3H,broad), 7.80 (3H, broad), 6.93 (IH, d, J=8.5 Hz), 6.64 (2H, m), 4.00-3.90 (2H, m), 3.60 (IH, m), 3.30 (2H, m), 3.20-3.05 (2H, m), 1.92 (IH, m), 1.84 (IH, m), 1.61 (2H, m), 0.69 (3H, t, J=7.5 Hz), 0.59 (3H, t, J=7.5 Hz). compound #20 3-(3-Amino-4,4-diethyI-6-hydroxy-1^ ,4-tetrahydro-naphthalen-2-yIoxy)-propionic acid; trifluoroacetic acid salt NMR (1H, DMSO): 9.25 (bs, IH), 7.87 (s, 3H), 6.93 (m,lH), 6.60 (m, 2H), 3.90 (m, 2 H), 3.71 (m, 2H), 3.30(m, IH), 3.20 (m, IH), 2.60 (m, 2H), 2.48 (m, IH), 1.88 (m, IH), 1.77 (m, IH), 1.54 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H), 0.58 (t, J = 6.9 Hz, 3H). BIOLOGICAL ASSAYS A. Receptor Affinity - Radioligand Binding Assay Affinity for μ and δ opioid receptors was assessed in vitro using radioligand binding assay employing rat brain membrane preparations as described in Schiller et al., Biophys. Res. Commun., 85, p.1322 (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 and (3H) DAGLE were used as radioligands for the μ and δ receptors, respectively. Radioligand 50 μl, membranes 100 μl and serially diluted test compound were incubated for 1 hr at 22°C. Non specific binding was determined using 500 fold excess of unlabeled ligand 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 ml 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 #1 male mice weighing between 18 and 22g. The mice were weighed and marked and administered peritoneally with 0.3ml/20g by weight 0.02% solution of phenylbenzoquinone (PBQ) . The contortions which appeared during a 15 minute time period following the injection were counted and ED50 values (dose of compound which induced a 50% reduction in the number of writhes observed compared to the control) was calculated. The PBQ was injected at time intervals of 5, 20 or 60 minutes after subcutaneous or oral administration of the compound (or medium, or standard). PBQ solution was prepared by dissolving 20mg of PBQ in 5ml ethanol 90% (sigma, reagent, alcohol). The dissolved PBQ was slowly added to 95ml of distilled water continuously shaken and preheated (not boiled). The PBQ solution was left 2 hours before use, and at all times, protected from light. A new solution was prepared every day for the test. 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. 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 derivatives thereof; wherein; X is selected from anyone of (i) a bond; (ii) -CR Rβ- wherein R and Re 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^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 Ci-ealkyl, C 2 ^alkenyl or C 2-6 alkynyl; R 7 and R« can also be connected to form C 3- β 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 -i 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, 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- i 2 aralkyl, C 6- ι 2 aryloxy, C1.12 acyl, heteroaryl having from 6 to 12 atoms, and phosphoryl; R 2 and R 3 are independently selected from the group consisting of C 1-6 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, C 6- i 2 aryl, C 6- ι 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 4 and Rs are independently selected from the group consisting of Cι_s 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, 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; 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 - 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-Cι- 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 R 4 and Rs are H; and 2) at least one of R2 and R 3 is H or Cι -6 alkyl. 2. The compound of claim 1 wherein 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 4 and Rs are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl. 8. The compound of claim 5 wherein j 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, C 6- i 2 aryl, and C 6- i2 aralkyl. 11. The compound of claim 5 wherein Ri is selected from the group consisting of C 1-6 alkyl, C 6- ι 2 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 C6-t2 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 Ci- δ alkynyl, O-C 1-6 alkyl, O-C 2-6 alkenyl, O-C^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 C h alky!, C ∑ -βalkenyl or C 2-6 alkynyl. 