BACKGROUND OF THE INVENTION Dopamine has been implicated in numerous heuroiogica ! disorders. It is generally recognized that either excessive or insufficient functional dopaminergic activity in the central and/or peripheral nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.

A number of ligands for the treatment of. dopamine-related. dysfunction of the central and peripheral nervous system are described in International Patent No. WO 97/06799, published 27 February 1997, having the general tetrahydro-1 H-naph[1,2,3-de]isoquinoline chemical structure described below.

In particular, the international application specifically describes the synthesis and use of ()-8, 9-dihydroxy-2, 3h7, 11b-tetrahydro-1H- naphtho [1, 2,3-delisoquinoline denominated as"dinapsoline"in the description. The synthesis of dinapsoline is depicted generally in Figures 1 and 2 as well as in the experimental section. Further description of the synthesis and pharmacological evaluation of dinapsoline is described by D. Ghosh, et al. in J. Med. Chem., Vol. 39, pp. 549-555 (1996).

Although the prior art process works on a small scale, the overall process is a long synthesis which involves as many as 14 steps to complete, including protection and deprotection schemes. The cyclization step near the end of the synthesis was found to be problematic and the yield'not reproducible, if there is any product at all. Thus, there is a need for a simple, convenient, economical and scale-up for the preparation of dinapsoline and derivatives thereof. The present inventors have found a suitable process that avoids the problematic cyclization step which uses an isoquinoline system and a highly regioselective carbon-carbon bond forming technique to establish the entire tetracyclic framework in a few simple steps.

SUMMARY OF THE INVENTION The present invention relates to fused isoquinoline compounds of the formula wherein RI R2, R4, R5, R6 and A are as defined herein which are useful for the treatment of movement disorders. More specifically, the invention relates to a process for their preparation.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of dinapsoline and derivatives thereof which are useful for the treatment of movement disorders, and have the formula wherein Ri and R2 each are independently hydrogen or a hydroxy- protecting group; or Ri and R2 may be joined together to form -(CH2)n-; n is 1 to 3; A is CH2, CHOR1 or C=O ; and R4, R5 and R6 each are independently hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy or halogen. The novel and improved process is illustrated in Reaction Scheme 4.

The present invention also provides certain dinapsoline derivatives of Formula IX which are useful for the treatment of movement disorders, The term"C.4aikyi"as used herein and in the claims (unless the context indicates otherwise) means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl.

The term"Cl-4 alkoxy"'as used herein and in the daims means straight or branched chain alkoxy groups such as methoxy, ethoxy, propoxy and butoxy. Preferably, these groups contain from 1 to 2 carbon atoms.

Unless otherwise specified, the term"halogen"as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine while the term"halide"is intended to include bromine, chloride and iodide anion. The term "A" as used herein and in the claims is independently selected from a methylene (-CH2-) group, a hydroxy or hydroxy-protected methylene (-CHOR1) group or a carbonyl (C=O) group.

The term"hydroxy-protecting group"refers to those groups well- known to those skilled in the art which can be employed in the present invention to blocK or protect the hydroxyl group. Preferably, said groups can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule, for example, by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation.

Suitable hydroxy-protecting groups include acyl groups such as acetyl, propionyl, butyryl, chloroacetyl, dichloroacetyl and trichloroacetyl, phenoxycarbonyl, benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, p-nitro-benzyloxyearbonyl and 2,2,2-trichloroethoxy- carbonyl ; aroyl groups such as benzoyl and substituted benzoyl, for example, methoxybenzoyl, nitrobenzoyl, methylbenzoyl and the like ; alkyl groups such as methoxymethyl, benzyloxymethyl, alkyl; aralkyl groups such as benzyl, benzhydryl, trityl or p-nitrobenzy) ; or t riorganosilyl groups such as tri (Ci-C6) alkylsilyl (e. g. trimethylsilyl, triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, t-butyidimethylsilyl, meth methyldi-t-butylsilyl), triarylsilyl (e. g. triphenyl-silyl, tri-p-xylsilyl) or triaralkylsilyl (e. g. tribenzylsilyl). Examples of these and other suitable hydroxy-protecting groups and methods for their formation and removal are known in the art, e. g. see Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons, New York, 1991, Chapter 2, and references therein.

Preferred hydroxy-protecting groups are acyl groups such as acetyl, propionyl and chloroacetyl ; aroyl groups such as benzoyl and substituted benzoyl and aryl groups such as benzyl and substituted benzyl. Most preferably, the hydroxy-protecting group is achieved when Ri and R2 are joined together to form a methylene (-CH2-) group.

It should be appreciated by those skilled in the art that the final deblocking step will naturally vary depending on the protecting groups present in substituents R1 and R2. The deblocking step such as illustrated in Reaction Scheme 4, step (g), to produce compounds of Formula IX wherein Rl and R2 are hydrogen is accomplished by conventional procedures such as hydrolysis, chemical reduction, hydrogenation and the like, and includes the method illustrated for the removal of the hydroxy-protecting group wherein R1 and R2 are joined together to form-CH2-.

