WO2003014089A1

WO2003014089A1 - Aminotetrahydroisoquinoline derivatives as analgesics

Info

Publication number: WO2003014089A1
Application number: PCT/US2002/023698
Authority: WO
Inventors: Richard A. Glennon; Billy R. Martin; Malgozata Dukat; Imad M. Damaj
Original assignee: Virginia Commonwealth University
Priority date: 2001-07-31
Filing date: 2002-07-25
Publication date: 2003-02-20
Also published as: WO2003014089A8

Abstract

Tetrahydroisoquinolines are provided having a secondary, tertiary or quaternary amino group spaced by three carbon atoms from the ring nitrogen, and pharmaceutically acceptable salts and prodrugs thereof. Preferred compounds are of Formula (I), wherein R?1, R2 and R5¿ are independently selected from the group consisting of hydrogen, C¿1-6? alkyl and a moiety wherein any two of R?1, R2 and R5¿, together with the nitrogen to which they are attached, form a heterocyclic ring of 2 to 5 carbons, provided that R?1 and R2, and R5¿ when present, are not each hydrogen, R?3 and R4¿ are independently selected from the group of moieties which are effective to alter the solubility of the compound in physiological fluids or pharmaceutical carriers n and m are independently selected from integers of 0 to 3 and 0 to 4 respectively, p is an integer 0 or 1 and pharmaceutically acceptable salts and prodrugs thereof.

Description

AMINOTETRAHYDROISOQUINO INE DERIVATIVES AS ANALGESICS

The present invention relates to novel compounds that are members of a new class of pharmaceutical agents having antinociceptive activity with an apparently novel mechanism of action.

Nicotine has long been known to possess analgesic activity; however, its toxic effects have hampered its therapeutic application. During the course of investigations to develop novel nicotinic acetylcholinergic analgesics with reduced toxicity, the present inventors have studied the structure-activity relationships required for nicotmic acetylcholinergic (nACh) receptor binding. They have also dissected the structure of nicotine to determine what portions of the nicotine molecule are required for activity. As a result of their studies they have prepared conformationally-restricted aminotetrahydroisoquinolines or AIQs that are active against pain yet surprisingly do not appear to bind effectively to the nACh receptor. Thus a first aspect of the present invention provides a novel aminotetrahydroisoquinoline characterised by presence of a secondary, tertiary or quaternary amino group spaced by three carbon atoms from the ring nitrogen, together with pharmaceutically acceptable salts and prodrugs thereof.

Preferred compounds of the first aspect of the invention have secondary, tertiary or quaternary amino groups at the 8 position as shown in general formula I.

Thus particularly preferred compounds of the present invention are of general formula

Formula I wherein R¹, R² and R⁵ are independently selected from the group consisting of hydrogen, Cj_-6 alkyl and a moiety wherein any two of R¹, R² and R⁵, together with the nitrogen to which they are attached, form a heterocyclic ring of 2 to 5 carbons, provided that R and R , and R , if present, are not all hydrogen,

R³ and R⁴ are independently selected from the group of moieties which are effective to alter the solubility of the compound in physiological fluids or pharmaceutical carriers n and m are independently selected from integers of 0 to 3 and 0 to 4 respectively, p is an integer 0 or 1 and pharmaceutically acceptable salts and prodrugs thereof.

The expression 'moieties which are effective to alter the solubility of the compound in physiological fluids or pharmaceutical carriers' particularly refers to alkyl, aryl, carboxyl, hydroxy, hydroxyalkyl, aralkyl, carboxylalkyl, haloalkyl, alkyloxy, aryloxy, acyloxy, alkoxyalkyl, amino, amido, nitro, nitrate and halo groups. Alkyl chains in such moieties are preferably of from 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms. Where alkyl is cycloalkyl this will be from 3 to 7 carbon atoms, more preferably 5 or 6 atoms in the ring.

By pharmaceutically acceptable salts is particularly meant salts with pharmaceutically acceptable anions and cations, particularly anions in acid form associated with the amino group such is well known to those skilled in the art. Thus particularly preferred salts would be the hydrochloride, hydrobromide, hydroiodide, trifluoroacetic acid, acetic acid or other equivalent acid salts.

