WO1992021654A2 - Carboxamido-(3,2n)-carbocyclic-2-aminotetralin derivatives - Google Patents

Abstract

This invention is therapeutically useful tetralins and pharmaceutically acceptable acid addition salts thereof of formula (I), wherein R is C1-C8 alkyl and n is 1 or 2.

Description

Carboxamido-(3,2N)-CARBOCYCLIC-2-AMINOTETRALIN DERIVATIVES

FIELD OF THE INVENTION

The present invention is related to new carboxamido-(3 ,2N)-carbocyclic-2-amino- 1,2,3,4-tetrahydronaphthylene derivatives, to processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation.

BACKGROUND OF THE INVENTION

Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal systems, particularly those involving serotonin (5-HT) and dopamine (DA).

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

Dopamine autoreceptor antagonists are a new class of drug that increase release of DA by releasing the DA neuron from autoreceptor control. Thus, these drugs can be expected to be useful in conditions treatable with amphetamine and other similar stimulants which directly release DA. However, because DA autoreceptor agonists will be much milder stimulants because, rather than directly releasing DA, they simply increase the release associated with the normal DA activity by releasing the cell from autoreceptor control. Thus, DA autoreceptor antagonists can be expected to be useful in treating overeating, attention deficit disorders, psychiatric, cognitive and motor retardation in demented and elderly patients, and in treating nausea and dizziness with space travel.

The compounds of the present invention have a variety of effects at the DA receptors, and offer a variety of utilities associated with those activities.

Drugs acting on central dopamine transmission are clinically effective in treating a variety of central nervous system disorders such as parldnsonism, schizophrenia, and manic-depressive illness. In parldnsonism, for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic dopamine receptor stimulation. In schizophrenia, the condition can be normalized by achieving a decrease in postsynaptic dopamine receptor stimulation. Classical anti-psychotic agents directly block the postsynaptic dopamine receptor. The same effect can be achieved by inhibition of intraneuronal presynaptic events essential for the maintenance of adequate neuro- transmission, transport mechanism and transmitter synthesis.

In recent years a large body of pharmacological, biochemical and electrophysical evidence has provided considerable support in favor of the existence of a specific population of central autoregulatory dopamine receptors located in the dopaminergic neuron itself. These receptors are part of a homeostatic mechanism that modulates nerve impulse flow and transmitter synthesis and regulates the amount of dopamine released from the nerve endings.

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

INFORMATION DISCLOSURE STATEMENT

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

Arvidsson, L.-E., et al., J. Med. Chem., 24, 921 (1981), describes hydroxy-2- aminotetralins where the amine is substituted with one n-propyl, one benzyl or two n-propyl substituents. The 5-, 6-, and 7-hydroxy compounds are described as active central dopamine-receptor agonists and the 8-hydroxy compound is described as a central

5-HT receptor agonist devoid of dopamine receptor stimulating activity.

Arvidsson, L.-E., et al., J. Med. Chem., 27, 45 (1984), describes 2-aminotetralins where the amine is substituted with one or two methyl, ethyl, n-propyl, i-propyl, n-butyl, or benzyl substituents. The 2-piperidinyltetralin is also described. Several of these compounds were found to be potent 5-HT agonists devoid of dopamine-mimetic effects. Arvidsson, L.-E., et al., J. Med. Chem., 30, 2105 (1987), describes 8-hydroxy- 1-methyl-2-(di-n-propylamino)tetralins. These compounds were 5-HT receptor agonists.

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

McDermed, et al., J. Med. Chem., 18, 362 (1975) describes 5,6-dihydroxy-2-aminotetralins. In addition, the 5,8 and 7,8 disubstituted compounds are also disclosed. The amine can be a mono or di substituted with simple alkyl groups, benzyl groups alkylalkoxy groups or the amine can be a 5 or 6 membered hydrocarbon or heterocyclic amine. These compounds are indicated to have dopaminergic properties although certain compounds are reported to be inactive.

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

Rusterholz, et al., J. Med. Chem., 19, 99 (1976) describes 5,8 disubstituted-2-aminotetralins with the amine being substituted with hydrogen, methyl, or cyanopropyl groups. Some of these compounds are 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 compounds, where the aromatic ring is substituted by methoxy, ethoxy, n- or iso-propoxy, or n-, sec- or tert-butoxy group in the 5 or 8 position and the amine is substituted by hydrogen or alkyl groups having 1-4 carbon atoms. The compounds are indicated to be prepared for pharmacological testing. However, no utility or pharmacological activity is yet known for the compounds just mentioned.