The compounds of Formula IX may be prepared by various procedures such as those illustrated herein in the examples, in the Reaction Schemes and variations thereof which would be evident to those skilled in the art. The fused isoquinolines of Formula IX may advantageously be prepared by reduction methods from benzo benzoisoquinoline compounds of Formula Vil followed by removal of the hydroxy-protecting groups as illustrated in Reaction Scheme 4. The various benzo benzoisoquinolines of Formula Vil may advantageously be prepared using free radical carbon-carbon bond formation from aryl isoquinotines of Formula VI as illustrated in Reaction Scheme 3 while the aryl isolquinolines of Formula V may be prepared from isoquinolines of Formula I and appropriately substituted phenyl derivatives by the method illustrated in Reaction Scheme) and the alternative method illustrated in Reaction Scheme 2.

REACTION SCHEME 1 Reagents : (a) Br2/AICI3/neat ; (b) n-BuLi then DMF; (c) LDA then III.

As illustrated in Reaction 1, the compounds of Formula V may be prepared from substituted or unsubstituted isoquinolines of the Formula I which are generally known to undergo eiectrophilic substitution preferentially at the 5-position to give 5-bromo-isoquinolines of the Formula II. The bromination reaction (a) can be done in neat form and in the presence of a Lewis Acid catalyst such as anhydrous aluminum chloride, or alternatively, the bromination can be carried out in an inert organic solvent such as methylene chloride. In both cases, the overall yields are comparable to each other, and preferably, the bromination is carried out in neat form since it avoids the additional solvent evaporation step. The 5-bromo-isoquinoline compound of Formula II can be trans- metallated to the corresponding 5-lithio-isoquinoline using n-butyl lithium in asuitableinertorganicsolvent such as THF and the reaction is preferably carried out at a temperature below-50 to-80°C. This versatile 5-lithio-isoquinoline can be alkylated, acylated into a variety of 5-substituted isoquinolines. The addition of DMF to said 5-litho- isoquinoline followed by warming to room temperature and neutralization with an equivalent amount of mineral acid, this 5-lithio-isoquinoline produced the 5-formyl-isoquinoline of Formula III in excellent yields.

Using a recently published procedure described by R. Mattson, et al., in ACS Organic Division, 1998, Boston Abstract No. 059, the aldehyde of Formula III may advantageously be reacted with the 4-bromo-3-lithio-1, 2- (methylenedioxy) benzene derived from the corresponding hydrocarbon precursor of Formula IV to furnish the desired benzhydrol of Formula V, in crystalline form.

REACTION SCHEME 2 Reagents: (a) Br2/AlCl3/neat; (b) LDA then IVa ; (c) n-BuLi then DMF The desired compounds of Formula V can alternatively be prepared by a similar but different route which differs in the formulation step as illustrated in Reaction Scheme 2.

The formulation reaction in converting the compound of Formula li to the compound of Formula III which is described above and shown in Reaction Scheme 1 can be carried out on 4-bromo-3-lithio-1, 2- (methylenedioxy) benzene to give the corresponding 2-bromo-5, 6- (methylenedioxy) benzaidehyde iof Formula IVa. The aldehyde of Formula IVa is then readily reacted with the lithiated 5-bromo-isoquinoline to produce the identical benzhydrol of Formula V. These complementary and convergent processes are provided to accommodate different pairs of isoquinolines and 4-bromo-1, 2-(methylenedioxy) benzenes of the present invention.

REACTION SCHEME 3 Reagents : (a) MnO2/benzene; (b) n-Bu3SnH/AlBN ; (d) Et3SiH/TFA; (e) n-Bu3SnH/A)BN The benzhydrols of Formula V can readily be converted to the aryl isoquinolines of Formulas Vla, Vlb and Vlc which are usefu!intermediates for the preparation of dinapsoline and derivatives thereof. It should be appreciated by those skilled in the art that the alcohol of Formula V can readily be oxidized to the corresponding ketone of Formula Via ill a conventional manner with an oxidizing agent such as maganese dioxide.

The alcohol of Formula V can readily be protected with a hydroxy- protecting group to afford the compound of Formula V!cwhiiereduction provides the compound of FormulaV)b.

The cyclization of the compound of Formulas Via, Vlb and Vlc to the corresponding compounds of Formulas VIIa, VIIb and Vllc can be initiated by a variety of reaction conditions well-known to those skilled in the art. However, it was found that the best results were achieved by free radical initiated carbon-carbon bond formation since this method was the least sensitive to the electronic environment of the selected precursor.

The carbon-carbon bond reaction is preferably carried out with a hydrogen radical source such as trialkyltin hydride, triaryltin hydride, trialkylsiiane, triarylsilane or the like and a radical initiator such as 2,2'- azobisisobutylronitrile, sunlight, controlled potential cathodic (Pt) or the like in the presence of a proton source such as a mineral acid, for example, sulfuric acid and hydrochloric acid or an organic acid, for example, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid. In the conversion of compound of Formula Vib to the cyclized compound of Formula Vllb, it is advantageous and preferred to use tributyltin hydride with a variety of well-know initiators and specifically, 2,2'- azobisisobutylronitrile in the presence of acetic acid.