The expression prodrugs thereof is particularly directed at esters of carboxy or hydroxy derivatives and amides of amino compounds where these may be used to effect increased distribution of the active compound to a site in the patient body where effect is desired. All such esters and amides would be of commonly used pharmaceutical length, ie. where Cj-ie alkyl carboxylic acids or alcohols are provided as esterifying or amidating acids, dependent upon the presence of carboxy, hydroxy or amino groups on the active molecule. The prodrug molecule would thus be metabolised to give the compound of the invention in the patient body by removal of the aforesaid Cι_ι₆ alkyl carboxylic acid or alcohol residue in vivo.

Most preferred compounds of the invention are those where n, m and q are all 0 and R¹ and R² are independently selected from the group consisting of hydrogen, methyl and ethyl, remembering that both should not be hydrogen.

It will be realised that preferred compounds of this type will also be provided where the amino group at position 8 is a quaternary amino group, particularly being selected from trimethylamino, triethylamino, methyldiethylamino and dimethyletheylamino groups. It will be further realised by those skilled in the art that such quaternary compounds will be charged, thus require a balancing anion. Thus these compounds would be potentially restricted in effect to the peripheral nervous system, unless administered directly to the CNS, due to difficulty in passage across the blood brain barrier. Such compounds would be of formula II

Formula II

wherein R¹ to R⁵, n and m are as defined for Formula 1, X is a counterion and p is the number of negative charges on the counterion. More preferably R¹, R² and R⁵ are independently selected from methyl and ethyl and more preferably are all methyl or all ethyl.

It will further be realised by those skilled in the art that compounds of formula I and II may exist as isomers with different optical activity and thus can exist as racemate or in a form where one particular optical isomer is in the majority or perhaps the only form present. The present invention provides for racemates and for optically pure enantiomers and mixtures of these. Production of pure or mixed forms other than 50:50 may be provided by selection of appropriate starting materials and reaction mechanisms which retain the purity of the starting isomers. Alternatively resolution of isomers may be undertaken, eg. by use of column chromatography separation techniques, eg. using chiral columns if necessary.

In a second aspect of the present invention there is provided a method of treating a patient in need of therapy for pain comprising administering a therapeutically effect amount of a compound as described in the first aspect.

In a third aspect of the present invention there is provided a compound of the first aspect for use in therapy, and particularly to treat pain.

In a fourth aspect of the present invention there is provided the use of a compound of the first aspect in the manufacture of a medicament for the treatment of pain.

In a fifth aspect of the present invention there is provided an analgesic composition comprising a compound of the first aspect. Particularly such compositions are sterile and pyrogen free if for parenteral administration. Also for such parenteral administration, and further for non-parenteral administration, ie. via oral, buccal, rectal, topical or transdermal routes, the composition will preferably comprise a pharmaceutically acceptable carrier, excipient or diluent

In a sixth aspect of the present invention there is provided a method of synthesising a compound of the first aspect of the invention comprising oxidising a tetrahydroisoquinoline to provide an 8-oxotetrahydroisoquinoline, and then reductively amidating the aforesaid 8-oxo group oxygen using a secondary amine and a reducing agent.

Preferably the reducing agent is a hydride, eg sodium cyanoborohydride or lithium aluminium hydride, although such reactions may be performed using catalyst, eg. Raney Nickel catalyst, in presence of hydrogen and the selected amine. A modification of this route takes the 8-oxo compound produced by the oxidation and reduces this to the corresponding 8-hydroxy compound using a reducing agent such as sodium borohydride and the resultant hydroxy group then replaced with a halogen atom, eg. chloride, using a reagents such thionyl chloride. Appropriate solvents to use for these reactions will occur to those skilled in the art, but are illustrated in the Examples below.

It will be realised by those skilled in the art that compounds bearing substituents R³ and R⁴ may be conveniently provided, at least in some cases by starting with an appropriately substituted tetrahydroisoquinoline bearing these substituents.

