BACKGROUND OF THE INVENTION Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal sys particularly those involving serotonin (5-HT) and dopamine (DA). Anxiety is associated with increased activity in 5-HT systems. In animals where 5-HT has depleted, benzodiazepine anxiolytics are not active in anti-anxiety assays that they otherwise are eff in. Seronotin neurons have autoreceptors that, when activated by agonists, depress firing rates of cells. These receptors are of the 5-HT _1A subtype. Because they depress 5-HT neuronal activity, it c expected that 5-HT _1A agonists will be an effective anxiolytic. Clinically,5-HT _1A agonists have demonst anxiolytic properties. The drug Buspirone, is the only currently available marketed 5-HT _1A agonist h anxiolytic activity. This compound antagonizes dopamine receptors at the same dose it stimulates 5- receptors. A similar drug, Gepirone, also has dopamine antagonist properties. These dopamine antag properties reduce the clinical utility of these compounds because long term treatment with dopa antagonists can produce tardive dyskinesia. Depression is a psychiatric condition thought to be associated with decreased 5-HT release. anti-depressants potentiate the effects of 5-HT by blocking the termination of activity through re-uptak nerve terminals. Since some 5-HT _1A receptors are activated postsynaptically by 5-HT, 5-HT _1A agonist also be anti-depressants. Since the postsynaptic 5-HT _1A receptor may be less sensitive tha autoreceptor, high doses of 5-HT _1A agonists, particularly very effective ones (i.e., those causing g stimulation of the 5-HT _1A receptor, a parameter referred to as "efficacy"),can be expected to be eff anti-depressants. Gepirone has already been demonstrated to have ameliorative effects on some depr endpoints in some patients.

Serotonin is also involved in the regulation of feeding and sexual behavior and in cardiova regulation. Thus, 5-HT _1A agonists may be useful in treating overeating and sexual dysfunction. compounds have been shown to alter feeding and sexual behavior in animals. 5-HT _1A agonists ar known to depress sympathetic nerve discharge and thus lower blood pressure. Thus, they may be in treating hypertension, congestive heart failure (by reducing cardiovascular afterload) and heart atta removing sympathetic drive to the heart).

Schizophrenia is thought to be due to hyperactivity in DA systems. Thus, currently availabl psychotics are DA antagonists. Dopamine autoreceptors depress DA neuron firing rates, DA synthes release. Thus DA autoreceptor agonists can also be expected to be anti-psychotics. DA agonists a useful for treating Parkinsonism, a disease caused by degeneration of DA neurons, and hyperprolactin

since DA agonists depress prolacϋn release.

Dopamine autoreceptor antagonists are a new class of drug that increase release of DA b releasing the DA neuron from autoreceptor control. Thus, these drugs can be expected to be useful i conditions treatable with amphetamine and other similar stimulants which directly release DA. Howeve because DA autoreceptor agonists will be much milder stimulants because, rather than directly releasin DA, they simply increase the release associated with the normal DA activity by releasing the cell fro autoreceptor control. Thus, DA autoreceptor antagonists can be expected to be useful in treatin overeating, attention deficit disorders, psychiatric, cognitive and motor retardation in demented and elderl patients, and in treating nausea and dizziness with space travel. The compounds of die present invention have a variety of effects at 5-HT _1A and DA receptors, an offer a variety of utilities associated with those activities.

The search for new CNS active compounds is focused on finding compounds with selective 5-HT _j receptor agonist effects without detrimentally influencing centra] dopamine receptors.

Drugs acting on central dopamine transmission are clinicallyeffective in treating a variety of centr nervous system disorders such as parkinsonism, schizophrenia, and manic-depressive illness. I parkinsonism, for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynapti dopamine receptor stimulation. In schizophrenia, the condition can be normalized by achieving a decreas in postsynaptic dopamine receptor stimulation. Classical anti-psychotic agents directly block die postsynapti dopamine receptor. The same effect can be achieved by inhibition of intraneuronal presynaptic even essential for the maintenance of adequate neurotransmission, transport mechanism and transmitter synthesi in recent years a large body of pharmacological, biochemical and electrophysical evidence h

*_ provided considerable support in favor of the existence of a specific population of central autoregulator dopamine receptors located in the dopaminergic neuron itself. These receptors are part of a homeostati mechanism that modulates nerve impulse flow and transmitter synthesis and regulates the amount dopamine released from the nerve endings.

Direct dopamine receptor agonists, like apomorphine, are able to activate the dopamin autoreceptors as well as the post synaptic dopamine receptors. The effects of autoreceptor stimulati appear to predominate when apomorphine is administered at low doses, whereas at higher doses t attenuation of dopamine transmission is outweighed by the enhancement of postsynaptic recept stimulation. The anti-psychotic and anti-dyskinetic effects in man of low doses of apomorphine are lik due to the autoreceptor-stimnlator properties of this dopamine receptor agonist. This body of knowled indicates dopamine receptor stimulants with a high selectivity for central nervous dopamine autorecepto would be valuable in treating psychiatric disorders.

INFORMATION DISCLOSURE STATEMENT The following documents could be important in the examination of this application.

Arvidssoα, L.-E.,et al., J. Med. Chem., 2 , 921 (1981), describes hydroxy-2-aminotetralins whe the amine is substituted with one n-propyl, one benzyl or two n-propyl εubstitutents. The 5-, 6-, and

hydroxy compounds are described as active central dopamine-receptor agonists and the 8-hydroxycompou is described as a central 5-HT receptor agonist devoid of dopamine receptor stimulating activity.

Arvidsson, L.-E.,et al., J. Med. Chem., 22.45 (1984), describes 2-aminotetralins where the am is substituted with (me or two methyl, ethyl, n-propyl, i-propyl, n-butyl, or benzyl substituents. The piperidinyltetralin is also described. Several of these compounds were found to be potent 5-HT agon devoid of dopamine-mimetic effects.

Arvidsson, L.-E., et al., J. Med. Chem., 22, 2105 (1987), describes 8-hydroxy-l-methyl-2-(d ρropylamino)tetralins. These compounds were 5-HT receptor agonists.

The Arvidsson, L.-E., et al 8-hydroxy and 8-methoxy tetralin compounds are also disclosed Derwent documents 00389J/47, 94981D/51 and 045535J.48.

McDermed, et al., J. Med. Chem., _\i, 362 (1975) describes 5,6-dihydroxy-2-aminotetralins. addition, the 5,8and 7,8disubβtituted compounds are also disclosed. The amine can be a mono or di sub tuted with simple alkyl groups, benzyl groups alkylalkoxy groups or the amine can be a 5 or 6 member hydrocarbon or heterocyclic amine. These compounds are indicated to have dopaminergic propert although certain compounds are reported to be inactive.

McDermed, et al. . Med. Chem., 19, 547 (1976) describes 5-,6-,or 7-hydroxy-2-diρropylamino ralins. These compounds are described as dopaminergic compounds.

Rusterholz, et al., J. Med. Chem., 9, 99 (1976) describes 5,8 disubstituted-2-aminotetralins the amine being substituted with hydrogen, methyl, or cyanopropyl groups. Some of these compounds potent prolactin inhibitors and believed to be dopamine agonists.

Ames, et al.,J. Chem. Soc.2636(1965) describes the preparation of a large number of compou where the aromatic ring is substituted by methoxy, ethoxy , n- or iso-propoxy , or n-, sec- or tert-butoxy gr in the 5 or 8 position and die amine is substituted by hydrogen or alkyl groups having 1-4 carbon ato

The compounds are indicated to be prepared for pharmacological testing. However, no utili pharmacological activity is yet known for the compounds just mentioned.

German Patent DE-A1-2 803582 describes 2-aminotetralins where the aromatic ring is substit on die 5,6,7or 8 position with the group R _j , where R _j is hydrogen, alkanoyl having 1 to 20 carbon at or a group -CO-(CH ₂ ) _n -R ₇ , n is a number 0 to 5, R ₇ is a phenyl group with substituents as defined furt &2 is hydrogen, hydroxy, halogen or alkylsulfonylamino, R _j is hydrogen, R ₄ is hydrogen, CH _j OH, CH CO-R _j or CH ₂ -0-CO-(CH ₂ ) _I .-R ₇ with further definition and R _j and R^ are hydrogen, alkyl or ary aralkyl groups further defined or 5 and Rg are together an alkylene with 4 to 6 carbon atoms. compounds are disclosed as having pharmacodynamic activity in particular a stimulating effect on alpha- beta-adrenoceptors and dopamine receptors. Among the compounds described are compounds havin group R ₁₀ in the 8 position and having _j or R ₄ other than hydrogen. Great Britain Patent l,377,356describes 2-aminotetralins where the aromatic ring is substit on the 5, 6,7 or 8 position by R _j , where ~R_ is hydrogen or methyl, the aliphatic ring is substituted b where R _j is alkyl having 1-6 carbon atoms, and the amine is substituted by R3, where 3 is hydroge

alkyl having 1-6 carbon atoms are described. Such compounds are stated to possess analgetic activity. 1, Dimethyl-2-(N,N-<iin__ethylamino)-7-hydroxytetralin is mentioned as one example of a compound cover by the patent This compound is also described in Chem. Ab.,79: 146294bas having analgesic and intestin movement accelerating actions. J. Pharm. Sci., 67, 880-82 (1978) describes die compound l-methyl-2-(cyclopropylamino)- methoxytetralin and indicates the compound possess local anesthetic activity.

Derwent documents 58,247B/32, 40 378A 23, 83-729388/32, 83-72987/32, 29348D/17 a 06733V/05 refisr to 8-carboxyamino tetralins. Additional O7833V/05 refers to 8-amido and 8-alkylami tetnlin. EPO patent application EPO 270947 (1988) discloses 8-hydroxyand 8-methoxy-tetralins.

EPO patent application EPO 0 272 534 (1988) discloses aminotetralins including 8-ami compounds.

The references cited herein are disclosures describing work related to the invention:

Hjorth, S.; Carlsson, A; Lindberg, P.; Sanchez, D.; Wikstron, H.; Arvidsson, L.-E.;Hacksell, Nilsson. J.L.G..J. Neural Transm.. 1982.55. page 169.

