6-SUBSTITUTED-4-DIALKYLAMINOTETRAHYDROBENZ(C,D)INDOLES

Abstract: (±)-4-Substituted-amino-6-substituted-1,3,4,5-tetra­ hydrobenz[c,d]inoles, or a pharmaceutically-acceptable salt thereof, are central serotonin agonists.

Description: 6-SUBSTITUTED-4-DIALXYLAMINOTETRAHYDROBENZ[c,d]INDOLES This invention concerns a class of novel 6-substituted-4-dialkylaminotetrahydrobenz[c,d]indoles, which have been discovered to be central serotonin agonists, and therefore useful as anti-obesity, antialcoholism, senile dementia, and anti-smoking agents. The benz[c,d]indole ring system (I) has been known since 1949. EMI1.1 For example Uhle et al. J. Am. Chem. Soc., 71, 1611 (1949); ibid, 73, 2402 (1951); Grob et al. Helv. Chim. Acta., 33, 1796, 1955 (1950), 35, 2095 (1952), 36, 839 (1953) and Stoll et al. ibid, 33, 2254, 2257 (1950); 35, 148 (1952), prepared, among other compounds, a 5-keto-1,3,4,5-tetrahydrobenz[c,d]indole plus the corresponding 4-amino and 4-acetylamino derivatives. A useful starting material for the synthesis of these compounds was a l-benzoyl-l,2,2a,3,4,5-hexahydro derivative, II. EMI1.2 formed by the Friedel-Crafts ring closure of 1-benzoyl 2(3-indolnyl)propionylchloride. Kornfeld et al., J.A.C.S., 78, 3087 (1956) also prepared this compound and converted it, via a series of intermediates, to the 4-amino-5-keto derivative which was, in itself, a key intermediate in the first total synthesis of lysergic acid. In this synthetic procedure, a fourth ring (an N-methyl piperidine ring) was grafted onto an appropriately substituted tricyclic 1,2,2a,3,4,5-hexahydro- benz[c,d]indole. Stoll et al. Helv. Chim. Acta, 35, 148 (1952) also prepared (i)-4-dimethylamino-1,3,4,5- tetrahydrobenz[c,djindole. Bach and Kornfeld, United States Patent 4,110,339, prepared the corresponding 4-(di-n-propyl)amino compound. Ledelec et al., United States patent 4,447,438 discloses 4-piperidyl-substituted-lH-indole having dopaminergic properties. Certain naturally occurring alkaloids, agroclavine and elymoclavine, have been converted by Cassady et al., J. Med. Chem. , 17, 300 (1974) to N-methyldioxychanoclavine, N-methylchanoclavine, and chanoclavine, all 4,5-disubstituted tetrahydrobenzc,dlinoles (III). EMI2.1 wherein X is H or OH and R1 is CH3 or H. Compounds according to III were without significant prolactin inhibiting activity, unlike the Bach-Kornfeld (i)-4 (dì-n-propyl)amino-1,3,4-5-tetrahydrobenz[c,duindole, which was found to be a selective dopamine agonist as shown by its action in inhibiting dopamine uptake in bovine striatal membrane in vitro. The corresponding 4-(dimethyl)amino derivative of Stoll et al. (loc. cit.) was used only as an intermediate. The 4-aminotetrahydrobenz[c,d]indoles and related derivatives are weak serotonin antagonists with one exception, the 4-acetylamino-5-oxo derivative -- see Harris and Uhle, J. Pharm. & Exper. Therap., 128, 358 (1960). Surprisingly, it has now been discovered that the class of compounds shown by formula IV below are strong central serotonin agonists, useful as an anti-depressant, anti-obesity, anti-alcoholism, senile dementia or anti-smoking agent. The present compounds display minimal other activity, usually dopaminergic properties, which are undesired side-effects in the prior art compounds. This invention provides 4-amino substituted-6-substituted-1,3,4,5-tetrahydrobenz[c,d]- indoles of the EMI3.1 wherein R1 and R2 are individually hydrogen, methyl, ethyl, n-propyl or allyl, and X is F, CI, Br, CN, CONH2, NH2, NO2, O(C1-C3 alkyl), O-acyl, OH or O-benzyl; or a pharmaceutically-acceptable salt thereof. The compounds of formula IV are prepared by: a) reacting a compound of the formula EMI4.1 wherein X5 is F, C1, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl; R5 and R6 are individually