German Patent DE-A1-2 803 582 describes 2-aminotetralins where the aromatic ring is substituted on the 5,6,7 or 8 position a group R₁, where R₁ is hydrogen, alkanoyl having 1 to 20 carbon atoms or a group -CO-(CH₂)_n-R7, n is a number 0 to 5, R₇ is a phenyl group with substituents as defined further, R₂ is hydrogen, hydroxy, halogen or alkylsulfonylamino, R₃ is hydrogen, R₄ is hydrogen, CH₂OH, CH₂O-CO-R₈ or CH₂-O-CO-(CH₂)_n-R₇ with further definition and R₅ and R₆ are hydrogen, alkyl or aryl or aralkyl groups further defined or R₅ and R₆ are together an alkylene with 4 to 6 carbon atoms. The compounds are disclosed as having pharmacodynamic activity in particular a stimulating effect on alpha-and beta-adrenoceptors and dopamine receptors. Among the compounds described are compounds having the group R₁₀ in the 8 position and having R₂ or R₄ other than hydrogen.

Great Britain Patent 1 ,377,356 describes 2-aminotetralins where the aromatic ring is substituted on the 5, 6,7 or 8 position by R₁, where R₁ is hydrogen or methyl, the aliphatic ring is substituted by R₂, where R₂ is alkyl having 1-6 carbon atoms, and the amine is substituted by R3, where R₃ is hydrogen or alkyl having 1-6 carbon atoms are described. Such compounds are stated to possess analgesic activity. 1,1-Dimethyl-2- (N,N-dimethylamino)-7-hydroxytetralin is mentioned as one example of a compound covered by the patent. This compound is also described in Chem. Ab., 79: 146294b as having analgesic and intestinal movement accelerating actions.

J. Pharm. Sri., 67, 880-82 (1978) describes the compound 1-methyl-2-(cyclopro- pylamino)-5-methoxytetralinand indicates the compound possess local anesthetic activity.

Derwent documents 58,247B/32, 40 378A/23, 83-729388/32, 83-72987/32,

29348D/17 and 06733V/05 refer to 8-carboxyamino tetralins. Additional 07833V/05 refers to 8-amido and 8-alkylamido tetralin.

EPO patent application EPO 270947 (1988) discloses 8-hydroxy and 8-methoxy- tetralins.

EPO patent application EPO 0272534 (1988) discloses aminotetralins including 8-amido 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, U.; Nilsson, J.L.G., J. Neural Transm., 1982, 55, page 169.

Mellin, C.; Bjork, L.; Karlen, A.; Johansson, A.M.; Sundell, S.; Kenne, L.; Nelson, D.L.; Anden, N.-E.; Hacksell, U., J. Med, Chem. , 1988, 31, page 1130.

Cossery, J.M.; Gozlan, H.; Spampinato, U.; Perdicakis, C.; Guillaumet, G.: Pichat, L.; Hamon, M., European J. Pharmacol. , 1987, pages 140, 143.

INFORMATION DISCLOSURE STATEMENT

Trans-7- and trans-9-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo [P]quinolines have been synthesized and their effects on central dopamine and α-receptors have been studied. Arvidsson, L.-E. et al, J. Med. Chem. 1983, 27, page 45.

Octahydrobenzo-isoquinolines are also described in Derwent 84-073373/13. Hexahydrobenzo-isoquinolines are described in Derwent 55370A/31 (DT 2801 576).

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

French patent 1.555.553 (Derwent37216 describes 2, 3,4,4a,5,6-hexahydrobenzo-[f]quinolines.

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

Derwent 63503T-B, 52201R-B, 23543R, 30016 and 41102 disclose hexahydroine-nopyridinols.

Derwent 67323W/41 discloses benzoisoindolines as anti-aggressive and analgesic agents.

SUMMARY OF THE INVENTION

This invention encompasses compounds of Formula I, wherein R is C₁-C₈ alkyl and n is 1 or 2. The compounds of this invention possess selective pharmacological properties and are useful in treating central nervous system disorders including schizophrenia, Parkinson's disease, anxiety and depression.

Preferred compounds for treating schizophrenia and Parkinson's disease are those wherein the carboxamide group is in the 5, 6 or 7 position. Particularly preferred compounds are those wherein the carboxamide group is in the 5 position.