16. The compound of claim 5 wherein Ri is C 6 -i2 aralkyl. 17. The compound of claim 16 wherein Ri is selected from the group consisting of wherein A is selected from the group consisting of Cι -6 alkyl, Cι- alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, O-C [-6 alkyl, O-C 2-6 alkenyl, O-C^alkynyl, , S-C !-6 alkyl, S-C 2-6 alkenyl, S-C 2-6 alkynyl, N-C 2 - 6 alkyl, N-C 2 . 6 alkenyl, N-C 2 -6alkynyl, CF , 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 2 . 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-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#l); Trans-7-Amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#2); Trans-7-Amino-8,8-dimethyl-6-phenoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#3) ; Trans-7-Amino-6-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol compound#4 ; Trans-7-Amino-8,8-dimethyl-6-propoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#5) ; Trans-7-Amino-8,8-dimethyl-6-(2-phenoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#6) ; Trans-7-Amino-6-ethoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#7) ; Trans-7-Amino-8,8-diethyl-6-(2-methoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#8) ; Trans-7-Amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#9) ; Trans-7-Amino-8,8-diethyl-6-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#10) ; Trans-7 -Amino-8,8-spiropentanyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#ll) ; Trans-7-Amino-6-methoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#12) ; Trans-7-Amino-6-ethoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#13) » Trans-7- Amino-6-(2-phenoxy-ethoxy)-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound#14) ; Trans-3-Amino-4,4-diethyl-l,2,3,4-tetrahydro-naphthalene-2,6-diol (compound#15) ; (-)Trans-3-Ethoxy- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3 ,4-tetrahydro-naphthalen-2-yl-ammonium chloride (compound #16) ; (+)Trans-3-Ethoxy- 1 , 1 -diethyl-7-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride (compound #17 ) ; 1 , 1 -diethyl-7-hydroxy-3-trans-(3-hydroxy-propoxy)- 1 ,2,3 ,4-tetrahydro-naphthalen-2-yl- ammonium; chloride (compound#18); 7-Amino-6-(2-amino-ethoxy)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2- ol; BIS- trifluoroacetic acid salt (compound#19); 3-(3-Amino-4,4-diethyl-6-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-2-yloxy)-propionic acid; trifluoroacetic acid salt (compound#20); and pharmaceutically acceptable derivative thereof. 19. The compound of claim 18 wherein said compound selected from the group consisting of compound#l, compound#2, compound#3, compound#4, compound#5, compound#6, compound#7, compound#8, compound#9, compound#12, compound#16, compound#17, compound#18 and compound#19. 20. The compound of claim 19 wherein said compound selected from the group consisting of compound#l, compound#2, compound#5, compound#8, compound#9, compound#16 and compound#17. 21. The compound of claim 19 wherein said compound selected from the group consisting of compound#16 and compound#17. 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 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 anyone of claims 1-24, for the manufacture of a medicament for the treatment of pain.

Inventors: BEDNARSKI KRZYSZTOF, DIXIT DILIP, LAVALLEE JEAN-FRANCOIS, LI TIECHAO, ROBERTS EDWARD, STORER RICHARD, WANG WUYI, BEDNARSKI, KRZYSZTOF, DIXIT, DILIP, LAVALLEE, JEAN-FRANCOIS, LI, TIECHAO, ROBERTS, EDWARD, STORER, RICHARD, WANG, WUYI
Applicants: ASTRA AB, ASTRA PHARMA INC, BEDNARSKI KRZYSZTOF, DIXIT DILIP, LAVALLEE JEAN FRANCOIS, LI TIECHAO, ROBERTS EDWARD, STORER RICHARD, WANG WUYI, ASTRA AKTIEBOLAG, ASTRA PHARMA INC., BEDNARSKI, KRZYSZTOF, DIXIT, DILIP, LAVALLEE, JEAN-FRANCOIS, LI, TIECHAO, ROBERTS, EDWARD, STORER, RICHARD, WANG, WUYI
Application year: 1999
Main classification: C07C215
IPC codes: A61K31, A61P25, A61P43, C07B53, C07C53, C07C215, C07C217