methyl, ethyl, n-propyl or allyl, with an oxidizing agent to provide the compounds of formula IV wherein X is F, Cl, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl, and R1 and R2 are individually methyl, ethyl, n-propyl or allyl; or b) reacting a compound of the formula EMI4.2 wherein R14 and R13 are individually ethyl, n-propyl or allyl, with cuprous cyanide or an alkali or alkaline earth cyanide and cuprous iodide in l-methyl-2-pyrrolidone to provide the compounds of formula IV wherein X is CN and R1 and R2 are individually ethyl, n-propyl or allyl; or c) reacting a compound of the formula EMI5.1 wherein R14 and R13 are defined as before, with a hydroxide base in a C1-C4 alkanol to provide the compounds of formula IV wherein X is CONY, and R1 and R2 are individually ethyl, n-propyl or allyl; or d) reacting a compound of the formula EMI5.2 wherein R14 and R13 are defined as before, with NaX2 and CuI where X2 is O-benzyl, O-acyl or O(C1-C3 alkyl) to provide the compounds of formula IV where X is O(C1-C3 alkyl), O-bentzyl 3r m-acyl and R1 and R2 are individually ethyl, n-propyl or allyl; or e) reacting a compound of the formula EMI6.1 wherein X4 is O-benzyl, or O(C1-C3 alkyl) and R14 and R13 are defined as before, with a de-etherifying agent to provide the compounds of formula IV wherein X is OH and R1 and R2 are individually ethyl, n-propyl or allyl; or f) reacting a compound of the formula EMI6.2 where R13 and R14 are defined as before, with a hydroxide or alkoxide base to provide the compounds of formula IV wherein X is OH and R1 and R2 are individually ethyl, n-propyl or allyl; or g) reacting a compound of the formula EMI7.1 wherein R1 and R2 are defined as before, with a reducing agent to provide the compounds of formula IV wherein X is NH2; ; or h) reacting a compound of the formula EMI7.2 wherein X1 is F, C1 or O(C1-C3 alkyl), Z7 is C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, or O-benzyl, and R15 is H or C1-C3 alkyl, with basic cleavage or when Z7is O-benzyl with catalytic hydrogenation to provide the compounds of formula IV wherein X is F, C1 or O(C1-C3 alkyl) and R1 is hydrogen and R2 is C1-C3 alkyl or hydrogen; or i) reacting a compound of the formula EMI8.1 wherein X5 and R15 are defined as before, with an alkylating agent or by reductive amination to provide the compounds of formula IX where X is F, Cl, Br, NO2, O(C1-C3 alkyl), O-alkyl or O-benzyl, and RÚ and Rê are individually methyl, ethyl, n-propyl, or allyl or one of RÚ and Rê may be hydrogen; or j) reacting a compound of the formula EMI8.2 where R8 is hydrogen, methyl, ethyl or n-propyl and Y is hydrogen, methyl, ethyl or chloromethyl, with a borane complex to provide the compounds of formula IV where X is CN and R1 and R2 are individually hydrogen, methyl, ethyl or n-propyl; or k) reacting a compound of the formula EMI9.1 where R1 and R8 are defined as before, with a peptide coupling agent and ammonia to provide the compounds of 2 formula IV where X is CONH2, R is H, methyl, ethyl or n-propyl and R1 is defined as before; or 1) reacting a compound of the formula EMI9.2 wherein R8 is defined as before, with an RÚ halide or by reductive amination with a hydrogen catalyst to yield the compounds of formula IV where X is CONH2, R2 is H, methyl, ethyl or n-propyl and R1 is defined as before; m) optionally salifying the compounds of formula IV. Compounds of formula IV in which X is NO2, Br, O(C1-C3 alkyl), O-acyl, O-benzyl or CN, are, in addition, useful intermediates for preparing other compounds coming within the scope of formula IV. Illustrative of some of those groups which NRÚRê represents are amino, methylamino, n-propylamino, ethyl-n-propylamino, diethylamino, ethylamino and n-propylamino. The term 11 acyl" includes groups derived