Mellin, C.; Bjork, L.; Karlen, A.; Johansson, A.M.;Sundell, S.j Kenne, L.; Nelson, D.L.;Ande N.-E.;Hacksell, U.. J. Med. Chem.. 1988,21, page 1130.

Coβsery, J.M.;Gozlan, H.; Spampinato, U.; Perdicakis, C.;Guillaumet, G.:Pichat, L.;Hamon,

European J. Pharmacol.. 1987,pages 140, 143. INFORMAΗON DISCLOSURE STATEMENT

Trans-7- and trans-9-hydroxy-l,2,3,4,4a,5,6,10b-octahydrobenz^]quinolines have been synthesiz and their effects an central dopamine and o-receptors have been studied. Arvidsson, L.-E. et al, J. M Chem. I983,2Z> P*ge 45.

Octahydrobenzo-isoquinolines are also described in Derwent 84-073373/13. Hexahydrobenzo-isoquinolines are described in Derwent 55370A/31 (DT 2801576).

Derwent 83-840180/50 and 86-298374/45 discloses tetra-hydro-benzo-isindoline derivatives whi interact specifically with various androgenic receptors and are useful for treating hypertension. 298374/45 also discloses that die compounds also have sedative activity.

French patent 1.555.553(Derwent 37216 describes 2,3,4,4a,5,6-hexahydrobenzo-(0quinolines.

*_ U.S. Patent 4,622,405discloses 1,2,3,1, 8, 8 t-hexahydro indero(l,2-C)pyrroles(s).

Derwent 63503T-B, 52201R-B, 23543R, 30016 and 41102 disclose hexahydroinenopyridinols. Derwent 67323W/41 discloses benzoisoindolines as anti-agressive and analgesic agents.

SUMMARY OF THE INVENTION This invention e com s-^es compounds of Formula I, where Y is hydrogen or halogen wherein R _j is

(a) -hydrogen

wherein m is 1-4 n is 0-3.

The compounds of this invention possess selective pharmacological properties and are usef treating central nervous system disorders including anti-depression symptoms, anxiolytic synφtoms, attacks, obsessive-compulsive disturbances, senile dementia, emotional disturbances related to dem disorders, and stimulation of sexual activity. The compounds of this invention are also useful to all

aggressive behavior, confiisional delirious states and impotence. In addition to their central nervous syst pharmacological activities, the compounds of this invention are also anti-diabetic, anti-obesity,a atheroβclerotic, and anti-hypertensive agents. Processes for preparation of these compounds, th pharmaceutical use and pharmaceutical preparations employing such compounds constitute further aspe of the invention.

According to a preferred embodiment the invention is related to compounds of Formula I. example, cis-- O-2 _» 3,3a,4,5,9b-hexahydro--6-medιoxy-3-{2-p^ exhi good selective dopamine activity.

An object of die invention is to provide compounds for therapeutic use, especially compou having a therapeutic activity in the central nervous system. Anodier object is to provide compounds hav an effect on the $-HT _1A receptor in mammals including man. A further object of this invention is provide compounds having an effect on the subclass of dopamine receptors known as the D ₂ receptor. nτ*rτAττ.F.r) DESCRIPTION OF THE INVENTION

The compounds of this invention are identified in two ways: by the descriptive name and refere to labelled structures contained in appropriate charts. In appropriate situations, die proper stereochemis is also represente in die charts.

In this document the parenthetical term (^-C^ is inclusive such that a compound of (C _j - would include compounds of one to 8 carbons and their isomeric forms. The various carbon moieties defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranc forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n pentyl, n-hexyl, isohexyl,n-heptyl, isoheptyl, and n-octyl.

Alkoxy as represented by -OR _j when R _j is (C _j -Cg) alkyl refers to an alkyl radical which is attac to the remainder of die molecule by oxygen and includes branched or unbranched forms such as meth ethoxy, n-propoxy, isopropoxy, n-butoxy , isobutoxy, sec-butoxy , t-butoxy, n-pentoxy , isopentoxy , neo-pent n-hexoxy,isohexoxy,n-heptoxy, isoheptoxy, and n-octoxy.

Alkenyl refers to a radical of an aliphatic unsaturated hydrocarbons having a double bond includes both branched and unbranched forms such as ethenyl, 1-methyl-l-ethenyl, 1-propenyl, 2-prope 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-butenyl, 1-pentenyl, allyl, 3-pentenyl, 4-pentenyl, l-methy pentenyl, 3-methyl-l-pentenyI, 3-metiιyl-allyl, l-hexenyl,2-hexeπyl,3-hexenyl,4-hexenyl, l-methyl-4-hexe 3-methyl-l-hexenyl, 3-medιyl-2-hexenyl, 1-beptenyl, 2-hepteπyl, 3-heptenyl, 4-heptenyl, l-methyl-4-hepte 3-methyl-l-heptenyl, 3-methyl-2-heptenyl, 1-octenyl, 2-octenyl, or 3-octenyl. Cycloalkyl refers to a rad of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyL

LDA is lithium diisopropyl amide. It will be apparent to those skilled in die art that compounds of this invention may contain c centers. The scope of this invention includes all enantiomeric or diastereomeric forms of Formula I c pounds either in pure form or as mixtures of enantiomers or diastereomers. The compounds of For

I contain two asymmetric carbon atoms in the aliphatic ring moiety, including die ring carbon at adjacent to the nitrogen atom. The therapeutic properties of die compounds may to a greater or le degree depend on the stereochemistry of a particular compound. Pure enantiomers as well as enantiom or diastereomeric mixtures are within the scope of the invention. Both organic and inorganic acids can be employed to form non-toxic pharmaceutically accept acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosph hydrochloric, citric, acetic, lactic, tartaric, palmoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulf fumaric, maleic, and benzoic acid. These salts are readily prepared by methods known in the art.

The compounds of this invention may be obtained by one of die following methods described b and outlined in the appropriate charts.

The (1,2N) carbocyclic 2-aminotetralins of this invention can be made in accordance wit processes illustrated in Charts A, B and C and die (3,2N) compound can be made in accordance wit process illustrated in Charts D, E, and F. Chart Δ In step 1, 2-tetralone (A-l) is reacted with allylbromide in the presence of IDA and tetrahyd ran to provide A-2. A-2 is then subjected to reductive amination by reacting it with the appropriate a in the presence of NaBH ₃ CN, acetic acid, tetrahydrofuran and metiiyl alcohol to yield compound A-3 is first reacted with mercuric acetate and methanol and die resulting compound is subjected to redu by sodium borohydride in sodium hydroxide to yield compound A-4. A-4 is O-demethylated via met known in the art to yield A-5. Chart g

In step 1 of method B, 2-tetralone (B-l) is reacted with an appropriate bromo-ester in the pres of LDA and tetrahydrofuran to provide B-2. In step 2, B-2 is subjected to the same reductive amin step as in step 2 in Method A to yield B-3. In step 3, B-3 is subjected to reduction to yield B-4. B-4 demethylated via methods known in the art to yield B-5. Chart C

In step 1, 2-tetralone (C-l) is reacted with dimethylcarbonate in the presence of base to gi carbomethoxy substituted tetralone derivative C-2. In step 2, C-2 is subjected to the same red amination step as in step 2 in Method A to yield C-3. In step 3, C-3 is subjected to lithium alum hydride to yield C-4. C-4 was treated witii p-toluene sulfonyl chloride and pyridine resulting in conve to C-5. Chart D

In step 1, tetralone derivative D-l is subjected to the same step as in step 1 in method C t substituted tetralone derivative -2. Allylation in the presence of base in step 2 gives l-carbomethoxy-3 derivative D-3. Decarboxylation in step 3 gives 3-allyl-tetralone derivative D-4. Reductive amination i 4 gives aminotet aline derivative D-5. Amino-mercuration in step 5 gives 3,2N tricyclic derivative D Chart £

In step 1, the keto group in 3-allyltetnlone derivative E-l (D-4) is protected to form ket derivative E-2. Oxidation of the allyl group of E-2 to an acid followed by esterification in step 2 gives a allyl-2-keto-ester derivative E-3. Reductive amination followed by lithium aluminum hydride reduction step 3 gives the 3,2N tricyclic derivative E-4. Chart E.

In step 1, ketal derivative F-l (E-2) is hydroborated to form alcohol F-2. F-2 is in step 2 oxidize hydrolyzedand esterified to giveketo-ester F-3. Reductive amination followed by lithium aluminum hydri reduction in step gives the 3,2N-tricyclicderivative F-4.

In clinical practice die compounds of the present invention will normally be administered orall rectaUy, or by injection, in die form of pharmaceutical preparations comprising the active ingredient eith as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochlorid lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The use a administration to a patient to be treated in the clinic would be readily apparent to a person of ordinary sk in the art. In therapeutical treatment the suitable daily doses of the compounds of die invention are 1-20 mg/kg for oral application, preferentially 50-500mg, and Ol-lOOmg for parenteral application, preferential 0.5-50 mg.

The compounds of this invention where R _j is in 8- position in the aromatic ring are very selecti 5-HT _1A receptor agonists having generally little or no dopaminergic activity. The IC50 ratio of dopami D ₂ to 5-HT _1A in Λαtro binding data shown in Table I for one compound of this invention, (Example compound #2) demonstrates the selectivity for the 5-H _1A receptor. The compound of this invention wh R _j is in 5- position in the aromatic ring, on the other hand, have dopaminergic activity with little 5-HT agonist activity. The data shown in Table I for one compound of this invention, (Example 4, compound # demonstrates low 5-HT _1A agonist activity yet showing a selective dopamine antagonist activity based evaluation of dopamine and serotonin metabolites. These compounds are particularly effective anxiol and antidepressant agents. Other uses for these compounds include panic attacks, obsessive-compulsi disturbances, and senile dementia particularly die emotional disturbances seen in dementia disorders. addition, central 5-HT receptor activation are believed to be involved in mediating sexual behavior. Th compounds would lie useful to stimulate sexual activity and to alleviate impotence. The compounds of t invention are also useful to alleviate aggressive behavior, confusional delirious states.

The compounds of this invention also have been shown to have high oral potency and a lo duration of action. Botii these features are beneficial to effective clinical treatment.