In addition to their central nervous system pharmacological activities, the compounds of this invention are also useful in treating hypertension, congestive heart failure and cardiac arrythmias. Processes for preparation of these compounds, their pharmaceutical use and pharmaceutical preparations employing such compounds constitute further aspects of the invention.

An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the central nervous system. A further object of this invention is to provide compounds having an effect on the subclass of dopamine receptors known as the D₂ receptor. The compounds of this invention have been found to have unexpectedly superior resistance to liver metabolism and have excellent oral plasma bioavailability.

DETAILED DESCRIPTION OF THE INVENTION

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

In this document the parenthetical term (C_n-C_m) is inclusive such that a compound of (C₁-C₈) would include compounds of one to 8 carbons and their isomeric forms. The various carbon moieties are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl.

LDA is lithium diisopropyl amide.

It will be apparent to those skilled in the art that compounds of this invention may contain chiral centers. The scope of this invention includes all enantiomeric or diastereomeric forms of Formula I compounds either in pure form or as mixtures of enantiomers or diastereomers. The compounds of Formula I contain two asymmetric carbon atoms in the aliphatic ring moiety, including the ring carbon atoms adjacent to the nitrogen atom. The therapeutic properties of the compounds may to a greater or lesser degree depend on the stereochemistry of a particular compound. Pure enantiomers as well as enantiomeric or diastereomeric mixtures are within the scope of the invention.

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

The (3,2N) compounds can be made in accordance with the process illustrated in Chart A.

Chart A:

The methoxy derivative A-1 is resolved as described in prep 1. The resolved A-1 is demethylated using diphenylphosphine and n-butyl lithium in THF to yield the hydroxy derivative A-2. A process for the preparation of 2,3,3a,4,9,91-hexahydro-5-methoxy-1-n-propyl-1H-benz[f]indole is described in Example 4 and Chart E of application PCT/US90/03551 filed June 27, 1990 and published January 24, 1991. In step 2, the hydroxy derivative A-2 is reacted with trifluoromethanesulfonic anhydride in the presence of pyridine and methylene chloride to provide the triflate A-3. In step 3, the triflate A-3 is then reacted with palladium acetate and 1,3- bis(diphenylphosphino)propane in methanol/ dimethylformamide in the presence of gaseous carbon monoxide to yield the methyl ester A-4. In step 4, A-4 is first hydrolyzed to the carboxylic acid which is coupled with gaseous ammonia in the presence of diethylcyanophosphonate and triethylamine in dimethylformamide to give the carboxamido derivative A-5.

In clinical practice the compounds of the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt in association with a pharmaceutically acceptable carrier. Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid. These salts are readily prepared by methods known in the art.

The use and administration to a patient to be treated in the clinic would be readily apparent to a person of ordinary skill in the art.

In therapeutical treatment the suitable daily doses of the compounds of the invention are 0.1-2000 mg/kg for oral application, preferably 0.5-500 mg/kg, and 0.1-100 mg/kg for parenteral application, preferably 0.5-50 mg/kg.

The compounds of this invention wherein the carboxamide group is in the 5, 6 and 7 position in the aromatic ring have dopaminergic activity with little 5-HT_1A agonist activity. It has been found that the compounds of the present invention and pharmacologically acceptable salts thereof have unexpectedly superior resistance to liver metabolism and excellent oral plasma bioavailability. Generally aminotetralins agonist activity are rapidly metabolized by the liver and have poor oral plasma bioavailability. The excellent oral bioavailability of compounds contained in this invention results in good potency and long duration of action following oral administration of the compounds. Both these features are beneficial to effective clinical treatment.

The utility of the compounds of this invention to treat central nervous system disorders is shown in behavioral, physiological and biochemical tests. The methods are given as follows:

BIOLOGICAL DATA

Receptor Binding

In order to be a dopaminergic agonist, the agent must bind to the dopamine receptor. Using in vitro tissue samples from the rat caudate nucleus, a tissue high in dopamine receptors, trans-(+)-2,3,3a,4,9,9a-Hexahydro—5-carboxamido-1-n-propyl-1H-benz[f]- indole [(-)A-5] dopamine receptors with an extremely high affinity (56 nM Table 1);

ELECTROPHYSIOLOGY

Dopaminergic agonists such as apomoiphine depress nerve impulses generated by dopaminergic neurons. Indeed, all full dopamine agonists can completely suppress impulse generation so that the dopamine cells stop firing completely. In contrast, dopamine antagonists either do not affect nerve impulse activity of dopamine neurons or increase them. Trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1-n-propyl-1H-benz[f]indole [(-)A-5] was a very potent dopamine agonist, depressing dopamine nerve discharges by 50% with a dose of only 4 ug/kg i.v.