The AIQs of the present invention have been evaluated for antinociceptive activity in mouse tail-flick assay and are found to be active. Interestingly, these analogs displayed very low or no affinity for nACh receptors suggesting that their antinociceptive effects are mediated via another population of receptors. Consistent with this conclusion, the nACh receptor antagonist mecamylamine was unable to attenuate the antinociceptive effects of the AIQs as measured in the tail-flick assay.

The preferred compounds of the invention produces antinociceptive effects in several different assays, do not bind effectively at opioid receptors and their analgesic actions were not antagonized by opioid antagonists. Thus these AIQs represent structurally novel antinociceptive agents. Additionally, they seem to produce their antinociceptive effects via a non-α4β2 nicotinic, non-opioid mechanism. Their mechanism of action is potentially unique. ,

The compounds of the invention may be formulated into the compositions of the invention by associating them, eg. by mixing or enclosing them, with a physiologically acceptable diluent or carrier for use as pharmaceuticals for veterinary, for example in a mammalian context, and particularly for human use, by a variety of methods.

For instance, they may be applied as a composition incorporating a liquid diluent or carrier, for example an aqueous or oily solution, suspension or emulsion, which may often be employed in injectable form for parenteral administration and therefore may conveniently be sterile and pyrogen free. Oral administration is preferred for the preferred compounds of the invention. Although compositions for this purpose may incorporate a liquid diluent or carrier, it is more usual to use a solid, for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate. Such solid compositions may conveniently be of a formed type, for example as tablets, capsules (including spansules), powders etc.

Other forms of administration than by injection or through the oral route may also be considered in both human and veterinary contexts, for example the use of suppositories or pessaries. Another form of pharmaceutical composition is one for buccal or nasal administration, for example lozenges, nose drops or an aerosol spray and as ointments or other creams for application topically. Compositions may be formulated in unit dosage form, i.e. in the form of discrete portions each comprising a unit dose, or a multiple or sub-multiple of a unit dose.

Typical dosages for use in human therapy will usually he in the region of about 0.1 to 50g daily, preferably 0.5 g to 20 g daily, particularly from about 1 or 2 g to 10 or 15 g daily, for example about 5 g, veterinary doses being on a similar g/kg body weight ratio. However, it will be appreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels. Where desired, more than one compound according to the present invention may be administered in the pharmaceutical composition, when the total dosage will usually correspond to those discussed above, or, indeed, other active compounds may be included in the composition.

Particularly formulations may be devised by those skilled in the art by using oprinciples well known ion the art , eg by reference to Remington: Science and Practice of Pharmacy, Mack Publishing (eg 19^th Edition (1995) and any later Edition) incorporated herein by reference.

The present invention will now be described by way of illustration only by reference to the following non-limiting examples and their associated figures. Further embodiments falling within the scope of the claims will occur to those skilled in the art in the light of these. FIGURES

Figure 1 shows an outline scheme for synthesising compounds of the present invention.

EXAMPLES

Example 1: 8-Amino-5,6 ,8-tetrahvdroisoquinoline (AIO-005/APX-422) 5,6-Dihydro-7(H)-isoquinolin-8-one Hydrochloride. (AIQ-001): 5,6,7,8- Tetrahydroisoquinoline (15 g, 112 mmol), AcOH (8.7 mL) and H₂O (500 mL) were stirred in a 2000-ml round bottom flask while MnO₄ (40 g, 253 mmol) was introduced in portions over a 5-min period. After 1 h the resulting black slurry was filtered through a sintered glass funnel, and the filtrate was washed with CH C1 (5 x 100 mL). The combined washes were dried (Na₂SO₄) and filtered, and the filtrate was concentrated in vacuo to an oil. The product was eluted from flash chromatography on silica gel 60 with EtOAc/ Hexane (3:7), concentrated in vacuo to an oil, and resuspended in anhydrous Et₂O. Precipitation with gaseous HCl and recrystallization from 2-PrOH/MeOH gave 2 g of AIQ-001 mp: 193-195 °C (lit¹ 194-197 °C). 1H- NMR (CDC1₃) δ: 9.15 (s, 1H, ArH), 8.62 (d, J = 6.0, 1H, ArH), 7.20 (d, J = 6.0, 1H, ArH), 2.97 (t, J = 6.9, 2H, CH₂), 2.79 (t, J = 7.5, 2H, CH₂), 2.18 (m, 2H, CH₂).