from both carboxylic and sulfonic acids; i.e., groups of the general structure R3Z1 wherein Z1 is CO or s02 (indicating radicals derived from carboxylic or sulfonic acids) and R3 is C1-C3 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, naphthyl and substituted phenyl wherein said substituents can be I or 2 members of C1, Br, F, methyl, ethyl, methoxy or ethoxy. Illustrative acyl moieties thus include benzoyl, p-tosyl, acetyl, propionyl, isobutyryl, mesyl, ethylsulfonyl, n-propylsulfonyl, p-chlorobenzenesulfonyl, 3,4-methylenedioxybenzoyl, anisoyl, ethoxybenzenesul fonyl, 2,4-xylylsulfonyl, 3,4-dichlorobenzenesulfonyl, cyclopropylcarbonyl, cyclobutylsulfonyl, cycloheptylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, cyclopentylcarbonyl, a-naphthoyl, -naphthoyl, a-naphthylsulfonyl, and t3-naphthoylsulfonyl. Since the O-acylated groups of formula IV above are chiefly useful as intermediates, or in some instances as prodrugs, it will be apparent to those skilled in the art that other acyl groups than those given above can function in an equivalent manner to protect the OH group. Useful intermediates for preparing the compounds of formula IV are shown by the following formulae. A compound of the formula EMI11.1 wherein R5 and R6 are individually methyl, ethyl, npropyl or allyl; X6 is NO2, O(C1-C3 alkyl), Br, Cl, or F; or an acid addition salt thereof. A compound of the formula EMI11.2 wherein X6, R5 and R6 are defined as before, and Z is a protecting group, or an acid addition salt thereof. A compound of the formula EMI12.1 wherein X6 and Z are defined as before, or an acid addition salt thereof Pharmaceutically-acceptable acid addition salts of the compounds of formula IV include salts derived from non-toxic inorganic acids such as: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, phosphorous acid and others, as well as salts derived from non-toxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacatef fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene sulfonate , chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, B-hydroxybutyrate, glycollate, malate, naphthalene-l-sulfonate, naphthalene-2-sulfonate and mesylate. The compounds of formula IV are central serotonin agonists, useful as anti-depressants. Thus, included within the present invention is a pharmaceutical formulation which comprises as an active ingredient a compound of formula IV, or a pharmaceuticallyacceptable salt thereof, associated with one or more pharmaceutically-acceptable carriers or excipients therefor. The formulation or the active ingredient thereof can be used as a method of treating depression, obesity, alcoholism, smoking, or senile dementia in a warm-blooded animal by administering to said animal a therapeutically-effective amount of a compound of formula IV, or a pharmaceutically- acceptable salt thereof. Compounds according to formula IV have an asymmetric center at C-4 and thus occur as a (i) or dl racemic mixture. This invention includes both the racemates and the individual stereoisomers of the chemical compounds represented by formula IV. The individual stereoisomers can be prepared by resolving a racemate of a 2,2a-dihydro indole intermediate (XIV, XIVa, XV, XVa, XVI, XVIa from Reaction Scheme 2 below or XXX from Reaction 1). Then oxidizing the separated stereoisomer to the indole and carrying out any further reactions to obtain a desired optically active product of formula IV. The resolution procedure can employ optically-active acids such as, for example, L-(+)-Rtartaric acid, (-)-dibenzoyltartaric acid, (+)-camphoric acid, (+)-10-camphorsulfonic acid, (-)-mandelic acid, (-)-malic acid, N-acetyl-L-glutamic acid, t-BOC-Dphenylglycine, D-(-)-S-tartaric acid, L-p-toluoyltartaric acid and the like. Compounds