REACTION SCHEME 4 Reagents : (f) NaBH3CN in HCI/THF ; (g) BBr3/CH2Cl2 ; (h) Pd/C in xylenes Once cyclized, the intermediates of Formulas Vlla, Vllb and Vllc are useful as starting materials for various derivatives which differ only at one position in the definition of substituent A as illustrated in Reaction Scheme 4. The compound of Formula V!ibisselectively reduced at the nitrogen bearing heterocyclic ring to give the corresponding tetrahydrosioquinoline of Formula Vlllb, the direct precursor of the dinapsoline derivatives of Formula lXb. The selective ring reduction may be carried out by a number of different reduction methods such as sodium cyanoborohydride in an acidic medium in THF, hydride reducing agents such as L-Selectridee or SuperhydrideO. and preferably, catalytic hydrogenation under elevated pressure may be employed. It should be appreciated by those skilled in the art that alternatively ; the reverse of said ring reduction can be carried out by using palladium catalyzed dehydrogenation at elevated temperature in an organic solvent such as boiling xylenes. Conversion of the protected compound of Formula Vltlb to the diol of Formula IXb may be accomplished by using boron tribromide in methylene chloride at low temperatures such as-60 to-80°C and the. final product may be isolated in the form of a hydrobromide salt, while the corresponding hydrochloride salt may advantageously be prepared by using boron trichionde instead. If it is desired to prepare the compound of Formula IXb wherein R is C1-4 alkyl, then it is advantageous to alkylate the compound of Formula Vlilb using conventional methods before the protecting groups are removed to afford the desired diol of Formula IXb.

When it is desired to prepare the corresponding compounds of Formula IX wherein A is a hydroxy group (lac) or a carbonyl group (IXa) as further illustrated in Reaction Scheme 4, the approximate precursor of Formula Villa may. be converted to the desired compound of Formula IXa while the suitably protected compound of Formula Vlllc may advantageously be deprotected to provide the alcohol compounds of Formula IXc. It should be appreciated by those skilled in the art, the conversion of and modification of the A substituent in the compound of Formula IX may be converted readily from one compound to the other by well-know conventional procedures as illustrated in Reaction Scheme 4 for the compounds of Formulas IXa, IXb and IXc.

In a preferred embodiment of the invention the compounds of Formula VI have the formula wherein Ri and R2 each are independently hydrogen or a hydroxy- protecting group; or R1 and R2 may be joined together to form -(CH2)n-; n is 1 to 3; R3 is chloro, bromo or iodo; A is CH2, CHOR1 or C=O ; and R4; R5 and R6 each are independently hydrogen, C1-4lkyl, C1-4alkoxy, hydroxy or halogen. It is most preferred that RI and R2 are joined together to form -(CH2)n- wherein n is 1, R3 is bromo, A is CH2 and R4, R5 and R6 are hydrogen.

In another preferred embodiment of the invention the compounds of Formula Vil have the formula wherein R1 and R2 each are hydrogen or a hydroxy-protecting group; or Ri and R2 may be joined together to form- (CH2)n-; A is cH2, CHOR1 or C=O; n is 1 to 3; and R4, R5 and R6 each are independently hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy or halogen. It is most preferred that Fil and R2 are joined together to form- (CH2) n- wherein n is 1, A is CH2 and R4, R5 and R6 are hydrogen.

In still another preferred embodiment of the invention the compounds of Formula IX have the formula wherein R1 and R2 each are hydrogen or a hydroxy-protecting group; or R1 and R2 may be joined together to form -(CH2)n0; n is 1 to 3; A is CHOR1 or C=O; R is hydrogen or C1-4alkyl ; and R4, R5 and R6 each are independently hydrogen, C1-4alkyl, C1-4lkoxy, hydroxy or halogen. It is most preferred that Ri and R2 are joined together to form- (CH2) n- wherein n is 1, A is CH2 and R, R4, R5 and R6 are hydrogen.

In another aspect, this invention provides a process for the preparation of a compound of Formula IX whereinRlandRSeach are hydrogen; A isCHg,CHOH or C=O ; R is hydrogen or C1-4alkyl ; and R4, R5 and R6 each are independently hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy or halog en, comprising the steps of (a) reducing a compound of the formula wherein R1 and R2 each are a hydroxy-protecting group; or RI and R2 may be joined together to form- (CH2) n- in which n is 1 to 3 and R4, R5 and R6 and A are as defined above; with a reducing agent and (b) deprotecting the resulting reduced product to produce the compound of Formula lX wherein Ri and R2 are hydrogen and (c) optionally, alkylating the product of step (a) or (b) to produce a compound of Formula IX wherein R is C1-4alkyl. Preferably, in the process of the invention R1 form -(CH2)n- wherein n is 1, R3 is bromo, A:is CH2 and R4,. R5 and R6 are hydrogen and R2 are joined together to form -(CH2)-, A is CH2 and R, R4, RB and R6 are hydrogen.

Binding to Dopamine Receptors: Dopamine produces biological responses through stimulation of its receptors on cell membranes. The affinity for D1 and D2 receptors were carried out in rat stratum using the in vitro binding assay adapted from C.

P. Manik, P. B. Molinoff and P. McGonigle in J. of Neurochemistrv, Vol.

51, pp. 391-397 (1988) and K. D. Burris, et al., in Neuropsychopharmacology, Vol. 12, pp. 335-345 (1995). In addition, membranes prepared from HEK-293 cells that express transfected human D2L receptors, sites labeled by the D2 receptor agonist [1251]-7- OH-PIPAT were used and the results show that the compounds of the present invention are active in these tests.

In another embodiment, this invention includes pharmaceutical compositions comprising at least one compound of Formula IX in combination with a pharmaceutical adjuvant, carrier or diluent.

In still another embodiment, this invention relates to a method for the treatment of movement disorders a mammal in need thereof, which comprises administering to said mammal a therapeutical effective amount of a compound of Formula IX or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.

In yet another embodiment, this invention relates to a method for treating Parkinson's disease in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula, IX or a non-toxic pharmaceutically acceptable salt, solvate or hydrate thereof.

