CA1266675A - 6-oxygenated-1,3,4,5-tetrahydrobenz(cd)indol-4-amines - Google Patents

Abstract

ABSTRACT

6-Oxygenated-1,3,4,5-tetrahydrobenz[cd]indol-4-amines having the following structure

Description

6-OXYGENATED-1,3,4,5-TETRAHYDROBENZ~ cd~ INDOL-4-AMINES

This invention relates to new 6-oxygenated-1,3,4,5-tetrahydrobenz~cd]indol-4~amines, to pharma-ceutical compositions containing these compounds and to methods of modulating serotonergic activity by administering them. The invention also relates to a process for preparing ~hese compounds and to indol-4-one intermediates.
The compounds of this invention are selective serotonin 15-HT) receptor antagonists. They bind selectively to 5-HTl (vs 5-HT2) serotonin receptors.
~; Such selective 5-HTl receptor antagonists are useful, for example~ in cardiovascular, gastrointestinal and renal ;~ disease s~ates, as well as in the treatment of other

2~ disorders, such as depression, in which serotonin modulation is important. The compounds have `~ antihypertensive activity.
The 6-oxygenated-1,3,4,5-tetrahydrobenz[cd]indol-4-amine compounds of this invention are represented by the following formula (I):
QRl 2 3 : ~ NR R

HN
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l is hydrogen or Cl 5 al'~yl; and R2 and R3, being the same or different, are hydrogen, Cl ~ alkyl, phenyl(CH2)n where n is 0-3, C5 ~ cycloalkyl or C3 5 alkenyl;
or a pharmaceutically acceptable acid addition salt thereof.
Particular compounds of formula (I) are those in which Rl is hydrogen or methyl.
Other particular compounds of for~ula (I) are those in which R2 and R3 are both hydrogen or are both methyl.
Specific compounds of formula (I) are:
6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4 amine 6-hydroxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N,N-dimethyl-6-methoxy-1,3,4,5-tetrahydrobenz-[cd]indol-4-amine.
The compounds of formula (I) are prepared by the following procedures.
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. O,R . oRl HN HN
(II) ,;
~ 30 . `i.~ 1 R is de~ined as in formula (I).
According to the procedure of Method A, a 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (II) is hydrogenated using a noble ~etal catalyst such as palladium, or prererably, platinum oxide.
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Method B
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R4 ~R4 ~0 ~\~ NR2R3 W ~
H HN
(III) O~I
¢~,NR~R3 R4 is Cl 5 alkyl and R2 and R3 are as defined in formula (I).
. The first step in Method B, which is a reductive amination method, is also included in this invention.
-~ The reductive amination is carried out with sodium cyanoborohydride and an amine of the formula:

:~ and an inorganic acid addition salt, such as a hydrochloride salt, of said amine~ The process is preferably carried out with the inorganic acid addition ~ 30 salt of the amine and the basic amine present in a ratio of :~ about 10:1 to 10:3.
According to the second step of Method B, compounds of ormula (I) where ~ is hydrogen are ~;~ prepared by dealkylating the 6-alkoxy compounds using, for ~; 35 example, boron tribromide, hydrobromic acid or pyridine .~ hydrochloride.

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The compouncls of formula (I) where R2 and R3 are other than hydrogen may be prepared by alkylation of the unsubstituted amino compounds when Rl is Cl 5 alkyl. However, these compounds, particularly where R2 and R3 are both other than hydrogen, are preferably prepared by the reductive amination process of Method B.
The secondary amine compounds of formula (I), i.e. where only one of R2 or R3 is other than hydrogen, may be prepared by acylating the primary amine with an acylating agent such as an acid halide, anhydride or activated ester such as a p-nitrophenyl or dinitro-phenyl ester, and then reducing, for example with an alkali metal hydride such as lithium (or sodium) aluminum hydride, or other reducing agent such as borane or borane/
tetrahydrofuran or borane/dimethylsulfide, to give the N-substituted amines of formula (I).
The compounds of formula (I) form pharmaceutically acceptable acid addition salts with organic or inorganic acids. Examples of these acids are hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, tartaric, citric, maleic, lactic, oxalic, succinic, methanesulfonic, and benzenesulfonic acids. The salts are formed according to methods known to the art. If the product is isolated as acid addition salt, it may be treated with base such as aqueous sodium hydroxide and converted to the corresponding base. The base can then be treated with an appropriate acid for example in an aqueous miscible solvent, such as a lower alkanol preferably methanol or ethanol, to give the desired salt.