The utility of the compounds of this invention to treat central nervous system disorders is sho in behavioral, physiological and biochemical tests. The methods are given as follows: Binding:. Inhibition of 8-OH-DPAT binding in a bovine brain homogenate. Potency is given nM dose required to inhibit 50% of DPAT binding (IC50). This test measures ability to bind to hydroxyhyptamine (5-ΗT _1A ) receptor.

Hypothermia: Starting with a dose of 30 mg/kg, four mice are injected subcutaneously with t compound. Twenty minutes later, the number of animals whose body temperature has decreased by 2 or more are counted. If all four animals reach criteria, the drug is considered "active", and subsequ readings are taken at 60 and 120 minutes after drug. The time for last statistically significant drug af on mean body temperature is indicated in minutes. For all "active" compounds, doses are lowered by log intervals until a dose which does not lower body temperature by 2#C.in any animal is found. Pote is given as mg/kg ED50 (dose required to depress temperature in two of four mice) as measured Speaπnan-Karber statistics.

Synφathetic Nerve Discharge (SND): The i.v.mg/kg dose causing a 50% depression in SND chloralose anesthetized cats and die maximum inhibition of sympathetic activity observed in the dose ra tested (0.001-l.Omg/kg i.v.).

BP SND/MAX: The blood pressure of the chloralose anesthetized cats in percent control at dose causing 50% depression in SND and die maximum reduction in blood pressure as percent of control blood pressure in the same animals observed in the dose range tested (0.001-1. Omg/kg i.v.). CNS and anti-hypertensive biological data are shown in Tables I and II respectively.

TABLE π ANΉ-HYPERTENSΓVE BIOLOGICAL DATA erotonin SN Assa

5 Compound #1 0.083 14.0 77 59

Without further elaboration, it is believed that one skilled in die art can, using die precedi description, practice the present invention to its fullest extent. The following detailed examples descri how to prepare the various compounds and/or perform the various processes of the invention and are be construed as merely illustrative, and not limitations of die preceding disclosure in any way whatsoev Those drilled in the art will promptiy recognize appropriate variations from me procedures both as reactants and as to reaction conditions and techniques.

Preparation I: l,2,3 Tetrahydro-2-oxo-l-(2-pr(φenyl)-naphthalene l,2,3,4-tetrahydro-2-oxo-l,l,di- propenyl)naphdιalene (A-2, Chart A).

To a solution of 7.3 g (50 mmol) 2-tetralone in 75 ml THF in a three-neck round-bottomed flas equipped with a gas inlet and septum, was added 36.7 mL DA (55 mmol, 1.5M in cyclohexane, at -30 under a nitrogen atmosphere. The solution was allowed to warm to Q#Cover a thirty-minute period a 5.6 mL (65 mmol) ethyl bromide was added. TLC analysis was used to monitor the reaction. After stirri for 24 hours at room temperature, the reaction mixture was quenched with 10% sodium bisulfite to pH2 After removal of THF under reduced pressure, the mixture was extracted witii ethyl acetate (2 X 1 L) a die combined organic layers were washed with brine, dried (MgSO^, filtered and concentrated in vac The crude product was purified by liquid chromatography on 800 g of silica gel 60 (230-400 m), eluting w 1 L hexane, followed by 5 L of 5% ethyl acetate/hexane, and collecting 40 mL fractions. Fractions 41- gave 4.2 g (37%) of pure and l,2,3,4-tetrahydro-2-oxo-l,l-di-(2-propenyl)naphthalene as a colorless oil a fractions 65-82 gave 3.1 g (33%) of pure l,2,3,4-tetrahydro-2-oxo-l-(2-propenyl)-naphthalene as a li yellow oil.

¹ HNMR (CDC1 ³ , TMS): i 7.27-7.16(m, 4H); 5.81-4.95(m, 3H); (s, 3H); 3.54-2.45(m, 7H). IR film: ή _aιtχ 1717, 1640 and 1582 cm ^*1 . MS: M ⁺ 186, other ions at m/z 168, 145, 128 and 117.

TLC (silica gel GF): f = 0.51 hexane/eϋiyl acetate (4:1).

Utilizing a similar procedure as in Preparation 1 but using the appropriate starting material, th is obtained l,2,3,4-tetrahydro-8-methoxy-2-oxo-2-(2-pπ)penyl)naphthalen e. 1HNMR (CDC1 ₃ , TMS): δ 7.21-6.76(m, 3H); 5.73-4.87(m, 3H); 3.82 (s, 3H); 3.88-382(m, 1

3.32-2.43(m. 6h),

IR (film): ή „„ 1712, 1640, 1586 cm ^*1 . MS: Calcd for C^gCy 216.1150. ound: 216.1151. Analysis: Calcd for C ₁₄ H ₁₆ 0 ₂ : C, 77.75;H, 7.46.

Found: C, 77.56;H, 7.68. TLC (Silica Gel GF): Rf = 0.32 in hexane acetone (4:1).

Preparation 2:trans-(+-)-3.4.4a.5,10.10a-hexahydro-9-me oxy-l-(2-propenyl-2(lH)-benzo| }quinolin-2- as A and £i§-(+- )- 3,4,4a,5,10-10a- ιexahydro-9-methoxy-l-(2-prorienyl)-2(lH)-benzo|g]-quiικ& gt;lin-^ B.(B-3, Chart B)

To a solution of 2.2 g (8.4 mmol) of (+-)-! ,2,3, 4-tetrahydro-5-methoxy-4-oxo-2-naphthale propanoic acid methyl ester (preparation 7) and 2.5 mL (33.6 mmol) of allylamine in 42 mL methanol/T

(1:1) was treated witii acetic acid (ca 6.7 mL) at 0-5#Cuntil die pH of the mixture was 4-5. The mixture stirred for 30 minutes and 1.06 g (16.8 mmol) of sodium cyanoborohydride was added. The result solution was stirred at room temperature for five days. The reaction was then quenched with 20% sodi hydroxide and concentrated in vacuo. The concentrate was extracted with methyleae chloride (2 1 The organic layer was washed with brine, dried (MgSO^, filtered and concentrated in vacuo. The cr product was purified by liquid chromatography on 400 g of silica gel 60 (230-400 m), eluting with hexa acetone (4:1) and collecting 40 mL fractions. Fractions homogeneous by TLC were combined concentrated in vacuo. Fractions 101-108 gave 0.26 g (11.6 %) of pure A as a white solid a recrystallization from hexane/ethyl acetate: mp. 104-105#C. Fractions 110-138afforded 1.8g(79 %) of p B as a white solid after recrystallization from hexane/ethyl acetate: mp. 71-721C.

Trans^+->3.4.4a.5.10-10a-hexahydro-9-methoxy-l-(2-prop CTvI)-2(lHVbenzorglquinolin-2-on ^J HNMR (CDC1 ₃ , TMS): 7.14-6.14(m, 3H); 5.88-5.16(m, 3H); 3.83 (s, 3H); 4.65-1.52(m, 12 IR (mull): ή „,„ 1652, 1637, 1602 and 1585 cm ^"1 . MS: M ⁺ 271, other ions at m/z 271,256,214, 186, 172, 159, 144, 134. Analysis: Calcd for C ₁₇ H2,N0 ₂ : C, 75.24;H, 7.80;N, 5.16.

Found: C, 75.36;H, 8.09;N, 5.21. Cis-(+-)3,4,4a,5,10,10a-hexahydro-9-me oxy-l-(2-prorjenyl)-2(lH)-benzo[g]quinolin-2-one. ¹ HNMR (CDC1 ₃ , TMS): 7.14-6.14(m, 3H); 5.88-5.16(m, 3H); 3.83(s, 3H); 4.72-1.58(m, 12 IR (mull): fi „,„ 1644, 1627, 1601 and 1587 cm ^*1 . MS: M ⁺ 271, other ions at m/z 256, 214, 186, 172, 159, 144, 134. Analjsis: Calcd for C ₁₇ H ₂₁

C, 75.24;H, 7.80;N, 5.16.

Found: C, 75.36;H, 8.09;N, 5.21. Utilizing a procedure similar to Preparation 2, using the appropriate starting material and subst there is obtained cis- l,3,3a.4,5,9b-hexahydro-3-(2-propenyl)-2H-benz[e]-indol-2-on αsaye oil.

¹ HNMR (CDC1 ₃ , TMS): δ 7.2-7.0(m, 4H); 5.80-5.20(m, 3H); 4.40 (m, 1H); 3.90 (m, 1H); (m, 2H); 2.90 (m, 1H); 2.80-2.60(m, 2H); 2.35 (t, 1H); 2.05 (m, 1H); 1.7 (m, 1H). TLC (Silica Gel GF): Rf = 0.29 in hexane-acetone (4:1). cis-(+-)-l,3,3a.4,5,9b-hexahydro-9-medιoxy-3- 2-propenyI)-2H-be^e3_ndoi-2-oneasa∞iories

¹ HNMR (CDC1 ₃ , TMS): 8 7.12-6.72(m, 3H); 5.87-5.22(m, 3H); 4.10-4.36(d of d, 1H); 3. 3H); 3.72-1.68(m, 9H).

IR (mull): ή _{m x} 3580, 3442, 1680, 1598 and 1572 cm ^*1 . MS: Calcd for C _j gH _jj NO^ 257.1416.

Found: 257.1414. Analysis: Calcd for C^H^NC^: C, 74.68;H, 7.44;N, 5.44. Found: C, 73.02;H, 7.70;N, 5.32.

Ci» +- .3.3a.4.5.9b--hexahydro-6-meflioxy-3--{2-prop^ mp. 89-90#C. .

"HNMR (CDα ₃ , TMS): 8 7.19-6.69(m, 3H); 5.38-5.20(m, 3H); 4.45-4.34(m,lH); 3.82(s 3 3.94-1.54(ιn, 9H)» . IR (mull): ή ___ 1684 and 1641 cm ^*1 .

MS: M ⁺ 257, other ions at m/z 242,228, 172, 158.

Analysis: Calcd for C ₁₆ H ₁₉ N0 ₂ : C, 74.68;H, 7.44;N, 5.40 Found: C, 74.40;H, 7.46;N, 5.60 trans-f -4— 1.3.3a.4.5.9b-hcxahvdro-6-methoxv-3-(2-propenvr)-2H-benzf elindol-2-one recrystalliz from hexane/ethyl acetate to give a white solid: mp. 137-138/TC.