8-Amino-5,6,7,8-tetrahydroisoquinoline (AIQ-005/APX-422). NaCNBH₃ (0.70 g, 1.5 mmol) was added in one portion to a solution of 5,6-dihydro-7(H)-isoquinolin-8- one¹ (AIQ-001) and NH₄OAc (1.15g 15 mmol) in MeOH (5 mL) at room temperature under N₂. The reaction mixture was stirred at room temperature for 48 h. Concentrated HCl was added carefully until pH~2. The mixture was stirred at room temperature for 30 min. MeOH was evaporated in vacuo. The residue was taken up in H₂O (20 mL) and washed with CH C1₂ to remove impurities. The aqueous solution was basified (pH~8-9) with 15% NaOH and extracted with CH₂C1₂ (3 x 15 mL). The combined extracts were dried (MgSO₄) and evaporated under reduced pressure to give a yellow oil which was purified by column on silica gel using a solvent system of MeOH/CHCl₃ (1:9). The product was obtained as an oil (745 mg; 65%, of AIQ-005). 1H-NMR (CDC1₃) δ: 8.84 (s, 1H, ArH), 8.53 (d, J = 4.9, 1H, ArH), 7.20 (d, J = 4.9, 1H, ArH), 4.28 (t, J = 5.5, 1H, CH), 2.95 (m, 2H, CH₂), 2.23 (m, 2H, CH₂), 1.92 (m, 2H, CH₂). The oil was converted into its oxalate salt by standard methods, mp: 158- 160 °C (MeOH). Anal. Calcd for (C₉H₁₂N₂-1.5C₂H₂O₄) C, H, N. 1. Glassco, W.; Suchocki, J.; Jeorge, C; Martin, B. R.; May, E. L. Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)- and (-)-cis- 2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[3,2-h]isoquiniline, a structural analogs of nicotine. J. Med. Chem. 1993, 36, 3381-3385 incorporated herein by reference.

EXAMPLE 2. 8-(Methylamino)-5,6,7,8-tetrahvdroisoqumoline (AIQ-006).

A saturated methanolic solution of HCl (2 mL) was added in a dropwise manner to a stirred solution of anhydrous 2N CH₃NH₂ (13.6 mL, 27 mmol) in absolute MeOH at 0 °C. The mixture was stirred for 10 min and then AIQ-001 (0.5 g, 2.7 mmol) and NaCNBH₃ (0.18 g, 2.7 mmol) were added at 0-5 °C under N₂. After addition, the reaction mixture was allowed to stir for 72 h at room temperature under N . The concentrated HCl was added in a dropwise manner to pH<2 and the MeOH was evaporated under reduced pressure. The residue was taken up in H O (30 mL) and washed with Et₂O (3 x 15 mL) to remove impurities. The aqueous solution was basified (pH = 8-9) with 15% NaOH and extracted with Et₂O (3 x 20 mL). The combined extract was dried (MgSO₄) and evaporated under reduced pressure to give a crude oil which was purified by column chromatography on silica gel using a solvent system of MeOH/CHCl₃ (1:9). The solution of product was concentrated in vacuo to an oil, and resuspended in anhydrous Et₂O. Precipitation with an ethereal solution of oxalic acid and recrystallization from 2-PrOH EtOH gave 0.41 g of AIQ-006, mp: 193-197 °C. 1H-NMR (D₂O) δ: 9.16 (s, 1H, ArH), 8.92 (d, J = 6.2, 1H, ArH), 8.20 (d, J = 5.5, 1H, ArH), 4.97 (t, J = 5.8, 1H, CH), 3.37 (m, 2H, CH₂), 3.11 (s, 3H, CH₃), 2.62 ( , 2H, CH₂), 2.32 (m, 2H, CH₂). Anal. Calcd for (C₁₀H₁₄N₂-1.8C₂H₂O₄) C, H, N. EXAMPLE 3. 8-(N,N-DimethvIamino)-5.6,7,8-tetrahydroisoquinoline (AIQ-007):