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. - 5 -The indol-4~one intermediates of this invention are represented by the following formula (IV):

. 5 ~ o (IV) HN~

in which R5 is hydrogen or Cl 5 alkoxy.
The compounds of formula (IV) in which R5 is Cl 5 alkoxy are intermediates of formula (III) in Method B. Those compounds in which R5 is hydrogen are : intermediates, for example, for the preparation of the NIN-dipropyl-1,3,4,~-tetrahydrobenz~cd]indol-4-amine of ~ U.S. 4,110,339 by reductive amination.
:~ The 4-nitro-tetrahydrobenz[cd]indole intermediates of formula (II) in Method ~ are prepared by the following process:

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~R4 R4 loR4 ~HO ~ CE=NNHCONH2 ~,~N

HN HN HN

:'' \~, ~ R~ oR4 oR4 ~ H=CHN02 ~H2CH2N02 ~[~3,No2 :~ 25 /
:` QH OR
~-N2 < ~`J2 ; ` ' R is methyl or ethyl and R4 is Cl 5 alkyl. This process is illustrated in examples 1 and 2.

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The 4-keto intermediates of formula (III) are prèpared by treating the 4-nitro compounds (~ormula II
where R is Cl 5 alkyl) with solid sodium methoxide in methanol, then with aqueous titanium trichloride. This process is illustrated in example 3 herebelow.
I The selective 5-HTl receptor antagonist activity of the compounds of formula (~) is demonstrated by the displacement of [ H~5-HT from rat frontal cerebral cortex preferably over the displacement of [3H]spiroperidol which binds preferentially with 5-H~2 receptors. Peroutka et al, Molecular Pharmacology 16:687-699 ~1979) describe this test procedure and designate as 5-HTl and 5-HT2 those serotonin receptors that are labeled by ~3H]5-HT and [3H]spiroperidol, respectively. The XC50 (concentration required to displace 50~ of [3~]5-HT binding from rat frontal cerebral cortex) for compounds of examples 1-3 is about 40-7OnM.
;~ Also, selective 5-HTl receptor antagonist activity of the compounds of formula (I) may be shown by the ability to antagonize the effect of serotonin in an in vitro dog basilar artery preparation, Peroutka et al, Braln Research 259:327-330 (1983). The compound of example 1 herebelow showed selective 5-HTl activity at KBY4.63 x lO 7M.
~; Inhibition of the activity of serotonin (i.e.
5-hydroxytryptamine) is an activity known to the art; in ;~ U.S. 4,435,405, certain quinoline compounds are described as 5-hydroxytryptamine antagonists which demonstrated binding a~ 5-HTl and 5-HT2 receptors.
Antihypertensive activity of compounds of formula `~ (I) is demons~rated by administration ~o spontaneously hypertensive rats (S~R) at doses of about 0.4-l.O mg/kg, i.v. In this test procedure, diastolic blood pressure and heart rate are reduced.
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-This invention also includes pharmaceutical compositions having 5-HTl receptor antagonist activity comprising a compound of formula (I) or a pharmaceutically I acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
The pharmacologically active compounds of formula (I) can be administered orally or parenterally.
Preferably, these compounds are administered in conventional dosage unit forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers. The dosage units will contain the active ingredient in an effective amount selected from about 0.01 mg. to about 500 mg., preferably 1 mg. to 50 mg.
; The pharmaceutical carrier employed may be, for example, either a solid or li~uid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent can include any time delay material well known to the art r such as glyceryl monostearate or glyceryl distearate alone or with a wax A wide variety o pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in hard gelatin capsule in powder or pellet form or in the form of a trouche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mgO ~o about 1 g. If a li~uid carrier is used, the preparation will be in the form or a ; 30 syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
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The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing when`necessary or variously mixing and dissolving the lngredients as appropriate to the desired composition.
The method of inhibiting the action o serotonin at the S-HTl receptors in accordance with this invention comprises administering internally to a subject in need of said activity a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce said activity.
Also, included in this invention is a method of producing antihypertensive activity which comprises administering internally to a subject in need of said activity a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce said activity.
The compound will preferably be administered in a - dosage unit form orally or parenterally. Advantageously equal doses will be administered one to four times daily with the daily dosage regimen being from about 1 mg. to about 250 mg~, preferably from 1 mg. to 10 mg. When the method described above is carried out, the action of serotonin at the 5-HTl receptors is inhibited.
; 25 One skilled in the art will recognize that in determining the amounts of the compound needed to produce the desired pharmacological effect without toxic side effects, the activity of the particular compound as well as the size of the host animal must be considered.
3Q The following examples illustrate the invention but are not to be construed as limiting the scope thereof.
Temperatures are in degrees Centigrade unless otherwise stated.
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A mixture of ethyl 5-methoxy-(lH)indole-2-carboxylate (186 g, 0.85 mol) and glacial acetic acid (4.2 L) was stirred and warmed on a hot plate until only a small amount of indole remained undissolved. The warm solution was stirred vigorously during the dropwise addition (15 min) of bromine (43.4 mL, 135.4 g, 0.85 mol), then allowed to stand at ambient temperature for 24 hours.
The resulting mixture was filtered, the crystalline product was washed sequentially with acetic acid (2 x 150 mL), hexane (2 x 200 m~), and then dried at 65C to give ethyl