(Table 2).

Invitro Rat Hepatocyte

Intrinsic clearance of 3 concentrations of compound (2, 5 and 15 μg/ml) following a 60 minute incubation at 37ºC in the presence of a suspension of freshly prepared rat hepatocytes (5.0 million cells/ml). Aliquots of each incubate were withdrawn at preset times during the incubation and analyzed for parent compound using HPLC methodology. Half life of the parent compound is determined using HPLC methodology. Metabolic stability relative to AJ-76 determined (Table 3). Table 1. DOPAMINE RECEPTOR BINDING

Ki (nM)¹ trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1-n-propyl-1H-benz[f]indole [(-)A-5]. 56

Quinpirole 86 1Dose for 50% occupation.

TABLE 2. EFFECTS OF DOPAMINERGIC AGENTS ON DOPAMINE NERVE IMPULSE GENERATION,

AGONIST ED50¹ MAX² trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1 -n-propyl-1H-benz[f]indole [(-) A-5] . 4 100%

APOMORHINE 10 100%

(-)-3-PPP 86 70%

HALOPERIDOL I.A. 0% 8 163% ¹Dose (ug/kg) to depress firing by 50%. Table 3: Metabolic stability in liver hepatocytes. trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1-n-propyl-1H-benz[f]indole(-)A-5]: t1/2 = 551 min, relative stability = 886

AJ-76: t1/2 = 0.64 min, relative stability = 1

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

Preparation 1 : Resolution of trans-(+-)-2,3,3a,4,9,9a-Hexahydro-5-methoxy-1-n-propyI- 1H-benz[f]indole. (A-1, Chart A)

Dissolve 18.6 g (45.9 mmol) of di-p-toluoyl-L-tartaric acid monohydrate in 100 mL methanol and add to a solution containing 10.7 g (43.7 mmol) of racemic A-1 in 50 mL of methanol. The solution is concentrated to about 100 mL in volume and allowed to stand at room temperature for two days. The white solid is isolated (14.4 g) and redissolved in 700 mL methanol and concentrated to about 150 mL in volume. After allowing to stand at room temperature for two days, 11.4 g (41.3 %) of the solid is isolated (mp 165-166º C, >95 % pure diastereomeric salt based on ¹ΗNMR in which one of the aromatic protons show triplet at 6.66 ppm whereas the other diastereomeric salt from the mother liquor show two sets of doublet centered at 6.58 ppm). This pure diastereomeric salt is free-based by refluxing the solid in the mixture of 50 mL 10% sodium hydroxide and 250 mL methanol overnight to give a white solid. The HCl-salt of this material is recrystallized from ethyl acetate/methanol to give a white solid as a (-) enantiomer of A-1: mp. 263-265 °C, [α]_D -140º (c 0.70, MeOH). The mother liquor is free-based as described above and recrystallized from methanol using an appropriate amount (1.05 equivalents) of di-p-toluoyl-D-tartaric acid to give 11.6 g (42 %) of apure diastereomeric salt as a white solid after two recrystallizations. Upon freebasing and recrystallization as HCl-salt gives the title compound as a white solid as a (+) enantiomer of A-1: mp.266-267º C, [α]_D +140º (c 0.67, MeOH).

Preparation2:trans-(-)-2,3,3a,4,9,9a-Hexahydro-5-hydroxy-1-n-propyl-1H-benz[f]indole [(-)A-2, Chart A].

A solution of 8.8 mL (51 mmol) diphenylphosphine in 20 mL tetrahydrofuran is cooled to 0° C and treated with 32 mL of n-butyl lithium in hexane (1.6M) over 5 min under a nitrogen atmosphere. The red solution is allowed to warm to room temperature over 10 min and a solution of 4:17 g (17 mmol) of (-) enantiomer of A-1 dissolved in 20 mL of tetrahydrofuran is added. The solution is refluxed for 24 h. The reaction is quenched with 300 mL water and extracted with 3x1 L of warm ethyl acetate. The organic layer is washed with water, brine, dried (MgSO₄), filtered, and concentrated. The resulting oil is purified by liquid chromatography on 400 g of silica gel 60 (230-400 mesh), eluting with 1 L methylene chloride followed by 6 L methylene chloride/acetone (1:1). Fractions homogeneous by TLC are combined and concentrated to give 3.67 g (93.4 %) of a white solid [(-)A-2]. The HCl-salt is recrystallized from ethyl acetate/methanol to give the title compound as a white solid: mp >300° C, [α]_D -156º (c 0.3, MeOH), ¹HNMR (CD₃OD, TMS) δ 7.05-6.58 (m, 3H); 3.32-1.65 (m, 14H); 1.07 (t, J=7 Hz, 3H). trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-hydroxy-l-n-propyl-lH-benz[f]indole [(+)A-2, Chart A].