NaCNBH₃ (84 mg, 1.34 mmol) was added to a stirred solution of AIQ-005 (0.2 g, 1.35 mmol) and 37% HCOH (1.1 mL, 13.5 mmol) in CH₃CN (10 mL). Glacial HOAc (14 mL) was added over 10 min, and the reaction mixture was stirred at room temperature for 4 h. An additional 0.14 mL of glacial HOAc was added and stirring was continued for 30 min more. The reaction mixture was evaporated to dryness under reduced pressure. The residue was poured into Et O (20 mL) and then washed with IN NaOH (3x10 mL). The combined ethereal solution was dried (K₂CO₃) and evaporated in vacuo to give 210 mg of crude product which was purified by column an silica gel with MeOH/CHCl₃ (1:9); the solution was concentrated in vacuo to an oil, and resuspended in anhydrous Et₂O. Precipitation with an ethereal solution of oxalic acid and recrystallization from 2-PrOH7MeOH gave 82 mg of AIQ-007 mp: 123-126 °C. 1H-NMR (D₂O) δ: 9.20 (s, 1H, ArH), 8.95 (d, J = 6.1, H, ArH), 8.24 (d, J = 6.1, 1H, ArH), 5.17 (t, J = 5.4, 1H, CH), 3.47 (m, 2H, CH₂), 3.21 (s, 3H, 2CH₃), 2.57 (m, 2H, CH₂), 2.27 (m, 2H, CH₂). Anal. Calcd for (CnH₁₆N₂-2C₂H₂O₄) C, H, N.

EXAMPLE 4. 8-(N-EthvI-N-methvIamino)-5,6,7,8-tetrahvdroisoquinoIine (AIQ- 012). LiAlH (624 mg, 15.62 mmol) was slowly added to a stirred solution of AIQ-013 (290 mg, 1.42 mmol) in dry THF (20 mL). The mixture was heated at reflux for 20 h and then hydrolyzed with H₂O and a 20% NaOH solution under ice-cooling. The inorganic precipitate was filtered off and washed with THF. The filtrate was evaporated under vacuum and the residue was dissolved in Et O and extracted with a 5% HCl solution. The aqueous phase was made alkaline with 50% NaOH solution and the oil that formed was extracted into CH₂C1₂ (4x10 mL). The CH₂C1₂ phase was dried (MgSO₄) and solvent was evaporated. The compound was purified by column chromatography on silica gel using a mixture of MeOH/CHCl₃ (5:95) as an eluent. After removal of the solvent, 103 mg (38%) of AIQ-012 was obtained as an oil, and resuspended in anhydrous Et₂O; precipitation with an ethereal solution of oxalic acid and recrystallization from 2-PrOH/MeOH gave 80 mg of AIQ-012 as the salt mp: 143-146 °C. Anal. Calcd for (C₁₂H₁₈N 2C₂H₂O₄) C, H, N.

EXAMPLE 5. 8-(N-Methyl-N-acetylamino)-5,6,7,8-tetrahvdroisoquinoline (AIO- 013).

Acetyl chloride (130 mg, 1.66 mmol) in anhydrous Et₂O (2 mL) was added in a dropwise manner to a stirred and ice-cooled solution of AIQ-006 (270 mg, 0.83 mmol) and Et N (356 mg, 3.32 mmol) in anhydrous Et₂O (7 mL). The mixture was stirred at room temperature for 15 h. The precipitated Et₃N hydrochloride was filtered off and washed with Et₂O, the filtrate was dried (MgSO₄) and the solvent was evaporated. The residue was purified by column chromatography on silica gel using MeOH/CH₃Cl (3:97) as eluent. After removal of the solvent, 112 mg (66%) of the title compound was obtained as yellow oil. LR: (C=O) 1660 cm^"1; 1H-NMR δ (ppm), 1.62-1.81 (m, 2H, CH₂), 1.91-199 (m, 2H, CH₂), 2.13 (s, 3H, CH₃), 2.66 (s, 3H, CH₃), 2.67-2.73 (m, 2H, CH₂), 5.89 (m, 1H, CH), 6.93 (d, 1H, J= .9 ArH), 8.15 (s, 1H, ArH), 8.24 (d, 1H, J=4.9, ArH).