4-bromo-5-methoxy-(lH)indole-2-carboxylate m.p. 176-178C
(softens at 166C).
A 5-L flask was charged with sodium hydroxide (60 g, 1.5 mol) and water (0.5 L), and the contents were stirred until homogeneous. Ethanol (l L), tetrahydrofuran (0.25 L), and ethyl 4-bromo-5 methoxy-(lH)indole-2-carboxylate (180 g, 0.6 mol) were added and the mixture was heated at re1ux for l hour, then cooled to ambient temperature. The solution was stirred vigorously as concentrated hydrochloric acid (0.25 L, 3 mol) and water (2.5 L) were added. The resulting thick yellow paste was cooled at 0C overnight, filtered/ and the crystalline product was washed with water (3 x 400 mL), and dried at 60C to give 4-bromo-5-methoxy-(lH)indole-2-carboxylic acid (161 g, 99.3%), m.p. 263C(d).
A l-L flask was charged with freshly distilled N,N'-dimethylacetamide (450 mL) and the solvent was degassed (15 min) with a vigorous stream of argon.
4-Bromo-5-methoxy-~lH)indole-2-carboxylic acid (75 g/ 0.28 ~ mol) and copper (I) cyanide (75 g, 0.84 mole) were added, ;~ the solution was stirred and heated at reflux for 28 hours, cooled to ambient temperature, and poured into a mixture or water (500 mL) and ethyl acetate (500 mL). The mixture was ~ 35 filtered through diatomaceous earth, the precipitate was .: `~
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~ washed with ethyl acetate (250 mL), the combined ethyl ; acetate ~iltrates were separated from the aqueous layer, and washed with water (5 x 250 mL) and brine. The solution was dried and concentrated, and the residue was recrystallized from ethyl acetate/hexane to give