¹ HNMR (CDα ₃ , TMS): « 7.20-6.64(m, 3H); 5.88-5.14(m, 3H); 4.22-4.14(d of d, 1H); 3.82 3H); 3.83-1.60(itt, 9H).

IR (mull): ή „,„ 1686, 1603, and 1582 cm ^*1 .

MS: M ⁺ 257, other ions at m z 242,228, 173. Analysis Calcd for C ₁₆ H ₁₉ N0 ₂ : C, 74.68;H, 7.44;N, 5.44.

Found: C, 74.74;H, 7.72; N, 5.44.

_Ss-(+-)-l»3,3a,4,5,9Wιexahydro-9-medιoxy-3-(2-propyl) -2H-bβιz e]indol-2-oneas a yellow oil

¹ HNMR?(CDC1 ₃ , TMS): β 7.15-6.70(m, 3H); 3.81 (s 3H); 3.79-1.50(m, 12H); 0.94(t, 3H).

MS: M ⁺ 259, other ions at m/z 244,230,216,202, 188, 173. TLC (Silica Gel GF): Rf = 0.47 in hexane-ethyl acetate (3:1).

Cis-( + -)-l ,4,4a,4,5,6, 10b^exahydro-10-memoxy-4-(2-propenyl)-benz f]quinolin-3(2H)-oπβsan

¹ HNMR (CDCI ₃ , TMS): 7.13-6.69(m, 3H); 5.83-5.13(m, 3H); 4.64-4.59(d of d, 1H); 3.83(s 3 3.60-1.73(m, 11H). TLC (Silica Gel Gf): Rf = 0.33 in hexane-acetone (2:1,5 % 2- ^12 *-tetrahydro*medιo

2-(2-propαιylamino)-l-naphdιalenecarboxylic acid mediyl acid methyl ester.(C-3, Chart C)

¹ HNMR (CDC1 ₃ , TMS): 8 7.25-6.78(m, 3H); 6.01-5.51(m, 3H); 3.81 (s, 3H); 3.71 (s, 3H); 4. 1.82 (m, 9H).

IR mulb ήmax 1731, 1604 and 1579 cm ^"1 . MS Calcd for C^H^NO.,: 275.1521.

Found: 275.1535 Analysis calcd for C^H _jj NCyHCl: C, 61.63;H, 7.11;N, 4.49

Found: C, 61.98;H, 7.34;N.4.73. TLC (Silica Gel Gf): Rf = 0.26 in hexane ediyl acetate (1:1). Preparation 2: l,2,3,4-Tetrahydro-2-oxo-l-naphtiιalene acetic acid methyl ester (B-2, Chart B).

A three-neck, round-bottomed flask equipped with a dropping funnel and a septum, was char with 6.6 mL (50 mmol) of beta-tetralone and 100 mL of THF under a nitrogen atmosphere. The solu was cooled to -30#Cand 36.6 mL (55 mmol) of IDA (1.5 M in cyclohexane) was added dropwise. solution was stirred for 30 minutes and warmed to 0#C. To this solution, 5.7 mL (60 mmol) of me bromoacetate was added. The solution was stirred at 0#Cfor 1 h. The reaction was quenched with 3N until pH of the mixture was <3.THF was removed in vacuo and die concentrate was extracted methylene chloride (2x 500 mL). The organic layer was washed witii brine, dried (MgSO^, filtered concentrated in vacuo to give a yellow oil. This oil was purified by liquid chromatography on 560 g s gel 60 (230-400 m), eluting with hexaπe-ethyl acetate (4:1) and collecting 40 mL fractions. Frac homogeneous by TLC were combined and concentrated in vacuo. The resulting oil needed die sec chromatography to afford 8.22 g (75.4 %) of > 95 % pure product as a near colorless oil. ¹ HNMR (CDC1 ₃ , TMS): 8 7.28-7.09(m, 4H); 3.98-3.94(t, 1H); 3.68 (s, 3H); 3.58-2.42(m, 6

TLC (Silica Gel GF): Rf = 0.25 in hexane-acetone (4:1).

Utilizing a procedure similar to that of Preparation 3 but using the appropriate starting mate there is obtained

(+- )-l,2,3,4-tetrahydro-8-methoxy-2-oxo-l-naphthalene acetic acid methyl ester. ¹ HNλfR (CDC1 ₃ , TMS): 7.19-6.78(m, 3H); 3.83 (s, 3H); 3.81 (m,lH); 3.56(s, 3H); 3.29-2.5

6H).

IR (film): _mtχ 1741, 1713, 1601, and 1587 cm ^*1 . MS: Calcd for C, ₄ H ₁₆ 0 ₄ : 248.1048.

Found: 248.1049. Analysis: Calcd for C ₁₄ H ₁₆ 0 ₄ : C, 67.72;H, 6.49.

Found: C, 67.60;H, 6.60. (+-)-l,2,3,4-Tetrahydro-5-methoxy-2-oxo-l-naphthalene acetic acid methyl ester. ¹ HNMR (CDC1 ₃ , TMS): 8 7.23-6.72(m, 3H); 3.94(t, 1H); 3.85(s, 3H); 3.68(s, 3H); 3.32-2. 6H). IR (film): ή „„ 1729, 1717, 1686, 1676, 1600 and 1588 cm ^*1 .

MS: M ⁺ at 248, other ions at m/z 217,216, 188, 174. Analysis: Calcd for C ₁₄ H ₁₆ 0 ₄ : C, 67.73;H, 6.50.

Found: C, 67.73;H, 6.73. l,2,3,4- εtπ_hydro-8-metiιoxy-2-oxo-l-naphtiιdenecarboxyIic acid metiiyl ester. (D-2, Chart ¹ HNMR (CDC1 ₃ , TMS): 8 7.23-6.72(m, 3H); 4.72 (s, 1H); 3.80 (s, 3H); 3.72-2.17(m, 7H).

IR (film): ή ^ 1750, 1718 and 1588 cm ^*1 . MS: M ⁺ at 234, other ions at m/z 202, 191, 174, 147, 131, 115, 103, 91.

Analysis: Calcd for C ₁₃ H ₁₄ 0 ₄ : C, 66.65;H. 6.02.

Found: C, 66.49;H, 5.93. TLC (Silica Gel GF): Rf = 0.33 in hexane/ediyl acetate (3:1). Preparation4(+-V3\4'-Dihvdro-8'-inethoxv-3 2-prorjenyl)^ Chart E)

A solution of l,2,3,4-tetrahydro-8-methoxy-3-(2-φropMiyl)-2-oxo-naphthale ne (15 g, 68 mmol), mL (272 mmol) trimethyl orthoformate, 38 mL (680 mmol) ethylene glycol,0.13g (0.68 mmol) p-toluen sulfonic acid monohydrate, and 306 mL methylene chloride was stirred at room temperature under nitrogen atmosphere for 24 hours. TLC analysis showed no starting material remaining. The reaction w quenched with saturated sodium bicarbonate and extracted with methylene chloride (2x 1 L). The organ layer was washed widi brine, dried (MgSO^, filtered and concentrated in vacuo to give a yellow oil. Th oil was purified by flash chromatography on 1 Kg of silica gel 60 (230-400 m), eluting wid 2 L bexane a 5 L bexane-etiiyl acetate (9:1) and collecting 500 mL fractions. Fractions 11-14 afforded 15.5 g (88%) a light yellow oil. ¹ HNMR (CDC1 ₃ , TMS): 7.12-6.64(m, 3H); 5.90-5.50(m, 3H); 4.13-3.92(m, 4H); 3.80(s, 3H

3.06-l.84(m, 7 H)»

IR(muIl): _{4 ntχ} 1640, 1604 and 1587 cm ^"1 .

MS: M ⁺ 260, other ions at m/z 245,219,206, 174, 160, 147, 134. Analysis: Calcd for C ₁₆ H2 ₀ O ₃ : C, 73.82;H, 7.74. Found: C, 73.48,H, 8.07.

Preparation _y. (+- l,2,3,4-Tetrahydro-5-methoxy-3-oxo-2-πaphthalMie-acetic acid methyl ester (E-3, Cha E).

A three-neck, round-bottomed flask, equipped with a mechanical stirrer and a gas inlet, w charged with 57.8 g (270 mmol) of sodium periodate and 1 L of water under a nitrogen atmosphere. T mixture was stirred for 10 minutes and 2.8 g (18 mmol) of potassium permanganate was added. T resulting purple colored mixture was stirred at room temperature for 30 minutes. Potassium carbona powder (7.5 g, 54 mmol) was then added and die mixture was stirred for 15 minutes. To this mixture 3 mL of t-butanol (distilled) as added over a period of 10 minutes while the temperature of the mixture w maintained at <30#C. A solution of 7.8 g (30 mmol) 3\4'-dihydro-8'-metiιoxy-3-2tørorjenyl)-spiro[l dioxolane-2,2'( H)-naphtiιalene in 300 mL t-butanol was then added over a period of five minutes. T color of the mixture immediately turned from purple to pink. After the mixture was stirred for three hou

TLC analysis showed no starting material remaining (the aliquot was treated widi a few drops of aqueo sodium bisulfite and extracted with ethyl acetate). The mixture was cooled to 0-5#Cand sodium bisul powder was added slowly until die pink-brown suspension became clear yellow solution. The mixture diluted wid 1 L water (pH <3)and extracted widi 2x2 L portions of methylene chloride. The organic la was washed widi water, brine, dried (N _j SO^ not MgSO^), filtered and concentrated in vacuo to give g of pale yellow solid, appeared to be d e ketal-acid. This solid was dissolved in 150 mL acetonitrile a

150 mL HCl MeOH (prepared by adding 24 mL acetyl chloride to 126 mL of medianol at 0-5#C). yellow solution was allowed to stand in the refrigerator overnight. The mixture was then stirred at temperature for 3 hours, TLC analysis showed die esterification was completed. To this solution, 30 of water was added and die solution was stirred at room temperature for 24 hours. The solvent was t removed in vacuo and die resulting yellow oil was extracted widi 2x 1 L of ethyl acetate. The organic l was washed widi brine, dried (MgSO _j ), filtered, and concentrated in vacuo to give a yellow oil. The oil purified by flash chromatography on 1 Kg of silica gel 60 (230-400 m), eluting widi 8 L 5%, 8 L 10% e acetate/hexane, and collecting 500 mL fractions. Fractions 20-31 afforded 4.28 g (57.5 % overall yiel a pale yellow solid. Recrystallization from etiiyl acetate/hexane as a -white solid: mp. 73-74#C. _j HNMR (CDC1 ₃ , TMS): 8 7.21-6.75(m, 3H); 3.83(s, 3H); 3.71(s, 3H); 3.79-3.38(q, 2H), 3.14

(m, 5H).