EXAMPLE 6. 8-(N-MethvI-«-propylamino)-5,6,7,8-tetrahvdroisoqumoline (AIQ- 016). 8-Hydroxy-5,6,7,8-tetrahydroisoquinoIine (AIQ-029). NaBH₄ (1.35 g, 35.3 mmol) was added to a stirred solution of AIQ-001 (1.30 g, 8.83 mmol) in MeOH (10 mL) and the stirring was continued for 12 h at room temperature. The solution was evaporated to dryness. The residue was dissolved in H₂O and extracted with CHC1₃ (3 x lOmL) and the combined solution was dried (MgSO₄). After removal of the solvent, 1.25 g (95%) of AIQ-029 was obtained as an oil. 1H NMR (CDC1₃) δ: 1.72-1.84(2H, m, CH₂); 1.89-2.04(2H, m, CH₂); 2.63-2.83(2H, m, CH₂); 4.84(H, t, J = 5.0, CH); 6.99(H, d, J = 5.0, ArH); 8.29(H, d, J = 5.0, ArH); 8.58(H, s, ArH). The product was used without further characterization in the preparation of AIQ-016.

8-(N-MethyI- .-propyIamino)-5,6,7,8-tetrahydroisoqumoIine (AIQ-016). SOCl₂ (8 mL) was added to a stirred solution of AIQ-029 (1.25 g, 8.37 mmol) in CHC1 (15 mL). The reaction mixture was heated at 70 °C for 3 h, then evaporated to dryness. The residue was dissolved in CHC1₃ (10 mL) and N-methyl-N-w- propylamine (1.4 mL, 13.09 mmol) was added. The reaction mixture was stirred at 60 °C overnight, diluted with CHC1₃ (30 mL); washed with saturated NaHCO3, dried (MgSO₄), and the solution was evaporated in vacuo. The product was eluted from a silica gel column with CHCl₃/MeOH (95:5) to give 1.4 g (84 %) of a colorless oil. The oil was distilled at 90 °C/0.03 mrnHg. 1H NMR (CDC1₃) δ: 0.90(2H, t, J = 7.3, CH₂); 1.47-1.55(2H, m, CH₂); 1.50-1.70(2H, m, CH₂); 1.96-2.10(2H, m, CH₂); 2.21(3H, s, CH₃); 2.41(2H, t, J = 7.5, CH₂); 2.68-2.72(2H, m, CH₂); 3.85(H, t, J = 6.0, CH); 6.93(H, d, J = 5.3, ArH); 8.27(H, d, J = 5.3, ArH); 8.85(H, s, ArH). Anal. Calcd for (C₁₃H₂₀N₂) C, H, N.

EXAMPLE 7; Biological activity studies.

Formula 2. Aminotetrahydroisoquinolines evaluated in an antinociceptive assay. Table 1. Nicotinic receptor affinity and antinociceptive potency.

nACh Receptor Tail-

Affinity (Ki, nM)^a flick (i.t.)

Assay

ED50

(μmol/anim al)

ATI-1 >10,000 — —

ATI-2 >10,000 14.5

ATI-3 330 10.8

ATI-4 930 12.3

ATI-5 1,500 >200

For comparison, (-)nicotine Ki = 2 nM. nACh =nicotinic acetylchohne receptor

Claims

CLAIMS.

1. A tetrahydroisoquinoline having a secondary, tertiary or quaternary amino group spaced by three carbon atoms from the ring nitrogen, and pharmaceutically acceptable salts and prodrugs thereof.