5-methoxy-(lH)indole-2-carbonitrile (21 g, 44~), m.p.
139-141 C.
A 450-mL Parr hydrogenation bottle was charged with sodium acetate (12 g, 0.146 mol), semicarbazide hydrochloride (16 g, 0.144 mol) and water (45 mL), and the ~ mixture was heated u~til homogeneous. A heaping tablespoon l~ of Raney nickel catalyst was added to the cooled Parr j bottle followed by a solution of ~-methoxy-(lH)indole-4-carbonitrile (20 g, 0.116 mol) in hot methanol (185 mL).
1 15 The mixture was hydrogenated at 50 p5i until the theoretical uptake of hydrogen was complete (18-24 hours).
The mixture was heated to near boiling on a steam bath, filtered hot, and the precipitate was washed with hot N,N-dimethylformamide until the catalyst was free o product. The filtrate was concentrated and traces of I solvent were removed from the residue by further ¦ ~ concentration using a dry ice cold trap to ~ive a solid residue. The residue was triturated with a mixture of ~ ethanol (60 mL) and water (180 mL), filtered, washed with i` ~ 25 water and dried at 60C to yield 5-methoxy-(lH)indole-4-carboxaldehyde semicarbazone (18.89 g, 70%), m.p.
219-221C(d).
A mixture of water (0.46 L), glacial acetic acid (0.91 L), freshly distilled pyruvic acid (33.23 g, 0.378 mol), and anhydrous sodium acetate (3~.16 g, 0.416 mol) was stirred un~il homogeneous, then 5-methoxy (lH)indole-4-carboxaldehyde semicarbazone (17.5 g, 0.0754 mol) was added and the mixture was stirred for 16 hours. The ~; resulting solution was concentrated with a dry-ice cold trap (water bath temperature ~25C), the residue was taken , .
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_, up in ethyl acetate (0.5 L) and filtered, and the filtrate was washed sequentially with water (2 x 250 mL), 5% aqueous sodium carbonate (3 x 250 mL), brine, dried, and warmed briefly with decolorizing charcoal before concentration.
The crude product was dissolved in a little ethyl acetate and applied to a silica gel (2S0 g) column; elution witn 2:1 ethyl acetate~hexane and concentration of the first 1.0 L of eluate gave 5-methoxy-(lH)indole-4-carboxaldehyde (9.8 g, 74.2%), mOp. 134-136C (softens at 125C).
A solution of 5-methoxy-(lH)indole-4-carboxaldehyde (8.61 g, 49.2 mmol) and ammonium acetate (l S g) in nitromethane (70 mL) was heated on a steam bath for 3 hours, and diluted with ethyl acetate (150 mL). The solution was washed twice with water, once with brine, dried, and concentrated. The solid product was recrystallized from ethyl acetate/hexane. The crystallization filtrates were concentrated, purified by 1ash chromatography using 1:1 hexane-ethyl acetate as eluant, recrystallized from ethyl acetate/hexane, and combined with the first crop of product to give 5-methoxy-4-(2-nitroethenyl)-(lH)indole (9.15 9, 85%), m.p.
175-176C.
A 2-L flask was charged with methanol (0.42 L) and , S-methoxy-4-(2-nitroethenyl)-(lH)indole (9.1 g, 41.7 mmol), and the resulting mixture was stirred during the slow (20 min) addi~ion of sodium borohydride (7.0 g, 0.185 mol).
During the addition, vigorous hydrogen evolution occurred and the mixture became warm. The solution was stirred for 20 minutes after the addition was completed, g~acial acetic acid (15 mL) was added to a pH of 6, and the solution was concentrated. The solid residue was partitioned between water and ethyl acetate. The aqueous layer was washed twice with ethyl acetate and the combined ethyl acetate phases were washed with water, twice with 10~ aqueous 3S sodium carbonate, brine, then dried, and concentrated. The . ~
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resulting oil was purified by flash chromatograph~ using 40~ ethyl acetate~hexane as eluant to give S-methox~-4-~2-nitroethyl)-(lH)indole (8.38 g, 91%), m.p. 77-79C.
N,N-Dimethyl~ormamide (20 mL) was stirred under argon in a 500 mL flask during the addition (over 2 minutes) of phosphorus oxychloride (3.45 mL, 37.1 mmol), then the flask was cooled in a cold water bath during the addition (over 2 minutes) of 5-methoxy-4-(2-nitroethyl)-(lH)indole (7.15 g, 32.5 mmol). After the addition was completed, the cooling bath was removed, stirring was continued for 15 min at ambient temperature, a mixture of water (6.5 mL, 0.36 mol) and N,N-dimethylformamide (26 mL) was added, and the resulting solution was stirred for 10 min. A mixture of triethylamine (45.5 mL, 0.33 mol) and methanol (130 mL) was added, the solution was heated at reflux for 30 min, water (75 mL) was added slowly ~o the hot solution and the mixture was cooled at 20C for 2 hours. The mixture was filtered and the precipitate was washed sequentially with water, 2:1 methanol-water 20 (2 x 25 mL), ether (3 x 50 mL), and then dried at 60C to yield 6-methoxy-4-nitro-1,5-dihydrobenz[cd]indole (6.8 g, 91%), m.p. 350C(d).
A mixture of 6-methoxy-4-nitro~1,5-dihydro-benz[cd~indole (7.26 g, 31 6 mmol) and methanol (0.5 L) was stirred vigorously in a 2-L flask during the slow (20 min) addition of sodium borohydride (18.25 g, 0.48 mol). During the addition, vigorous hydrogen evolution occurred and the mixture became quite warm. After stirring an additional 10 min, glacial acetic acid (45 mL) was added to a final pH
of 5-6. The solution was concentrated, partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, and the combined oryanic layers were washed sequentially with water, 5% aqueous sodium carbonate, and brine. The solution was dried and concentrated, and the solid residue was purified by flash '; `