For therapeutic use, the pharmacologically active compounds of Formula IX will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutical acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal. and intravenous) bronchial or-nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formu!a!XdirecHyinparenteraiformutations.The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound according to the invention.

See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.

The dosage of the compounds of Formula IX to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formuia IX or pharmaceutical composition thereof for a. mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0. 1-ptg/kg to 100 mg/kg body weight. For par'enteral administration, the dose may be in the range of 1 µg/kg to 10 mg/kg body weight for intravenous administration The active ingredient will preferably be administered in equal-doses-from one-to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.

However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms ; The following examples are given by way of illustration and are not to be construed as limiting the invention in any way inasmuch as many variations of the invention are possible within the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS f All new compounds reported displayed spectral characteristics (IR, MS, 1H and I NMR) which were consistent with their assigned structures. NMR's were run in the indicated solvent [deuterochloroform (CDCI3) or perdeuterodimethylsultoxide (DMSO-d6)] at 300 MHz using a Bruker ACP 300 spectrometer. Data are reported as follows : chemical shift (8) in PPM downfield from calculated tetramethylsilan6 (TMS); multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, p=pentuplet, and br=broadened), integration and coupling constant (given in Hz). Melting points were obtained using a Thomas Hoover capillary apparatus and are uncorrected.

EXAMPLE 1 S-Bromoisoquinoline The apparatus consisted of a 500 mL three-necked flask equipped with a condenser, dropping funnel. and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafturoethylene paddle. To isoquinoline (57. 6 g, 447 mmol) in the flask was added AlCl3 (123 g, 920 mmol). The mixture was heated to 75-85°C. Bromine (48. 0 g, 300 mmol) was added using a dropping funnei over a period of 4 hours. The resulting mixture was stirred for one hour at 75°C. The almost black mixture was poured into a vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16. 3 g, 78 mmol) from a fraction of about 1 25°C was obtained (26% yield). The product was further purified by recrystallization (pentane or hexanes) : mp 80-81 °C ; 1, H NMR (DMSO-d6) s 9.34 (s, 1H), 8.63 (d, 1h, J = 9. 0Hz), 8.17 (d, 1H, J = 7. 5Hz), 8.11 (d, 1H, J=6.6Hz), 7.90 (d, 1H, J = 6. 0Hz), 7.60 (t, 1H, J = 7. 5Hz); 13C NMR (DMSO-d6) # 153.0, 144.7, 134. 3,134.0,129.3,128.5,128.0, 120.3, and 118.6.

Anal. Calcd. for C9H6BrN : C, 51.96; H, 2. 91 ; N, 6. 73.

Found: C, 51.82; H, 2. 91, N, 6.64.

EXAMPLE 5-Isoquinolinecarboxa(dehyde To a solution of n-butyllithium (19.3 mL of 2. 5. M in hexanes, 48 mmol) in a mixture of ether (80 mL) and THF (80 mL) at-78°C was added dropwise a solution of bromoisoquinoline (5.0 g, 24 mmol) in THF (10 mL). The reaction mixture was stirred at-78°C under argon for 30 minutes. Following the general procedures described by Pearson, et al., in J. Heterocycl. Chem., Vol. 6 (2), pp. 243-245 (1969), a solution of DMF (3.30 g, 45 mmol) in THF (10mL) was cooled to-78°C and quickly added to the isoquinolyllithium solution. The mixture was stirred at-78°C for 15 minute. Ethanol (20 mL) was added followed by saturated NH4CI solution. The resulting suspension was warmed to room temperature.

The organic layer, combined with the ether extraction layer, was dried over Na2S04. A pale yellow solid (2.4 g, 15 mmol, 64% yield) was obtained from chromatography (SiO2 Type-H, 50% EtOAc in hexanes) and recrystallization (ethanol) : mp 114-116°C ; 1H NMR (DMSO-d6) # 10. 40 (s, 1H), 9.44 (s, 1H), 8. 85 (d, 1H, J = 6.0Hz), 8. 69(d, 1H, J = 6.0Hz), 8. 45 (m, 2H), 7.90 (t, 1H, J = 7.2Hz) ; 13C NMR (DMSO-d6)) 8 194. 23,153.5,146.2,140.2,135.2,132.6, 130.2, 128. 6,127.5, and 117. 2.

Anal. Calcd. for C10H7NO#0. 05 H20 : C, 75.99; H, 4.53; N, 8.86.

Found : C, 75.98; H, 4.66, N, 8.68.

EXAMPLE 3 4-Bromo-1,2-(methylenediox)-3-benzaldehyde To a solution of 4-bromo-1, 2-(methylenedioxy)benzene (24.9 mmol) in THF (52 mL) at -78°C, lithium diisopropylamide in 1. 5M in cyclohexane (27.4 mmol) was slowly added and the resulting solution was stirred for 15minutes-DMF(4.15 mL) was then added dropwise and the reaction solution was allowed to warm at room temperature for 1 hour.

The solution was washed with saturated NH4Cl and the organic layer was concentrated and dried under vacuo. The yellow solid product was recrystallized using isopropyl acetate to afford the title compound as yellow needles (69% yield). mp 158-159°C ; 1H NMR (CDCl3) # 10, 29 (s, 1H),7.08(d,-!H,J=8.25Hz), 6.83 (d, 1H, J=8. 22Hz), 6.17 (s, 2H); 13C NMR CDCl3) # 190. 8,149.8,149.1,126.5, 117.7,115.9,113.9, 103. 8.