IR(mull): ,„ 1742, 1717 and 1586 cm ^*1 . MS: M ⁺ 248, other ions at m/z 230, 216, 199, 188, 174, 159, 146. Analysis: Calcd for C^U^O . C, 67.73;H, 6.50. Found: C, 67.54.H, 6.71.

Preparation 6: (+-)-l,2,3,4-Tetrahydro-8-ιnethoxy-2-oxo-l-naphthalene propionic acid mediyl ester ( Chart B).

A three-neck, round-bottomed flask, equipped widi a dropping funnel and septum, was cha with 1.76 g (10 mmol) of 8-methoxy-2-tetralone and 20 mL of THF under a nitrogen atmosphere. solution was cooled to -30#Cand 7.5 mL (11 mmol) of LDA (1.5 M in cyclohexane) was added drop The solution was stirred for 30 minutes and warmed to 0#C. To this solution, 1.3 mL (12 mmol) of m bromopropionate was added. The solution was stirred at room temperature for two hours. The rea was quenched with 3 N HC1 until pH of the mixture was <3. THF was removed in vacuo and concentrate was extracted with methylene chloride (2x 500 mL). The organic layer was washed widi b dried (MgSO^, filtered and concentrated in vacuo to give a yellow oil. This oil was purified by l chromatography on 400 g silica gel 60 (230-400 m), eluting with hexane-acetone (4: 1), and collecting 4 fractions. Fractions homogeneous by TLC were combined and concentrated in vacuo to give 1.63 g ( of the title compound as a yellow oil.

¹ HNMR (CDC1 ₃ , TMS): 8 7.28-6.75(m, 3H); 3.83 (m, 1H); 3.80 (s, 3H); 3.56 (s, 3H); 3.2 (m, 8H).

¹³ CNMR: 203, 173, 158, 137, 127, 125, 119, 108, 56, 51, 46, 38, 31, 27.5,27.2. IR (film): fi „,„ 1736, 1711 and 1586 cm ^*1 . MS: Calcd for C ₁₅ 4H _lg 0 ₆ : 262.1205. Analysis: Calcd for C ₁₅ H _lg 0 ₄ : C, 68.68;H, 6.92.

Found: C, 68.74;H, 7.15. Preparation 7: (-1— )-l,2,3,4-Tetrahydro-5-methoxy-4-oxo-2-naphdιalene-propanoi c acid mediyl ester

Chart F).

A solution of 6.25 g (24 mmol) 3\4'-dihydro-8'-n-etiioxy-3-(2-propenyl)-spiro[l,3**dioxola 2,2'(l'H)-naphthalene in 120 mL THF was cooled to 0-5#Cunder a nitrogen atmosphere. The solution w then treated wid 144 mL (72 mmol) of 9-BBN in THF dropwise over a period of 30 minutes. The resultin mixture was stirred at room temperature for three hours. The solution was cooled again to 0-5#Cand mL water was added. After five minutes, die mixture was treated widi 28.8 mL of 3 N sodium hydroxi and was followed by dropwise addition of 28.8mL addition of 30% hydrogen peroxide. After die mixtu was stirred at room temperature for one hour, the mixture was carefully treated with 10% sodium bisulfi to destroy die excess hydrogen peroxide. The mixture was then adjusted to pH 8-9 by adding saturate sodium bicarbonate and extracted with methylene chloride (2 x 600 mL). The organic layer was washe widi brine, dried (MgSO^, filtered and concentrated in vacuo to give a near colorless oil. The oil w purified by LC on 800 g silica gel 60 (230400 m), eluting widi hexane-acetone (2: 1), and collecting 40 m fractions. Fractions 71-105 gave 6.48 g (97%) of pure A as a colorless oil. This oil (6.12 g, 22 mmol) w then dissolved in 220 mL acetone in a three-neck, round-bottomed flask, equipped with a mechanical stirre under a nitrogen atmosphere. The solution was cooled to 0-5#Cand 46.8 mL (125 mmol) of Jones reage in 93.6 mL acetone was added in five minutes. After the mixture was stirred for 10 minutes, the reactio was quenched with 10% sodium bisulfite until die brown color was converted from brown to green ( destroy die excess reagent). Acetone was removed in vacuo and die residue was extracted widi ethyl aceta (2 1 L). The organic layer was washed with brine, dried (Na _j SO^ not MgSO^), filtered and concentrate in vacuo to give the carboxylic acid as a brown oil. This oil was dissolved in 110 mL acetonitrile a hydrochloric acid in methanol (prepared by adding 17.6mL acetyl chloride to 93 mL methanol at 0#C). T resulting mixture was stirred at room temperature under a nitrogen atmosphere for three hours. T conversion of the carboxylic acid to methyl ester appeared to be completed by TLC. The solution was th treated with 22 L of water and the mixture was stirred at room temperature under a nitrogen atmosphe for 24 hours (to hydrolyze die ketal). The solvent was removed in vacuo and die residue was extracted w ethyl acetate (2 x 800 mL). The organic layer was washed widi saturated sodium bicarbonate, brine, dri (MgSO^, filtered and concentrated in vacuo. The deep brown oil was purified by LC on 800 g silica 60 (230-400 m), eluting widi hexane-ethyl acetate (4:1), and collecting 40 mL fractions. Fractions 47- afforded 2.35 g (41% overall) of pure B as a light yellow oil. Physical data for A (F-2, chart F):

¹ HNMR (CDC1 ₃ , TMS): 8 7.12-6.64(m, 3 H); 4.10-3.74(m, 4H); 3.80(s, 3 H); 3.78-3.63(m, 2 3.38-1.10(m, 9 H3.

IR (film): ή „„ 3400 and 1587 cm ^*1 .

MS: M ⁺ 278, other ions at m z 247, 233, 219, 206, 189, 175, 161, 143. Analysis Calcd for C^H^O^ C, 69.04;H, 7.97.

Found: C, 69.14;H, 7.91. Physical data for B (F-3, chart F):

¹ HNMR (CDα ₃ , TMS): 8 7.21-6.74(m, 3 H); 3.82 (s, 3 H); 3.66 (s, 3 H); 3.66-1.26(m, 9 H IR (film): „„ 1737, 1714, 1602 and 1587 cm ^*1 . MS: M ⁺ 262, other ions at m z 230, 175. Analysis: Calcd for C ₁₅ H _lg 0 ₄ : C, 68.68; H, 6.92. Found: C, 68.38;H, 7.01.

Preparation £ : trans*-<+-yi.3.3a.4.9.9b.-Hexahydro-8-medιoxy-H2-pro l,3,3a,4,9-9bΗexahydro-8-medιoxy-l- (2-propenyl) -2H-benz [f] indol-2-one. To a solution of 3.97 g (16 mmol) of (+-)-l^»3,4-Tetrahydro-5-methoxy-3-oxo-2-naphthalenβcetic Methyl Ester and 4.8 mL (64 mmol) of allylamine in 80 mL MeOH/THF (1:1) was treated widi acetic (ca 12.8 mL) at 0-5° C until the pH of the mixture was 4-5. The mixture was stirred for 30 min and 2 (32 mmol) of sodium cyanoborohydride was added. The resulting solution was stirred at room temperat for 5 days. The reaction was then quenched widi 20 % sodium hydroxide and concentrated in vacuo. concentrate was extracted with methylene chloride (2 x 1 L). The organic layer was washed widi br dried (MgSO^), filtered, and concentrated in vacuo. The crude product was purified by li chromatography on 800 g of silica gel 60 (230-400 m), eluting widi hexane/eώyl acetate/2-propanol (10: and collecting 40 mL fractions. Fractions homogeneous by TLC were combined and concentrated in va Fractions 57-61 gave 0.60 g of a yellow oil which was recrystallized from hexane/ethyl acetate to give g (13 %) of pure trans as a white solid: nφ. 102-104 C. Fractions 94-140 afforded a yellow oil which recrystallized from hexane/ethyl acetate to give 2.46 g (60 %) of pure cis as a white solid: mp. 65-6

Physical data for trans isomeπ

^• HNMR (CDC1 ₃ . TMS): 7.16-6.71(m, 3H); 5.78-5.17(m, 3H); 4.38-4.28(m,lH); 3.84 (s 3H); 3.78 (m, 9H).

IR (mull): v ^ 1683, and 1578 cm ^*1 .

MS: M ⁺ 257, other ions at m/z 242,226,214,199,172,158.

Analysis: Calcd for C^H^O^ C, 74.68;H, 7.44;N, 5.44. Found: C, 73.79;H, 7.37;N, 5.24. Physical data for sis iso er:

¹ HNMR fCPα ₃ . TMS 7.26-6.75(m, 3H); 5.81-5.20(m, 3H); 4.35-4.28(m, 1H); 3.82 (s, 3H); 3.5

(m, 9H).

IR (muin:v „,„ 1641, and 1589 cm ^*1 .

MS: M ^4" 257, other ions at m/z 242,229,213,198,172,158. Analysis: Calcd for C ₁₆ H ₁₉ N0 ₂ : C, 74.68;H, 7.44;N, 5.44.

Found: C, 74.61 H, 7.44;N, 5.27.

Utilizing a procedure similar to that of Procedure 8 but using the appropriate starting materials the

afforded: tBHg-<+- l,3,3a.4,9,9a.-Hexahyd-_o-5-methoxy-l-propyl- 2H-benz[f]indol-2-ooe as a -white soli after recrystallization from hexane ethyl acetate: mp. 121-123° C.

¹ HNMR (CDC1 ₃ , TMS): 7.19-6.72(m, 3H); 3.83 (s, 3H); 3.55-1.52(m, 12H); 0.93 (t, 3H). IR (muir>:v ^ 1685, and 1579 cm ^*1 . MS: Calcd for C^H^NC^: 259.1572.