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` chromatography using 2:1 hexane-ethyl acetate as eluant to give 6 methoxy-4-nitro 1,3,4,5-tetrahydrobenz[cd]indole (6.5 g, 89~), m.p. 134-136C.
~, Platinum oxide (300 mg) was reduced under 60 psi hydrogen pressure in methanol (30 mL) for 30 min.
6~Methoxy-4-nitro~1,3,4,5-tetrahydrobenz[cd]indole (1.0 g, 4.31 mmol) was added and the resulting solution was hydrogenated under 60 psi hydrogen pressure until hydrogen uptake ceased (about 2 houxs). The mixture was filtered, the filtrate was concentrated, and the residue was dissolved in chloroform and decolorized with activated carbon. The resulting mixture was filtered and the filtrate was concentrated. The residue, which contained 6-methoxy-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole-4-amine, lS was dissolved in absolute ethanol (8 mL) and the solution was stirred and heated to near reflux as a solution of oxalic acid dihydrate (540 mg, 4.31 mmol) in absolute ethanol (S mL) was added slowly. The mixture was diluted with acetone (10 mL), cooled at 0C, filtered, and the precipitate was washed with acetone (2 x 10 mL), hot methanol (2 x 10 mL), and dried to yield 6-methoxy-1,3,4,5-tetrahydrobenæ[cd]indole-4-amine hemioxalate (0.74 g, 70%), ;~ m.p. 260-265C(d).
Exam~le 2 6-Methoxy-4-nitro-1,3,4,5-tetrahydrobenz[cd]indQle (0.210 g) was dissolved in 30 ml of anhydrous methylene chloride under nitrogen in a flame dried flask. The mixture was cooled ~o 0C and 4 mL o 1 molar boron ~` tribromide-in methylene chloride was added. The mixture was stirred at 0C or 6 hours. The reaction was quenched with 5% aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic extracts were dried and the solvent removed. The residue was chromatographed over silica using 60~40 hexane/ethyl acetate to give 6-hydroxy-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole.

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6~Hydroxy-4-nitro 1,3,4,5-tetrahydrobenz~cd]indole I (52 mg) was dissolved in 10 mL of methanol. The solution i was added to 50 mg of platinum oxide which had been reduced with hydLogen at 50 psi in 10 mL of methanol for 3 hours, then filtered under argon into a flask containing 21.5 mg (1 equiv.) of oxalic acid in 2 mL of methanol. The solution was concentrated to about 10 mL volume and 100 mL
of diethyl ether was added. After 1 hour at -20C, the solid material was filtered, washed with diethyl ether and dried to yield 31 mg of 6-hydroxy-1,3,4,5-tetrahydro-benz[cd]indol-4-amine oxalate, m.p. 218-220C(d).
. .
Exam~le 3 A mixture of 6-methoxy-4-nitro-1,3,4,5-tetrahydro-benz[cd]indole (1.16 g, 5 mmol) and methanol (25 mL) was treated with solid sodium methoxide (0.3 g, 5.5 mmol) and stirred under argon until homogeneous. A solution made by mixing 20% aqueous titanium trichloride (17.5 mL) with ammonium acetate (10.5 g) dissolved in water (35 mL) was added, and the resulting suspension was stirred for 1 hour.
The mixture was shaken vigorously and aecanted with diethyl ether (8 x 50 mL). The diethyl ether extracts were washed se~uentially with water (3 x 100 mL), 5% aqueous sodium carbonate (2 x 100 mL) and brine, then dried and concentrated to give 6-methoxy-1,5-dihydrobenz[cd]indol-; 25 4(3H)-one (0.82 g, 81~) m.p. 130-132C(d).
A solution of anhydrous dimethylamine (0.26 g, 5.76 mmol), dimethylamine hydrochloride (2.45 g, 30.0 mmol), and sodium cyanoborohydride (1.88 g, 30.0 mmol) in methanol (30 mL) was prepared. 6-~ethoxy-1,5-dihydro-benæCcd]indol-4(3H)-one (0.60 g, 3.0 mmol) in methanol (30 ;~ mL) was added. The reaction mixture was stirred at ambient ~ temperature for 1 hour, then poured into 5~ aqueous sodium ;; bicarbonate solution (100 mL). The resulting mixture was ;~ extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with 5% a~ueous hydrochloric :;`