Anal. Calcd. for C8H5BrO3: C, 41.95; H, 2.20 ; Br, 34.89 Found : C, 41. 91 ; H, 2.09; Br, 34. 56.

EXAMPLE 4 α-(5-Bromo-1,3-benzodioxol-4-yl)-5-isoquinolinemethanol To a solution of 4-bromo-1,2- (methylendioxy) benzene (3.01 g, 15 mmol) in THF (20 mL) at-78°C was added dropwise ithium diisopropylamide (10. 6 mL of 1. 5 M in cyclohexane, 16, mmol). The reaction mixture was stirred at-78°C under argon for 20 minutes. A brown solution was formed. A solution of 5-isoquinotinecarboxaldehyde (1. 90 g,. 12 mmol) in THF (4 mL) was added dropwise. The resuming mixture was stirred at-78°C for 10 minutes and warmed to room temperature. Stirring was continued for 30 minutes at room temperature, and then the mixture was quenched with saturated NH4CI solution. The product was extracted with EtOAc and the solvent was removed under reduced pressure. Chromatography (Si02 Type-H, 35% EtOAc in Hexanes) of the residue yielded the title compound as a yellow solid (2.8 g, 7.8 mmol, 65% yield) : mp 173-175°C ; 1 H NMR (DMSO-d6) # 9.32 (s, 1H), 8.47 (d, 1 H, J = 6.0Hz), 8.05 (d, 1H, J = 8.1 Hz), 7.96 (d, 1H, J = 7.2Hz), 7. 76 (d, 1 H, J = 6.0Hz), 7.66 (t, 1 H, J = 7.8Hz), 7.14 (d, 1H, J = 8.1Hz), 6.84 (d, 1h, J = 8.1Hz), 6. 58 (d, 1H, J = 8.1Hz), 6.28 (d, 1H, J = 5, 4Hz), 5.95 (s, 1 H), 5.80 (s, 1H); 13C NMR (DMSO-d6) # 153.1,147.6,147. 0,142.9,136.9,132.7,128. 9, 128.3,127.3,126.7,125.6,124.4,116.3,114.0,109.3,101.6, and 69.0.

Anal. Calcd. for C17-H12BrNO3 : C, 57.01 ; H, 3.38; N, 3.91.

Found : C, 57.04; H, 3. 51, N, 3.89.

EXAMPLE 5 α(5-Bromo-1,3-benzodioxol-4-yl)-5-isoquinolinemethanol To a solution of 5-bromoisoquinoline (0.50g, 24 mmol) in ether (8mL) at-78°C was added dropwise t-butyllithium (3.6 mL of 1.7 M in pentane, 6.0 mmoi) under argon. The mixture was stirred at-78°C under argon for 30 minutes then continued for 15 minutes with the flask right above the dry-ice acetone bath. 4-Bromo-1, 2-(methylenedioxy)-3- benzaldehyde (0.524 g, 2.4 mmol) was added in one portion at-78°C under argon. The mixture was stirred at-78°C for five minutes and then was warmed to room temperature using a water bath. Stirring was <BR> <BR> continued for 20 minutes at room temperature and then the mixture was<BR> <BR> <BR> <BR> quenched with saturated NH4Cl, extracted with EtOAc and dried over Na2SO4. Chromotography (SiO2, 35% EtOAc in hexanes) yielded the title compound as, a yellow solid (0.18 g, 0.50 mmol, 21% yield) which is identical to the compound of Example 4.

EXAMPLE 6 5-f (5-Bromo-1. 3-benzodioxol-4-yl) methyl]isoquinoline To a solution of secondary alcohol a- (5-bromo-1, 3-benzodioxol-4- yl)-5-isoquinolinemethanol (8.37 mmol) in trifluoroacetic acid (100 mL), triethylsilane (83. 7 mmol) was added and the resulting solution was refluxed for an hour at 70-75°C and stirred overnight at room temperature.

The solvent was removed under vacuo and the residue was dissolved in ethyl acetate, washed with saturated NH4Cl dried over Na2SO4, filtered and concentrated. Purification was performed by column chromatography to afford the trifluoroacetate sait of the title compound as a white . crystalline solid (67% yield) : mp 138-140°C; 1H NMR (CDCl3) # 9.64 (s, 1 H), 8.63 (d, 1H, J = 6. 59Hz), 8.45 (d, 1 H, J = 6, 62Hz), 8.14 (d, 1 H, J = 8. 22Hz), 7.77 (t, 1H, J = 7.39Hz), 7.64 (d, 1 H, J = 7.2SHz), 7. 13 (d, 1H, J = 8.33HZ), 6. 71 (d, 1H, J = 8.31 Hz), 5. 94 (s, 2H), 4.53 (s, 2H); 13C NMR (CDC 8 147. 8,147.7,147. 1,137.2, 35.1, 134.7,133.4, 130. 3,128.6, 128. 3, 125. 9,120.7, 119.4, 116.3, 109. 1, 101. 9 and 31.7.

Anal. Calcd. for C17H12BrNO2#C2HF3O2 : C, 50.02 H, 2.87; Br, 17.51; N, 3.07 Found : C, 49.91 ; H, 3.02 ; Br, 17.95 ; N, 3. 04.