Found: 259.1582. Analysis: Calcd for C^H^NO^ C, 74.10;H, 8.16;N, 5.40. Found: C, 74.13;H, 8.50;N, 5.31. £is-(-l-)- 1^ a,4,9-9aHexahydπ>-5-πιethoxy-l-propyt2H-benz If] indol-2-one as a white sol after recrystallization from hexane/ethyl acetate: mp. 105-107° C.

¹ HNMR (CDα ₃ . TMS^: 7.15-6.76(m, 3H); 3.81 (s, 3H); 3.99-1.45(m, 12H); 0.92 (t, 3H). IR famTO: _β W78. and 1588 cm ^*1 . Found: 259.1568.

Analysis: Calcd for C _l6 H ₂ ιN0 ₂ : C, 74.10;H, 8.16;N, 5.40.

Found: C 74.15 H, 8.38;N, 5.40. Eτaτηple 1.; (+-)-2α,3α,4,5,9b«(-hexahydro-2-methyl-3-pπφyl-lH-benz[ e]indole hydrochlorid (A-4, Cha A). A solution of 4.1 g (18 mmol) £is-(+-)-l,2,3,4-tetrahyd^o-l-(2-propenyl)-N-propyl-2■^la phdu en mine and 17.2 g (54 mmol) of mercuric acetate in 360 mL of methanol was stirred at room temperatur under a nitrogen atmosphere for five days. TLC analysis showed no starting material remaining (the aliqu was quenched widi small amount of sodium hydroxide/sodium borohydride). The greenish-gray mixtu was then treated with a solution containing 2.72 (72 mmol) sodium borohydride in 20% sodium hydroxi and die resulting mixture was stirred vigorously for three hours. Methanol was removed under reduc pressure and d e concentrate was extracted widi memylene chloride (2x 1 L). The combined organic laye were washed with brine, dried (MgSO^, filtered and concentrated in vacuo. The resulting oil was purifi by liquid chromatography on 560 g of silica gel 60 (230-400 m), eluting widi hexane-acetone (4:1), a collecting 40 mL fractions. Fractions 17-23 afforded 2.46 g of the cyclized product as a greenish oil. T oil was repurifϊed again by LC to give 2.0 g (48%) of the desired product as a yellow oil. This oil w converted into HCl-salt by treating widi excess HCl/methanoI (prepared by adding acetyl chloride methanol at 0#Q, and recrystallized from ethyl acetate/methanol as a white solid: mp. 226-237#C.

¹ HNMR (CDC1 ₃ , TMS): 8 7.20-7.11(m, 4H); 3.85-1.85(m, 13 H); 1.75(d, J=7 Hz, 1 H); 1.05 J=7Hz, 3H). IR(mull); ή ^ 1603 and 1578 cm ^*1 .

MS: Calcd for C^H^N: 229.1830.

Found: 229.1817.

Analyβis: Calcd for C^H^N-HCl: C, 72.29;H, 9.10;N, 5.27.

Found: C, 72.34,H, 9.13;N, 5.45. Utilizing a procedure similar to that of Example 1 but using die appropriate starting material t is obtained: (+-)α,3,3a£,4,5,9b*-hexahydro-9-methoxy-2-methyl- 3-propyMH-benz e]indole hydrochlori a white solid mp: 177-178 ^# C.

¹ HNMR (CDα ₃ , TMS): 8 7.28-6.71(m, 3H); 3.83 (s, 3H); 3.76-1.70(m, 13 H); 1.74(d, J=7 3 H); 1.04(t, J=7Hz, 3H).

IR(mull): ή „„ 1603nd 1586 cm ^*1 . MS: Calcd for C ₁ -rH _jj NO: 259.1936.

Found: 259.1934. Analysis: Calcd for C H _jj NO.HCl: C, 69.02;H, 8.86;N, 4.74

Found: C, 68.99.H, 8.84;N, 4.85 2α a.B^-9b -^exBh}dro-9-memθ-ty-2-memyl-3-prop)i-lH-4)eιιz[e}_ndole hydrochloride as a - solid mp: 206-207#C.

¹ HNMR (CDC1 ₃ , TMS): 8 7.27-6.68(m, 3H); 3.80(s, 3H); 4.22-1.60(m, 13 H); 1.70(d, J= 3 H); 1.03(t, J=7Hz, 3H).

IR(mull): ή „„ 1609 and 1578 cm ^*1 . MS: Calcd for C _j γH^NO: 259.1936. Found: 259.1934.

Analysis: Calcd for C^H^NO.HCl: C, 69.02;H, 8.86;N, 4.47.

Found: C, 68.14.H, 9.24; N, 4.87. Example 2: (- -V-2tt.3.3ag.4.5.9bα-hexahvdro-2-methvl-3-(2-propenvπ-lH-b enzfe1indol-9-ol hydrochl (A-5, Chart A). A solution of 1.0 mL (6.0 mmol) diphenylphosphine in 12 mL THF in a three-neck, r bottomed flask, equipped with a condenser and a septum, was treated widi 4.4 mL (6.0 mmol) butyllithium (1.6 M in hexane) at 0#C under a nitrogen atmosphere. The mixture was stirred at temperature for 10 minutes and 0.77 g (3.0 mmol) £is-<+- l,2,3,4-tetrahydro-8-methoxy-<N,l propenyl)-2-naρhthalenamine in 12 mL of THF was added. The red solution was refluxed (bath temper 70#Q for 48 hours. The reaction was quenched widi water and extracted with ethyl acetate (2x 500 The organic layer was washed wid brine, dried (MgSO^), filtered and concentrated in vacuo to give a y oil. This oil was purified by liquid chromatography on 400 g silica gel 60 (230-400 m), eluting with 1 and 3 L 33% acetone/hexane, and collecting 40 mL fractions. Fractions 31-50 gave 0.32 (44%) o base ss a light yellow oil. The oil was treated with excess anhydrous hydrochloric acid/methanol concentrated in vacuo. Recrystallization from ediyl acetate-methanol afforded a white solid: mp.257- 1HNMR (CDC1 ₃ , TMS): 8 7.0-6.6(m, 3H); 6.13-5.61(m, 3H); 4.03-1.50(m, 11H); 1.50, 1. 3H).

IR (mutt): ή _mtχ 1606 and 1584 cm ^"1 MS: Caled for C ₁₆ H ₂ ,N0: 243.1623.

Found: 243.1621. Analysis: Calcd for C _jβ H^NO.HCl: C,68.68;H,7.93;N,5.01. 5 Found: C,68.64;H,8.25;N,5.15.

Tfr? fnple :Trans-C-l- -V-2 a ,3.3aa .4.5.9bg-Jiexahvdro-2-medivl-3-propvl-lH-benzre1indol-9-ol hydrochlorid (A-5, Chart A).

A solution of 1.3 g (5.0 mmol) of the free base of (+-)2α,3,3aM,5,9b,β-hexahydro-9-metiκ>xy- methyl-3-propyl-lH-benz e]mdole hydrochloride and 10 mL of 48% hydrobromic acid was refluxed (baύ 10 tenφerature 120#C) for six hours. The mixture was cooled to room temperature and treated with 20 NaOH until pH >9.The mixture was extracted widi ethyl acetate (2x 1 ). The organic layer was washe with brine, dried (MgSO^), filtered and concentrated in vacuo to give a tan colored solid. The solid wa treated widi excess HCl/MeOH and recrystallized from ethyl acetate/methanol to give 1.26 g (89%) as white solid: mp. 212-213#C. 15 ¹ HNMR (CDC1 ₃ , TMS): 8 7.0-6.6(m, 3H); 4.08-1.55(m, 13 H); 1.51 (d, J=7 Hz, 3 H); 1.07 (

J=7Hz, 3H).

IR(mull): ή _tm3i 1610 and 1587 cm ^*1 . MS: Calcd for C^H^NO: 245.1780.

Found: 245.1799. 20 Analysis: Calcd for C _i ^NO-HCl: C, 68.19;H, 8.58; N, 4.97.

Found: C, 67.92.H, 8.69;N, 5.22. Utilizing a procedure similar to that of Example 3 but using the appropriate starting material the is obtained: cjs-2,3,3a,4,5,9b-hexahydro-3-ιι-propyl-lH-benz[e]indol-9- ol hydrochloride as a white solid: m 25 223#C(gecompXB-5, Chart B).

¹ HNMR (CDC1 ₃ , TMS): 8 7.95-6.61(m, 3H); 3.50-1.50(m, 14 H); 0.97 (t, 3H). IR(muU): fi „„ 3172, 1609, and 1587 cm ^*1 . MS: Calcd for C _jj H^NO: 231.1623.

Found: 231.1625. 30 Analysis; Calcd for C^H^NO-HCl: C, 67.28;H, 8.28; N, 5.23.

Found: C, 63.32;H, 8.01;N, 4.93. Jj∞s- +-)-2.3,3a,4,9,9a-hexahydro-l-^ropyl-lH-benz f]mdol-5-olhydrochloride as a white soli mp. 180-181#CQ$£, Chart B).

^IMR. (CDα ₃ , TMS): 8 7.04-6.58(m, 3H); 3.38-1.45(m, 15 H); 0.94 (t, J=7H∑, 3H). 35 IR(mull): _fi m^ 1606 and 1580 cm ^"1 .

MS: Calcd for C^H^NO: 231.1623.

Found: 231.1623.

Analyais: Calcd for C^ _j NCHQ: C, 77.88;H, 9.15;N, 6.05.

Found: C, 77.76;H, 9.24; N, 6.06. Cis-(+-V-2.3.3a.4.9.9a-hexahydro-l-propyl-lH-benzfflindol-5- ohvdrochloride as a white solid: 174-175#C(B-5, Chart B). ¹ HNMR (CDC1 ₃ , TMS): 8 7.00-6.63(m, 3H); 3.14-1.42(m, 15 H); 0.92 (t, J=7Hz, 3H).

IR(mull): fi „„, 1611 and 1589 cm ^*1 . MS: Calcd for C^H^NO: 231.1623.

Found: 231.1625. Analyais: Calcd for C _ig l^ _j NCHCl: C, 77.88;H, 9.15;N, 6.05. Found: C, 78.00;H, 9.03;N, 6.20.