2. A compound of Formula I

Formula I

wherein R¹, R² and R⁵ are independently selected from the group consisting of hydrogen, C_1-0- alkyl and a moiety wherein any two of R^l, R² and R⁵, together with the nitrogen to which they are attached, form a heterocyclic ring of 2 to 5 carbons, provided that R¹ and R² , and R⁵ when present, are not each hydrogen, R³ and R⁴ are independently selected from the group of moieties which are effective to alter the solubility of the compound in physiological fluids or pharmaceutical carriers n and m are independently selected from integers of 0 to 3 and 0 to 4 respectively, p is an integer 0 or 1 and pharmaceutically acceptable salts and prodrugs thereof.

3. A compound as claimed in Claim 2 wherein the moieties which are effective to alter the solubility of the compound in physiological fluids or pharmaceutical carriers are selected from the group consisting of alkyl, aryl, carboxyl, hydroxy, hydroxyalkyl, aralkyl, carboxylalkyl, haloalkyl, alkyloxy, aryloxy, acyloxy, alkoxyalkyl, amino, amido, nitro, nitrate and halo groups.

4. A compound as claimed in Claim 3 wherein alkyl chains in the moieties selected from those containing from 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms.

5. A compound as claimed in Claim 3 wherein the alkyl is cycloalkyl of 3 to 7 carbon atoms.

6. A compound as claimed in Claim 1 or Claim 2 being a hydrochloride, hydrobromide, hydroiodide, trifluoroacetic acid, acetic acid salt.

7. A prodrug as claimed in Claim 1 or Claim 2 being selected from the group consisting of an esters of a carboxy or hydroxy derivatives and amides of amino compounds wherein said esterifying or amidating group effects increased distribution of the active compound to a site in the patient body where effect is desired.

8. A compound of Claim 1 or Claim 2 wherein n, m and q are each 0 and R¹ and R are independently selected from the group consisting of hydrogen, methyl and ethyl.

9. A compound as claimed in Claim 1 wherein the amino group is at position 8 and is a quaternary amino group.

10. A compound as claimed in Claim 1 wherein the amino group is at position 8 and is selected from the group consisting of trimethylamino, triethylamino, methyldiethylamino and dimethyletheylamino groups.

11. A tetrahydroisoquinoline salt of general formula II

Formula II

wherein R¹ to R⁵ and n and m are as defined in Claim 2, X is a counterion and p is an integer of 1 to 3 respective to the negative charge, wherein the number of tetrahydroisoqumoline molecules in the salt is equal to the mteger p.

12. A compound as claimed in Claim 11 wherein R , R and R are independently selected from hydrogen, methyl and ethyl but are not all hydrogen.

13. A method of treating a patient in need of therapy for pain comprising administering a therapeutically effect amount of a compound as claimed in Claim 1.

14. A method of treating a patient in need of therapy for pain comprising administering a therapeutically effect amount of a compound as claimed in Claim 2.

15. A method of treating a patient in need of therapy for pain comprising administering a therapeutically effect amount of a salt as claimed in Claim 11.

16. A compound, salt or prodrug as claimed in any one of Claims 1 to 12 for use in therapy.

17. The use of a compound, salt or prodrug as claimed in any one of Claims 1 to 12 in the manufacture of a medicament for the treatment of pain.

18. An analgesic composition comprising a compound as claimed in any one of Claims 1 to 12.

19. A composition as claimed in Claim 18 in sterile and pyrogen free form.

20. A composition as claimed in Claim 18 comprising a pharmaceutically acceptable carrier, excipient or diluent.

21. A method of synthesising a compound as claimed in any one of Claims 1 to 12 comprising oxidising an tetrahydroisoquinoline to provide an 8-oxoisoquinohne, and then reductively amidating the aforesaid 8-oxo group oxygen using a secondary amine and a reducing agent.

22. A method as claimed in claim 21 wherein the reducing agent is a hydride or hydrogen.

23. A method of synthesising a compound as claimed in any one of Claims 1 to 12 comprising oxidising a tetrahydroisoquinoline to provide an 8- oxotetrahydroisoquinoline reducing that to the corresponding 8-hydroxy compound using a reducing agent, replacing the resultant hydroxy group with a halogen atom replacing the halogen atom with a desired amino group using an amine of formula FΓNR'R² or R⁵NR¹R².