EXAMPLE 7 12H-Benzo[d,e][1,3]benzodioxol[4,5-h]isoquinoline Method A: A solution of 5-[(5-bromo-1,3-benzodioxol-4-yl) methyl]-isoquinoline (0. 357 g, 1.0 mmol) and 2, 2'-azobisisobutylronitrile (0.064 g, 0.39 mmol) in benzene (10 mL) was cooled to-78°C, degassed four times with N2 and then heated to 80°C under argon. A solution of tributyltin hydride (1. 14 g, 3.9 mmol) in 10 mL of degassed benzene was added in two hours. TFA (0. 185 g, 1. 6 mmo !) was added in four equal portions (1/4 each half. hour). The reaction mixture was stirred at 80°C under argon for six hours after addition of TFA. Additional tributyltin hydride (0.228 g, 0. 80 mmol) was added dropwise. The stirring continued overnight (16 hours). Another 2, 2'-azobisisobutylronitrile (0.064 g, 0. 39 mmol) and TFA (0.093 g, 0.80 mmol) were added in one portion. A solution of tributyltin hydride (1.14 g, 3.9 mmol) in 10 mL of degassed benzene was also added in two hours. More TFA (0. 185 g, 1.6 mmol) was added in four equal portions (1/4 each half hour). The stirring continued for another six hours and tributyltin hydride (0. 456 g, 1.6 mmol) was added dropwise.

The reaction mixture was stirred overnight (16 hours). The solvent was removed under reduced pressure. Pentane (100 mL) was added to residue and resulting mixture was cooìed to-78°C. A brown gum was formed and filtered. The filtrate was extracted with MeCN. The MeCN layer was combined with the brown gum. The crude product from evaporation of MeCN was purified by chromatography (Si02 Type-H, 15% EtOAc in hexanes). The isolated compound was dissolved in CH2CI2 and extracted with HCI (1 N). The aqueous layer was basified to pH-10 using 10 N of NaOH, solution and reextracted with CH2Cl2. The organic layer was dried over Na2SO4. Evaporation of solvent yielded the title compound as an orange solid (0.068 g, 0.26 mmol, 25% yield) : mp 194- 197°C ; 1H NMR (DMSO-d6) # 9. 12 (s, 1H), 9. 06 (s, 1H), 7.93 (d, 1 H, J = 6. 9Hz), 7. 83 (d, 1H, J = 8.1Hz), 7. 73 (dd, 1h, J = 7. 2,1. 5Hz), 7.66 (t, 1H, J = 7.8Hz), 6.96 (d, 1H, J = 8. 4Hz), 6.14 (s, 2H), 4.44 (s, 2H) ; 13C NMR (DMSIO-d6) # 150.6,147.0,145.2,135.6, 130.6,129.3,129.1, 127.7, 127.5, 125. 0, 123. 6,117.2,116.1,107.5,101.6, and 26.6.

Anal.'Calcd. for C17H11NO2#0.12CH2"Cl2: C, 75. 75; H, 4.17; N, 5.16.

Found: C, 75.75 H, 4.03, N, 4.83.

Method B: A solution of 5-[(5-bromo-1,3-benzodioxol-4-yl)methyl]-isoquinoline (12.6 g,. 36.8 mmol) and 2, 2'-azobisiobutylronitrille (5. 92 g, 360 mol) in benzene (1500 mL) was cooled to-78°C, degassed/purged four times with nitrogen and then heated to 80°C under argon. A solution of tributyltin hydride (39.9 g, 137 mmol) in 30 mL of degassed benzene was added dropwise over a period of three hours. Acetic acid (12.6 d, 210 mmol) was added in one portion before the addition of tin hydride. The reaction mixture was stirred at 80°C under argon for 16 hours. Excess triethylamine was added to neutralize the residual acetic acid component.

The solvent was removed'under reduced pressure. Methylene chtoride (250 mL) was added to dissolve the semi-solid. It was followed by the addition of hexanes to a point just before the mixture became cloudy.

This solution was poured over a short bed of silica gel and the tri-n- butyltin acetate was removed by washing with hexanes until it is no longer, detected by TLC. The product was then eluted out with mixtures of hexanes and ethyl acetate to give the desired title compound (6. 1 g, 23.4 mmol, 63.5 % yield) which was identical to the product prepared by Method A.

EXAMPLE 8 (~)-8,9-Methylenedioxy-2, 3. 7, 11 b-tetrahydro-1 H-napth[1,2,3 de]isoquinoline Method A: To a solution of 12H-benzo [d,e][1,3benzodioxol[4 5-h] isoquinoline (0. 085 g, 0. 33 mmol) in THF (43 mL) was added 2N HCI (1.7 mL, 3.4 mmol) and an orange precipitate formed. Sodium cyanoborohydride (0. 274 g, 4.4 mmol) was added in one portion. The resulting suspension was stirred at room temperature for two hours. HCI (2N, 10 mL) was added and stirring continued for 5 minutes. Saturated NaHCOg solution was added (pH-7-8). The resulting mixture was extracted with EtOAc, dried over Na2SO4 and the solvent was removed under reduced pressure. Chromatography (SiO2 Type-H, 5% MeOH in CH2Cl2) of the residue yielded the title compound as a yellow gum (0. 066 g, 0.25 mmol, 75% yield) ; 1H NMR (CDCl3) # 7.15 (m, 2H), 6.97 (d, 1H, J = 6.9Hz), 6.83 (br, s, 1h), 6. 68 (d, 1H, J = 8.1Hz), 6. 59 (d, 1H, J = 8.1Hz), 6.01 (d, 1H, J = 1.4Hz), 5. 91 (d, 1Hm, J = 1.4Hz), 4.40-4.00 (m, 5H), 3.55 (dd, 1H, J _ 17.7,3.0Hz), 3.10 (t, 1H.J=12.0Hz) ; 13C NMR (CDCl3) # 146. 1,144.8,136.0,132.2, 130. 4, 128. 6, 127. 1, 127.0,124.5, 18. 5,116.2,106. 2, 101.2,45.8,35.1,34.3, and 28.9.