F.Ta lft 4: Qs-( --y-2.3.3a.4.5.9b-hexahvdro-3-(2-propenvlMH-bcnzfelindole hydrochloride (B-4, C B).

To a suspension of 3.15 g (83.2 mmol) of lithium aluminum hydride in 20 mL THF at 0#C added dropwise 4.74 g (20.8 mmol) of £is-(+-)-l,2,2a,4,5,9b-hexahydro-3-(2-propenyl)-2H-benz[e]- ind one in 10 mL of THF. The solution was refluxed for 1.5 hours under a nitrogen atmosphere. TLC ana showed no starting material remaining. The mixture was cooled to room temperature, transferred in Erlenmeyer flask, and quenched at 0#Cby slow addition of saturated aqueous sodium sulfate. The mi was diluted widi 1 L ethyl acetate and dried over anhydrous sodium sulfate with vigorous stirring. mixture was then filtered through a Celite pad, concentrated in vacuo. The resulting oil was purifie liquid chromatography on 400 g of silica gel 60 (230-400 m), eluting with hexane-ethyl acetate (1. Fractions homogeneous by TLC were combined and concentrated in vacuo to give 3 g (68 %) of the de product as a colorless oil. This oil was treated with excess HCl/MeOH and recrystallized from acetate/methanol as a white solid: mp. 170-1721C.

¹ HNMR (CDC1 ₃ , TMS): 8 7.18-7.12(m, 4H); 6.36-5.51(m, 3H); 4.10-3.90(m, 1H); 3.82-1.9 11H).

IR (mull): ή ^ 1680 and 1598 cm ^*1 . MS: Calcd for C _jj H _j pN: 213.1517.

Found: 213.1515. Analysis: Calcd for C ₁₅ H ₁₉ N.HC1: C, 72.13;H, 8.07;N, 5.60. Found: C, 71.82;H, 8.06;N, 5.55.

Utilizing a procedure similar to that of Example 4 but using the appropriate starting material is obtained: cjs-(+-)-2,3,3a,4,5,9b-hexahydro-9-medιoxy-3-(2-propenyl)-l H-benzle]indole hydrochloride white solid: mp. 152-154#C(B-4, Chart B). ¹ HNMR (CDC1 ₃ , TMS): 8 7.26-6.70(m, 3H); 6.40-5.05(m, 3H); 3.83 (s, 3H); 3.90-1.90(m, 1

IR (mull): ή „,„ 1639, 1603 and 1585 cm ^"1 . MS: Calcd for C^INO: 243.1623

Found: 243.1618. Analysis: Calcd for C^H^NO-HCl: C, 68.68;H, 7.92;N, 5.01.

Found: C, 68.74;H, 8.17;N, 4.97. Ss +-)-2»3,3a,4,5,9b ιexahydro-6-methoxy-3-(2-ρropenyl)-lH-benz e]indole hydrochloride as white solid: p. 173-174#C(B-4, Chart B).

-*HNMR (CDC1 ₃ , TMS): 8 7.16-6.70(m, 3H); 6.73-5.45(m, 3H); 3.82(s, 3H); 4.80-1.36(m, 12H) IR (mull); ή _ma 1647 and 1591 cm ^"1 . MS: Calcd for C^INO: 243.1623.

- Found: 243.1630. Analysis: Calcd for C^H^NO-HCl: C, 68.68;H, 7.92;N, 5.01.

Found: C, 68.47;H, 8.26;N, 5.10. 3J^^+- 2,3,3a,4,5,9b-h_exahydro-6-methoxy-3-{2-propβιyl)-lH-benz[ e]indole hydrochloride a a white solid: mp. 234-235° C (B-4, Chart B).

¹ HNMR <CDC1 ₃ , TMS): 8 7.18-6.66(m, 3H); 6.26-5.45(m, 3H); 3.82(s, 3H); 4.12-1.85(m, 12H) IR (mull); ή __ 1646 and 1583 cm ^"1 .

MS: Calcd for C^INO: 243.1623

Found: 243.1635. Analysis: Calcd for C^ _j O.HCl: C, 68.68;H, 7.92; N, 5.01.

Found: C, 68.55;H, 7.53;N, 5.31. 3ja∞-(+-)-2,3,3a,4,9,9a-4exahydro-8-medιoxy-l-(2-propenyl )-lH-benz f]indole hydrochloride a white solid: mp. 237-239#C(E-4, Chart E).

¹ HNMR (CDC1 ₃ , TMS): 8 7.17-6.68(m, 3H); 6.30-5.51(m, 3H); 3.80(s, 3H); 4.08-1.58(m, 13H) IR (mull): S ^ 1602 and 1583 cm ^*1 . MS: Calcd for C ₁₆ H ₂ 1N0: 243.1623. Found: 243.1615.

Analysis: Calcd for C^lNO-HCl: C, 68.68;H, 7.93;N, 5.01.

Found: C, 68.38:H, 8.00;N, 5.01. Cis-( +-V-2.3.3a.4.9.9a--hexahvdro-8-medιoχy-l-(2-propenvl)-lH- benzf flindole hydrochloride as white solid: mp. 173-174#C(E-4, Chart E). ^I HNMR (CDC1 ₃ , TMS): 8 7.14-6.75(m, 3H); 6.38-5.40(m, 3H); 3.81(s, 3H); 4.08-1.60(m, 13H

IR.( uU) δ _BΛX 1603 and 1587 cm ^*1 . MS: Calcd for C^INO: 243.1623.

Found: 243.1617. Analysis: Calcd for C _i6 H ₂ lNO.HCl: C, 68.68;H, 7.93;N, 5.01. Found: C, 68.80:H, 8.23;N, 5.08.

Trans-(+-V2.3.3a.4.9.9a-hexahvdn 5-methoxv-l-propvl-lH-benzfflindole hydrochloride as a whi solid: nφ. 264-265fC(E-4, Chart E).

¹ HNMR (CDC1 ₃ , TMS): 8 7.22-6.76(m, 3H); 3.82 (s, 3H); 3.82-1.62(m, 15H); 1.07 (t, 3H) IR (mull): ή „,„ 1638 and 1582 cm ^*1 . MS: Calcd for C^ft^NO: 245.1780.

Found: 245.1781. Analysis: Calcd for C^H^NO-HCl: C, 68.19;H, 8.58;N, 4.98.

Found: C, 68.09:H, 8.80;N, 5.05. Cis-(- -)-2.3.3a.4.9.9a- ιexahvdro-5-methoxy-l-propyl-lH-benzf flindole hydrochloride as a solid: mp. 250-251#C(E-4, Chart E).

¹ HNMR (CDC1 ₃ , TMS): 8 7.22-6.86(m, 3H); 3.81 (s, 3H); 3.81-1.58(m, 15H); 1.05 (t, 3H) IR (mull): ή „,, 1605 and 1587 cm ^*1 .

MS: Calcd for C _j gH^NO: 245.1780.

Found: 245.1778. Analysis: Calcd for C _lβ H^3NO.HCl: C, 68.19;H, 8.58; N, 4.98.

Found: C, 68.30: H, 8.72; N, 5.10. Cis^+- 1.2.3.4.4a.5.6.10b-octahydro-10-medιoxy-4-(2-propenvl-lH-4& gt;enzofflquinolhjdrocM as a white solid: mp. 231-235#C(B-4, Chart B).

¹ HNMR (CDC1 ₃ , TMS): 8 7.12-6.68(m, 3H); 6.50-5.51(m, 3H); 3.79 (s, 3H); 3.90-1.90(m, 1 IR (mull): ή ___„_ 1601 and 1582 cm ^*1 . MS: Calcd for C _j7 H _j 3 _N 0: 257.1780. Found: 257.1774.

Analysis: Calcd for C ₁₇ H ₂ 3N0.HC1: C, 69.49;H, 8.23; , 4.77.

Found: C, 69.16;H, 8.30;N, 4.84. Trans-(+-)-3A4a 0.10a-Jιexah-vdro-9-medιoχy-H2-propen\i)- lH-beαzo[g]quinoline hydroch as a white solid: mp. 236-238#C(F-4, Chart F). ¹ HNMR (CDC1 ₃ , TMS): 8 7.14-6.65(m, 3H); 6.13-5.52(m, 3H); 3.80(s, 3H); 3.92-1.18(m,

IR (mull): fi „,„ 1590 cm ^*1 . MS: Calcd for 257.1780.

Found: 257.1782. Analysis: Calcd for C _j - _j H^NO.HCl: C, 69.49;H, 8.23;N, 4.77. Found: C, 69.48;H, 8.24;N, 4.84.

Cis-f-t- -)-3 ,4,4a,5, 10, 10a-hexahydro-9-methoxy-l-(2-φropenyl)-lH-benzo[g]quinolind ιydroch as a white solid: mp. 195-197#C(F-4, Chart F).

-ΗNMR (CDC1 ₃ , TMS: 8 7.19-6.69(m, 3H); 6.74-5.49(m, 3H); 3.85(s, 3H); 3.95-1.28(m, IR (ύull): ή _Bmχ 1587 cm ^*1 . MS: Calcd for 257.1780.

Found: 257.1777. Analysis: Calcd for C^H^NO.HCl: C, 69.49;H, 8.23;N, 4.77.

-24-

Found: C, 69.67;H, 8.45; N, 4.81. Iθ^-2,3,3a,4,9,9a*iexahydro-5-methoxy-l-(2-propenyl)-lH-ben 4f]indolelιydrochloride as a whit solid: m.p. 213#-215#OΕ*4, Chart E).

¹ HNMR (CDC1 ₃ , TMS: 8 7.20-6.70(m, 3H); 6.28-5.49(m, 3H); 3.82 (s, 3H); 4.08-1.54(m, 13H IR (mull)t ή „,„ 1600 and 1583 cm ^*1 .

MS: Calcd for C^H^NO: 243.1623

Found : 243.1620 Analysis: Calcd for C^H^NOΗCl: C, 68.68;H, 7.93;N, 5.01

Found: C, 68.44;H, 8.06;N, 5.20 CHs-2.3.3a.4.9.9a iCTahydro-5-memoxy-l-(2-prorιenvl)-lH-b«ιzfflindole.hvdro chloride as a -whi solid: m.p. 189#-191#0^- , Chart E).