The reaction is run in an identical manner as described in the preparation of (-)A-2, using 3.93 g (16 mmol) of (+)A-1 and three equivalents of diphenylphosphine and n-butyl lithium. Upon work up and purification by liquid chromatography, there is obtained 3.52 g (82 %) of a white solid [(+)A-2]. The HCl-salt is recrystallized from ethyl acetate/methanol to give a white solid: mp. >300º C, [α]_D +154º (c 0.25, MeOH), 1HNMR is identical with that of (-)A-2 enantiomer.

Preparation 3: trans-(-)-2,3,3a,4,9,9a-Hexahydro-5-trifluoromethanesulfonyloxy-1-n-propyl-1H-benz[f]indole [(-)A-3, Chart A]. A solution of 3.57 g (15.5 mmol) of (-)A-2 in 20 mL pyridine and 20 mL methylene chloride is cooled to -20º C under a nitrogen atmosphere and treated with a solution of 4 mL (23.2 mmol) trifluoromethanesulfonic anhydride in 10 mL methylene chloride. The brown mixture is allowed to warm to room temperature and stirred for 2 h. The reaction is quenched with 20 mL 10 % sodium hydroxide and 300 mL water and then extracted with ethyl acetate. The organic layer is washed with water, brine, dried (MgSO₄), filtered, and concentrated to give a brown oil. This oil is purified by liquid chromatography on 400 g silica gel 60 (230-400 mesh), eluting with 3L hexane/acetone (4:1) and 2 L acetone. Fractions homogeneous by TLC are combined and concentrated in vacuo to give 3.75 g (63.7 %) of the title triflate (-)A-3 as an oil: ¹HNMR (CDCl₃, TMS) δ 7.28-7.06 (m, 3H); 3.42-1.50 (m, 14H); 0.95 (t, J=7Hz, 3H). trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-trifluoromethanesulfonyloxy-1-n-propyl-1H- benz[f]indole [(+)A-3].

The reaction is run in an identical manner as described in the preparation of (-)A-3, using 3.21 g (12.0 mmol) of (+)A-2 and 1.5 equivalents of trifluoromethanesulfonic anhydride. After work-up and purification by liquid chromatography, there is obtained 3.94 g (90.4 %) of pure (+) enantiomer of the title compound A-3 as a pale yellow oil: 1HNMR is identical with that of (-)A-3.

Preparation 4: trans-(-)-2,3,3a,4,9,9a-Hexahydro-5-carbomethoxy-1-n-propyl-1H-benz[f]indole [(-)A-4]. A solution of 3.5 g (9.7 mmol) (-)A-3, 3.0 mL (21.3 mmol) triethylamine, 10 mL methanol, and 30 mL dimethylformamide is saturated with carbon monoxide gas via bubbling the gas through a syringe needle in a three-neck flask equipped with a septum, a condenser, a gas inlet, and a magnetic stirring bar. A solution of 0.22 g (0.97 mmol) palladium acetate and 0.52 g (1.26 mmol) 1,3-bis-(diphenylphosphino)propanein 10 mL dimethylformamide/methanol (3:1), purged with nitrogen, is injected into the reaction flask via a syringe. The brown mixture is heated at 70º C while the carbon monoxide gas continues to bubble through the solution. After 24 h, the solution is purged with nitrogen gas, quenched with 200 mL saturated aqueous sodium bicarbonate,is extracted with 2×1 L ethyl acetate/ether (1:1). The organic layer is washed with water, brine, dried (MgSO₄), filtered, and concentrated in vacuo. The resulting brown oil is purified by liquid chromatography on 400 g silica gel 60 (230-400 mesh), eluting with 5 L hexane/acetone (9:1), and collecting 40 mL fractions. Fractions homogeneous by TLC are combined and concentrated to give 2.31 g (87.2%) of pure (-) title compound A-4 as a yellow oil: ¹HNMR (CDCl₃, TMS) δ 7.22-7.12 (m, 3H); 3.89 (s, 3H); 3.50-1.48 (m, 14H); 0.95 (t, J=7Hz, 3H). trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carbomethoxy-1-n-propyl-1H-benz[f]indole(+)A-4].