Anal. CalCd. for C17H15 NO2#0.52HCN#1.8H2O : C, 67. 49; H, 6. 18 ; N, 6.83.

Found : G, 67.45 H, 5.96, N, 6.75.

Method B: 12H-Benzo [d, e][1,3]benzodioxol[4,5-h]isoquinoline (11. 26 g) was dissolved into 500 mL of glacial acetic acid in a suitable glass liner that will fit into a 1-L Parr"bómb reactoK'. To this dark amber solution was added 480 mg PtO2 and a magnetic stirring bar. Usual purge cycles were repeated three times at-78°C. Finally hydrogen gas was charged into the steel bomb at 140 PSI while the content was still at-78°C. The reactor was allowed to warm to room temperature over a period of 2 hours while the internal pressure increased to 195 PSI. Gas absorption was faster after about 4 hours at room temperature. After 24 hours, the internal pressure returned to 165 PSI indicating roughly stoichiometric uptake of hydrogen gas. The black suspension was removed after the pressure was relieved, it was filtered over silica gel, rinsed with acetic acid and concentrated under reduced pressure to give about 19 gm of gummy <BR> <BR> substance. The crude product was neutralized with sodium bicarbonate<BR> <BR> <BR> <BR> <BR> solution followed by extraction with methylene chloride to yield 11.6 gm of the title compound whose 1H NMR was indistinguishable from the purified material prepared above by the Method-A.

EXAMPLE 9 5-Bromo-13,-benzodioxol-4-yl)-(5-isoquinolinyl)methanone To a solution of secondary alcohol α-(5-broo-1,3-benzodioxol-4- yl)-5-isoquinolinementhanol (1.39 mmol) in benzene (200 mL), manganese dioxide (28.0 mmol) was added and the reaction mixture was stirred vigorously overnight at room temperature. Excess MnO2 was filtered through Celite, washed with EtOAc (2x) and the filtrate washing were combined and concentrated to give a pure yellow solid product (quantitative yield). The product was recrystallized with EtOAc/Hexane to afford the title compound: mp 193-195°C ; 1H NMR (CDCl3) # 9.33 (s, 1H), 8.86 (d, 1H, J = 6.09Hz), 8.71 (d, 1 H, J = 6.06Hz), 8. 19 (d, 1H, J = 8.16Hz), 7.97 (d, 1Y, J = 38 Hz), 7.61 (t, 1H, J = 8.13Hz), 7.10 (d, t H, J = 8.28Hz), 6.81 (d, 1H, J = 8. 28Hz), 5.97 (s, 2H) ; 13C NMR (CDCl3) # 192. 8,153. 0, 147.7, 146.2, 136.6, 134. 3,133.9, 131.9,129. 1, 126.2, 126.1, 123.4,1 18. 8, 110. 9, 110.7, 102.7.

Anal. Calcd. for CHBrNOC.57. 33; H, 2.83; Br, 22.43; N, 3. 93 Found: C, 57,. 3; H, 2.76; BR, 22.73; N, 3.82.

EXAMPLE 10<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 12H-Benzofdf1.3benzod!oxo!f4.5-M!soqutno!<n-2-one To a solution of ketone (5-bromo-1, 3-benzodioxol-4-yl)-(5- isoquinolinyi) methanone (0.56 mmol) in benzene (12 mL), tributyltin hydride (0.06 mmol) and 2, 2'-azzobisisobutylronitrile (0.035 mmol) were added and the resulting mixture was refluxed for 40 hours under nitrogen.

The solvent was removed in vacuo and the residue was dissolved in acetonitrile and washed with hexane (3x). The extract was concentrated in vacuo and subjected to column chromatography (EtOAc/Hexane). The product was isolated to afford a yellow fluorescent solid. The product was recrystallized (10% yield) with EtOAc/Hexane to afford the title compound: MS (ESI) m/e 275.

1 H NMR (DSO-d6) # 9.59 (s, 1H), 9.47 (s, 1H), 8.69 (dd, 1H, J = 7. 50, 1. 20Hz), 8.61 (dd, 1H, J = 8.10,1.20Hz), 8.26 (d, 1 H, J = 8.40), 8.02 (t, 1 H, J = 7.50Hz), 7. 43 (d, 1 H, J = 8. 40Hz), 6.33 (s, 2H).