¹ HNMR (CDC1 ₃ , TMS: 8 7.18-6.77(m, eH); 6.38-5.42(m, 3H); 3.82 (s, 3H); 3.98-1.60M, 13H

IR (mmTjs fi _aax 1603 and 1588 cm ^*1 . MS: Calcd for C _j gH _jj NO: 243.1623

Found : 243.1626 Analysis: Calcd for C _i gH _jj NOHCl: C, 68.68;H, 7.93; N, 5.01

Found: C, 68.32;H, 8.05;N, 5.10 hydrochloride as A (C-4, Chart 4) and (+-)-l,2,2a,-3,4,8b-hexahydro-8-methoxy-2-φrop-2-«ι-l-y naphtiιo[2,l-B] azetidine hydrochloride as B (C-5, Chart C).

A solution of 2.75 g (10 mmol) cis-(+-)-l,2,3,4-tetrahydro-8-methoxy-2-(2-propenylamino)- naphtiialenecarboxylic acid mediyl ester in 110 mL of THF was added slowly 1.5 g (40 mmol) of lithiu aluminum hydride at room temperature under a nitrogen atmosphere. The mixture was refluxed for t hours. The mixture was transferred into a 2-LErlenmeyer flask equipped widi a magnetic stirring bar a diluted widi 1 L THF. The mixture was treated slowly with saturated aqueous sodium sulfate until die g suspension became white. The mixture was stirred vigorously and dried (MgSO^, filtered through a Celi pad, and concentrated in vacuo. The resulting yellow oil was purified by LC on 400 g silica gel 60 (230-4 m), eluting widi hexane acetone (9:1), and collecting 40 mL fractions. Fractions 36-62 afforded 2.37 (96 %) of an oil which later solidified. The solid was treated with HCl-metiianol and recrystallized from edi acetate/methanol to give white solid A. (C-4, chart C): m.;.203-204°C. A solution of die free base of (C-4,chart C) (1.24g,5.0mmol) and 1.14g (60 mmol) of p-toluenesulfonyl chloride in 5 ml of pyridine w stirred at room temperature for 24 h. Additional 1.14g (6.0 mmol) of p-toluenesulfonyl chloride was add and die mixture was heated for 3 h. the reaction was quenched -with saturated sodium bicarbonat extracted widi ethyl acetate, washed widi brine, dried (MgSO^, filtered and concentrated in vacuo. T crude product was purified by LC eluting with hexane/acetate to give 0.32 g (26 %) of the free base of (C-5, chart C) This oil was treated widi HCl-methanol and recrystallized from hexane-ethyl acetat

methanol to give pure B (C-5, Chart as a white solid: mp. 161-162#C. Physical data for A: ^l NMR (CDC1 ₃ , TMS): 7.20-6.65(m,3H); 6.30-5.38(m, 3H); 3.84 (s, 3H); 4.12-2.10(m, 1 IR (mull): v _ffl ax 3320, 1645, and 1585 cm ^*1 . MS: Calcd for C ₁ 5H ₂ 1N0 ₂ :247.1572.

Found:247.1574. Analysis: Calcd for C ₁ 5H ₂ 1N0 ₂ HC1: C, 63.48;H,7.81;N, 4.94.

Found: C, 63.14;H, 7.52;N, 4.95. Physical data for B: ¹ HNMR (CDC1 ₃ , TMS): 8 7.22-6.71(m, 3H); 6.88-5.53(m, 3H); 3.78(s, 3H); 4.54-1.82(m, 10

IR(mull): ή _β 1603 and 1587 cm ^'1 . MS: Calcd for C _jj H^ O (M ⁺ + H): 230.1545.

Found: 230.1545. Analysis: Calcd for C ₁₅ H,9N0.HC1: C, 67.79;H, 7.59; N, 5.27. Found: C, 69.63;H, 7.84;N, 5.39.

Example 6: Cjs-(+-)-2,3,3a,4,5,9b-hexahydro-9-methoxy-3-ιι-propyl-lH- benz[e]indole hydrochloride ( Chart B).

To a suspension of 3.63 g (95.7 mmol) of lithium aluminum hydride in 140 mL THF at (WC added dropwise 5.9 (23.7 mmol) of£is-(+-)-l,3,3a,4,5,9b-hexahydro-9-methoxy-3-(2-propyl)-2 H-be indol-2-one in 10 mL of THF. The solution was refluxed for two hours under a nitrogen atmosphere. analysis showed no starting material remaining. The mixture was cooled to room temperature, transfe into an Erlenmeyer flask and quenched at 0#C.by slow addition of saturated aqueous sodium sulfate. mixture was diluted widi 1 L ediyl acetate and dried over anhydrous sodium sulfate with vigorous stir The mixture was then filtered through a Celite pad and concentrated in vacuo. The resulting oil purified by liquid chromatography on 400 g of silica gel 60 (230-400 m), eluting with hexane-acetone Fractions homogeneous by TLC were combined and concentrated in vacuo to give 4.64 g (83 %) o desired product as an oil. This oil was treated widi excess HCl/MeOH and recrystallized from acetate/methanol as a white solid: mp. 153-156#C.

¹ HNMR (CDC1 ₃ , TMS): 8 7.15-6.71(m, 3H); 4.0 (t, 1H); 3.83 (s, 3H); 3.65-1.75(m, 13H); (t, 3H).

IR (mull): ή ^ 1601 and 1585 cm ^*1 . MS: Calcd for C^H^NO: 245.1780

Found: 243.1788. Analysis: Calcd for C _jg H^NO.HCl: C, 05.19;H, 8.58;N, 4.97. Found: C, 68.00;H, 8.56;N, 5.02.

Utilizing a procedure similar to that of Example 6 but using the appropriate starting material is obtained:

-26-

£js-(+-)-2,3,3a,4,5,9b-hexahydro-6-n__ethoxy-3-n-propyl- lHbenz[e]indole hydrochloride as a -whi solid: πφ. 197-198#C

¹ HNMR (CDC1 ₃ , TMS): 8 7.16-6.70(m, 3H); 3.82(s, 3H); 4.12-1.92(m, 14H); 1.03 (t, 3H). IR (mutt): ή „„ 1660 and 1590 cm ^"1 . 5 MS: Calcd for C^H^NO: 245.1780

Found: 243.1799. Analysis; Calcd for C^H^NO.HCl: C, 68.19;H, 8.58;N, 4.97.

_? Found: C, 67:91;H, 8.79; N, 5.09.

Example 7: C -4-y2α3.3aα4-9.9aα-hex_dι-γdro-8-meflιox^^ hydrochlori

10 asAand trans(+-V2g.3.-3aβ.4.9.9aβ-^exahydro-8-medιoxy-2-methyl-l -propyl-lH- jenzfe1-indo ride as B (D-6, Chart D)

A solution of 3.89g (15 mmol) cis-1.2.3.4-tetrahvdro-8-methoxv-3-2-propenvl-2-naphthalenam in and 14.3 g (45 mmol) of mercuric acetate in 450 mL of methanol was stirred at room temperature und a nitrogen atmosphere for three days. TLC analysis appeared to show no starting material remaining (t 15 aliquot was quenched widi small amount of sodium hydroxide/sodium borohydride). The greenish-g mixture was die treated widi a solution containing 2.27 g (60 mmol) sodium borohydride in 60 mL 20 sodium hydroxide and die resulting mixture was stirred vigorously for three hours. Methanol was remov under reduced pressure and die concentrate was extracted with methylene chloride (2x 1 L). The combine organic layers were washed widi brine, dried (MgSO^), filtered and concentrated in vacuo. The resulti 20 oil was purified by liquid diromatography on 800 g of silica gel 60 (230-400 m), eluting with hexan acetone(4:l) and collecting 40 mL fractions. Fractions 26-34 afforded 2.2 g which was repurified again give 2.05 g (53%) of die cyclized product as a light yellow oil (free base of A) and fractions 35-48 gave 0. g (18%) of a brown oil, identified by ¹ HNMR as the recovered starting material. Fractions 49-80 gave brown oil which was repurified again to give 0.33 g (8.5%) of die otiier cyclized product as a yellow oil (f 25 base of the gags isomer B). Both of the cyclized products were converted into HCl-salt by treating w excess HCl/methanol (prepared by adding acetyl chloride to methanol at 0#C.and recrystallized from et acetate/hexane. From die less polar product (the major product), pure cis isomer of the tide compou A was obtained as a white solid: mp. 240-242#C_From the more polar product (die minor product), pu trans isomer of the title compound was obtained as a white solid: mp. 180-1821C. 30 Physical data for A:

¹ HNMR (CDC^, TMS): 8 7.13-6.74(m, 3H); 3.81 (s, 3H); 3.71-1.72(m, 13 H); 1.69(d, J = 7 3H); 1.08 (t, J - 7Hz, 3H).

IR(mull): fi _a _ _tχ 1605nd 1587 cm ^"1 . MS: Cslcd for C _j - _j H^NO: 259.1936. 35 Found: 259.1939.

Analysis.: Calcd for C H^NO.HCl: C, 69.02;H, 8.86;N, 4.74.

Found: C, 68.38.H, 8.69; N, 4.98.

Physical data for B:

¹ HNMR (CDC1 ₃ , TMS): 8 7.16-6.74(m, 3H); 3.81(s, 3H); 4.15-1.60(m, 13 H); 1.23(d, J - 7 H); 1.04 (t, J - 7Hz, 3H).

IR(mull): ή „„, 1603 and 1586 cm ^"1 . MS: Calcd for CJTH^NO: 259.1936.

Found: 259.1931. Analysis: Calcd for C ₁₇ H25N0.HC1: C, 69.02;H, 8.86;N, 4.47

Found: C, 68.30.H, 9.09; N, 4.75

FORMULA

lb

-29-

FORMULA (continued)

CH(R * —

CHART A

A-l A-2

A-3 A- 4

A-5

CHART B

B-l B-2

B-3 B-4

B-5

CHART C

C-l C-2

C-3 C-4

C-5

-33- CHART D

D-l 0-2

0-3 D-4

D-6

CHART E

MeO

E-4

CHART F

F-l

F-2

F-3

F-4