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acid (3 x 30 mL). The acidic extracts were made basic with 20% aqueous sodium hydroxide and extracted with ethyl /, acetate (3 x 50 mL), the combined organic extracts were washed with 10% aqueous sodium sulfate, dried and concentrated to yield a product which was purified by 1ash chromatography using 5% diisopropylamine-ethyl acetate as eluant to give N,N-dimethyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine as an oil. This free base was dissolved in methanol (lOmL) and treated with a solution of oxalic acid (0.156 g, 1.73 mmol) in methanol (5 mL). The crystalline product was collected and dried (25~C, 0.1 torr) to yield N,N-dimethyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine oxalate.
Example 4 By the procedure o~ Example 3, using in place of dimethylamine the following amines:
diethylamine dipropylamine dibutylamine dibenzylamine - dicyclohexylamine diallylamine aniline : allylamine the products are:
N,N-diethyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N,N-dipropyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine : N,N-dibutyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amineN,N-dibenzyl-6-methoxy-1,3,4,5 tetrahydrobenz L cd]indol-4-amine N,N-dicyclohexyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N,N-diallyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N-phenyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N-allyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine : ~;
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Similarly, using N-butyl-~1-propylamine in place of dimethylamine, the product is N-butyl-N-propyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine.

A mixture of 6-methoxy-1,3,4,5-tetrahydrobenz~cd]-indol-4-amine (2.0 g, 0.01 mol), benzoyl chloride (2.1 g, 0.015 mol) and 10 ml of pyridine is stirred at room temperature for 10 minutes, then poured into water.
Extracting with ethyl acètate and then concentrating the extracts gives N-benzoyl-6 methoxy-1,3,4,5-tetrahydrobenz-[cd]indol-4-amine as the eesidue.
One gram o~ this N-benzoyl compound in 20 ml of tetrahydrofuran is added to one gram of lithium aluminum hydride in 20 ml of tetrahydrofuran and the resulting mixture is stirred at room temperature overnight, then quenched with water, filtered and concentrated to give N-benzyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine.
~y the same procedure, using 6-hydroxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine in place of the 6-methoxy ; 20 compound, the product is N-benzyl-6-hydroxy-1,3,4,5-tetra-~-~ hydrobenz[cd]indol-4-amine.
Example 6 A mixture of 6~methoxy-1,3,4,5-tetrahydrobenz-~cd]indol-4 amine (2.0 g, 0.01 mol) and p-nitrophenyl formate (1.7 g, 0.01 mol) in 25 ml of ethyl acetate and 10 ml of pyridine is stirred overnight at room temperature, `~ then washed with water and concentrated to giYe N-formyl-6-methoxy-1,3,4,5-tetrahydrobenz~cd]indol-4-amine.
The above prepared N-formyl compound is reduced with lithium aluminum hydride in tetrahydrofuran and the resulting mixture is worked up by the procedure of Example 5 to give N-methyl-6-methoxy-1,3,4,5-tetrahydro-benz~cd]indol-4-amine.
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By the same procedure, using 0.01 mol of acetic anhydride ln ethyl acetate, the product is N-acetyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine. Reducing with lithium aluminum hydride in tetrahydrofuran by the procedure of Example 5 gives N-ethyl-6 methoxy-1,3,4,5-tetrahydrob-enz[cd]indol-4-amine.
Using 6-hydroxy-1,3,4,5-tetrahydrobenz[cd~indol-4-amine in place of the corresponding 6-methoxy compound in the above procedures~ the products are:
N-methyl-6-hydroxy-1,3,4,5 tetrahydrobenz[cd]indol-4-amine and N-ethyl-6-hydroxy-1,3,4,5-tetrahydrobsnz[cd]-indol-4-amine.
Exarnple 7 By the procedure of Example 2, the following 6-methoxy compounds of Example 4 are reacted with boron tribromide:
N,N-dimethyl-6-methox~-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N,N-diethyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4 amine N,N-dibenzyl-6-methoxy-1,3,4,5-tetrahydrobenz[cd]indol-4-amine N,N~diallyl-6-methoxy-1,3,4,~-tetrahydxobenz[cd]indol-4-amine N-phenyl-6-methoxy-1~3,4,5-tetrahydrobenz~cd]indol-4-amine to give the corresponding 6-hydroxy compounds.
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6-Methoxy-1,3,4,5-tetrahydrobenz[cdlindol-4-amine ~S (50 mg) i9 mixed with 100 mg of lactose and 3 mg of magnesium stearate. The resulting mixture is filled into a hard gelatin oapsule.

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.

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1, A compound of the formula:
in which R5 is hydrogen or C1-5 alkoxy.

2. A compound according to claim 1 in which R5 is C1-5 alkoxy.

3. A compound according to claim 1, said compound being 6-methoxy-1,5-dihydrobenz[cd]indol-4(3H)-one.