EXAMPLE 1 (~)-8,9-Dihydroxy-2,3,7,11b-tetrahydro-1H-napth[1,2,3- deHsoquinoHne BBr3 (25. 0 mL of 1 M in CH2Cl2. 25.0 mmol) was added to a cooled solution (-78°C) of methylenedioxy dinapsoline as prepared in Example 8 (1.4 g, 5.3 mmol) in CH2Cl2. The mixture was stirred at-78°C under nitrogen for three hours and then at room temperature overnight. After the mixture was cooled to-78°C, methanol (50 mL) was added dropwise and the solvent was removed by reduced pressure. The residue was dissolved in methanol (100 mL) and the solution was refluxed under nitrogen for 2 hours. After removal of solvent, chromatography (SiO2, 10% MeOH in (CH2Cl2) of the residue yielded the title compound as a dark brown solid (1.65 g, 4. 94 mmol, 93% yield). MS (ESI) m/z 254 (MH+) ; 1H NMR (DMSO-d6) # 9.50 (br, s, 2H), 9.28 (s, 1H), 8.54 (s, 1 H), 7.32 (d, 1H, J = 8. 3Hz), 7.23 (t, 1 H, J = 8. 3Hz), 7.12 (d, 1H, J = 8.5Hz), 6.70 (d, 1 H, J = 9. 3Hz), 6.54 (d, 1H, J = 6. 7Hz), 4.37 (s 2H), 4.30-4.23 (m, 2H), 3. 97 (m, 1 H), 3.45-3.31 (m, 2H); 13C NMR (DMSO-d6) 8 143.8,142.0,136. 9, 132. 1,127.6,127.0,126.6, 124.1,123.7,114.0,112.7,48.6,44. 0, 32. 9, and 28.5.

Anal. Calcd. for C16H15NO2#1.28HBr#0.59H2O: C, 52.34; H, 4.79; N, 3.82.

Found: C, 52.29 ; H, 4.92, N, 4. 14.

EXAMPLE 12 12H-Benzo[d,e][1,3]benzodioxol[4,5-h]isoquinoline A sample of (~)-8,9-methylenedioxy-2, 3,7, 11b-tetahydro-1H- napth [1, 2,3-de] isoquinoline (651 mg) was dissoived into 250 mL of reagent grade xylenes. To this solution was added 40 mg of 5% Pd on charcoal catalyst and the suspension was warmed to reflux under nitrogen atmosphere. A small aliquot was removed after 24 hr and was analyzed by LC/MC to show complete oxidation. The catalyst was removed by filtration through a short bed of silica (Type-H) and the orange color filtrate was concentrated under reduced pressure to give 640 mg of dark orange crystals. The NMR of this sample of the title compound was indistinguishable from a sample prepared in Example 7.

EXAMPLE 13 (~)-N-Methyl-8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-napth[1,2 ,3- de]isoquinolie Step A. N-Methyl-12H-benzo[d,e][1,3]benzodioxol[4,5- hlisoquinoline.

To a solution of 12H-benzo [d, e] [1, 3] benzodioxol [4, 5-h]-isoquinoline (0.38 mmol) in warm dichloroethane (4 mL),methy) iodide (12.8 mmol) was added and after a few minutes a yellow suspension was observed.

The reaction was warmed to 40°C with stirring for 20 minutes. After all the starting material was gone, nitrogen was blown into the system to remove both the solvent and excess Mel and then dried further under high vacuum. The resulting yellow residue was resuspended in THF and then sodium triacetoxyborohydride (0.4 g) and sodium cyanoborohydride (0. 12 g) were added. After a few minutes the suspension turns orange and stirring was continued for 20 minutes. Saturated ammonium chloride and hydrochloric acid (2N) were added to the suspension to form two layers.

Then sodium cyanoborohydride (0. 12 g) was added and stirred for 30 minutes. The layers were separated and the organic layer was evaporated and dried under vacuo.-Partial isolation and purification of product was achieved by recrystallization to give the title compound (0. 047 g) and the mother liquor was purified by column filtration to afford more product (0.04 g, 82% yield) : 1 H NMR (DMSO-d6) 8 7.39 (d, 1 H, J = 7. 35 Hz), 7.28 (t, 1 H, J = 7. 47 Hz), 7. 13 (d, 1H, J = 7.29Hz), 6.86 (d, 1H, J = 8. 04Hz), 6.72 (d, 1H, J = 7.95Hz), 6.09 (s, 1Hz), 6.02 (s, 1H), 4.60-4. 25 (m, 3H), 4.20-4.03 (m, 2H), 3.75-3.68 (m, 1H), 3.60-3. 40 (m, 1 H), 3. 02 (s, 3H) ; LCMS Calcd. for C18H17NO2 (M+) : 279.13.

Found: (MH+) 280.13.

Step ()-N-MethyI-8.9-D)hydroxv-2.3.7.11b-tetrahydro- 1H-napth[1,2,3-de]isoquinoline To a solution of the compound of Step A (0.16 mmol) in dichloromethane (4 mL) cooled to-78°C,. boron tribromide (1 M in dichloromethane, 0.77 mmol) was added. The reaction solution was stirred at-784C for two hours and warmed to room temperature overnight. The solution was cooled to-78°C and dry methanol was added to quenched the reaction. After stirring for 10 minutes, the solvent was removed and dry methanol was added. The process was repeated three times. Purification was performed by recrystallizatjion with MeOH/CH2Cl to obtain the title compound (0. 035 g) : 1H NMR (MeOD-d3) 8 7.37 (d, 1 H, J = 7.26 Hz), 7. 29 (t, IH, J = 7.35 Hz), 7.11 (d, 1H, J = 7.32 Hz), 6.72 (d, 1H, J = 8.19 Hz), 6. 59 (d, 1H, J = 8. 49), 4.7-4.39 (m, 3H), 4. 20-4. 05 (m, 1H) 3. 70-3.40 (m, 2H), 3.20 (s, 3H) ; LCMS Calcd. for C17H17NO2 (M+) : 267. 13.

Found : (MH+) 268. 16.