The reaction is run in an identical manner as described in the preparation of (-)A-4, using 3.8 g (10.5 mmol) (+)A-3 as the starting material and appropriate amounts of the reagents and solvents. After work-up and purification, there is obtained 2.60 g (90.6 %) of pure (+) enantiomer A-4 as a yellow oil: The ¹HNMR is identical with that of (-)A-4

Example 1. trans-(-)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1-n-propyl-1H-benz[f]in¬dole [(-)A-5].

A solution of 2.28 g (8.4 mmol) (-)A-4 in 5.6 mL of 3N sodium hydroxide and 30 mL methanol is refluxed (bath temperature 70 º C) under a nitrogen atmosphere for 24 h. The mixture is cooled to room temperature, treated slowly with 6N hydrochloric acid until pH of the mixture is 3-4 and diluted with about 200 mL water. The mixture is allowed to stand in the refrigerator for 24 h. The resulting solid, the amino-acid, is isolated and dried in the vacuum oven to give 1.76 g of a tan colored solid: mp. >300° C, ¹HNMR (CD₃OD, TMS) δ 7.82-7.25 (m, 3H); 3.84-1.72 (m, 14H); 1.08 (t, J=7Hz, 3H). A solution of the amino-acid obtained above, 3.5 mL (25.2 mmol) triethylamine, and 50 mL dimethylformamide is stirred at room temperature while ammonia gas is bubbled through the solution via the syringe needle. After 10 min, 2.6 mL (16.8 mmol) diethylcyanophosphonate is added. The resulting mixture is stirred at room temperature while ammonia gas continues bubbling through. After 6 h, another portion of triethylamine (3.5 mL) and diethylcyanophosphonate (2.6 mL) is added and continues the bubbling of the ammonia gas. After 24 h, the solvent is removed via a high vacuum rotary evaporator and the residue is diluted with 300 mL acetone. The mixture is allowed to stand in the refrigerator for 24 h. The white precipitate (0.4 g) is isolated (mostly the unreacted starting material) and the filtrate is concentrated in vacuo. The oil is purified by liquid chromatography on 400 g silica gel 60 (230-400 mesh), eluting with

2 L of acetone and 3L methylene chloride/methanol(3M ammonia) (10: 1) and collecting

40 mL fractions. Fractions homogeneous by TLC are combined and concentrated in vacuo to give 0.98 g (45.3 %) of a white solid.Recrystallization from ethyl acetate/acetone gives the title compound as a white solid: mp.203-204° C,[α]_D -212.6° (c

0.78, MeOH), ¹HNMR (CD₃OD, TMS) δ 7.28-7.12 (m, 3H); 3.42-1.52 (m, 14 H);

0.97 (t, J=7 Hz, 3H). trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1-n-propyl-1H-benz[f]indole[(+)A-5].

The reaction is run in an identical manner as the preparation of (-)A-5, using 2.46 g (9.0 mmol) (+)A-4 as the starting material and appropriate amounts of the reagents and solvent. After work-up and purification, there is obtained 1.1 g (47.8 %) of (+)A-5. Recrystallization from ethyl acetate/acetone gives a white solid: mp.203-204º C, [α]_D +210.7º (c 0.78, MeOH), ¹HNMR is identical with that of (-)A-5.

Chart A

Claims

1. A compound having the formula

wherein R is C₁-C₈ alkyl and n is 1 or 2.

2. A compound according to claim 1, wherein the group CONH₂ is not in the 8 position.

3. A compound of claim 2, wherein n is 1. 4. A compound of claim 3, trans-(±)-2,3,3a,

4,9,9a-hexahydro-5-carboxamido-1- (n-propyl)-1H-benz[f]indole.

5. A compound of claim 3, trans-(+)-2,3,3a,4,9,9a-hexahydro-5-carboxamido-1-(n-propyl)-1H-benz[f]indole.

6. A compound of claim 3, trans-(-)-2,3,3a,4,9,9a-hexahydro-5-carboxamido-1-(n-propyl)-1H-benz[f]indole.