illustrative of formula IV include: (i)-4-diallylamino-6-chloro-1,3,4,5-tetrahydro- benz[c,d]indole sulfate (i)-4-methylethylamino-6-bromo-1,3,4,5-tetra- hydrobenz [c, dJ indole tartrate (i)-4-diallylamino-6-amino-1,3,4,5-tetrahydro- benz[c,d]indole succinate (i)-4-diethylamino-6-nitro-1,3,4,5-tetrahydro- benz[c,d]indole phosphate (-)-4-methyl-n-propylamino-6-aminocarbonyl1,3,4,5-tetrahydrobenz[c,d]indole dihydrogenphosphate (#)-4-(di-n-propyl)amino-6-aminocarbonyl- 1,3,4,5-tetrahydrobenz[c,d]indole bisulfate (#)-4-dimethylamino-6-aminocarbonyl-1,3,4,5- tetrahydrobenz[c,d]indole hydrobromide (#)-4-diethylamino-6-aminocarbonyl-1,3,4,5- tetrahydrobenz[c,d]indole tosylate (-)-4-diallylamino-6-aminocarbonyl-1,3,4 tetrahydrobenz [c, d] indole malate (#)-4-(di-n-propyl)amino-6-bromo-1,3,4,5- tetrahydrobenz[c,d]indole benzoate (-)-4-diethylamino-6-fluoro-1,3,4,5-tetrahydrobenz[c,d]indole phenylacetate (+)-4-dimethylamino-6-chloro-1,3,4,5-tetra hydrobenz [c,djindole l.,4-butyndioate (#)-4-diallylamino-6-nitro-1,3,4,5-tetra- hydrobenz[c,d]indole hydrochloride (+)-4-dimethylamino-6-amino-1,3,4,5-tetra- hydrobenz[c,d]indole sulfate (+)-4-(di-n-propyl)amino-6-cyano-1,3,4,5 tetrahydrobenz [c, d] indole fumarate (-)-4-amino-6-bromo-1,3,4,5-tetrahydrobenz [c, d] indole propiolate (t)-4-diallylamino-6-ethoxy-1,3,4,5-tetrahydro- benz[c,d]indole sulfate (¯)-4-methylethylamino-6-hydroxy-1,3,4,5-tetra- hydrobenz[c,d]indole tartrate (+)-4-dimethylamino-6-methoxy-1,3,4,5-tetrahydro- benz[c,d]indole maleate (i)-4-diallylamino-6-methoxy-1,3,4,5-tetrahydro- benz[c,d]indole succinate (i)-4-diethylamino-6-methoxy-1,3,4,5-tetrahydro- benz[c,d]indole phosphate (#)-4-dimethylamino-6-propionoxy-1,3,4,5- tetrahydrobenz [c, d] indole hydrobromide (#)-4-diethylamino-6-benzyloxy-1,3,4,5- tetrahydrobenz[c,d]indole tosylate (-)-4-diallylamino-6-hydroxy-1,3,4,5-tetrahydrobenz[c,d]indole malate (i)-4-(di-n-propyl)amino-6-hydroxy-1,3,4,5- tetrahydrobenz [c, d] indole benzoate (-)-4-diethylamino-6-benzyloxy-1,3,4,5-tetrahydrobenz[c,d]indole phenylacetate (+)-4-(di-n-propyl)amino-6-nitro-1,3,4,5-tetratetrahydrobenz[c,d]indole fumarate (-)-4-amino-6-hydroxy-1,3,4,5-tetrahydrobenz [c,d]indole propiolate and the like. Compounds of formula IV wherein X is C1, Br, O-benzyl, CN, CONH2, O(C1-C3 alkyl), O-acyl or OH can be prepared according to the following reaction scheme. Reaction Scheme 1 EMI16.1 Reaction Scheme 1 cont'd. EMI17.1 Reaction Scheme 1 cont'd. EMI18.1 Also the compounds of formula XXI can be reacted by the following modification to provide the compounds of formula XXV. Reaction Scheme 1 cont'd. EMI19.1 In Reaction Scheme 1, 5 and R6 R5 and R6 are individually methyl, ethyl, n- propyl or allyl; R7 is hydrogen, methyl or ethyl; R13 and R14 are individually ethyl, n-propyl or allyl; X2 is OCH2C6H5, O(C1-C3 alkyl) or O-acyl; Zê is O(C1-C3 alkyl), OCH2CC13 or O(C1-C3 alkyl) substituted by halogen. In the above reaction scheme, for example, l-benzoyli5-oxo l,2,2a,3,4,5-hexahydrobenz[c,djindole (XX) [from Kornfeld et al., J.A.C.S., 78, 3887 (1956) compound 4] is hydrolysed in acid to 5-oxo-1,2,2a,3,4,5- hexahydrobenz[c,djindole (XXI) [compound 10 of Kornfeld et al. when R is H]. The 5-ketone is reduced to a 5-hydroxyl[(i)-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz- [c,d]indole (XXII)] with an alkali metal borohydride, such as NaBH4, or aluminumhydride in a mutual inert solvent. Bromination in acetic acid yields the (i)-6bromo-5-hydroxy derivative (XXIII). This compound is then reacted with 2 moles of Z2-CO-Cl, e.g. ethyl chloroformate, to yield a (i)-l-ethoxycarbonyl-5-ethoxycarbonyloxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XXIV). This double acylation is conveniently carried out in pyridine solution (though other inert solvents may be used) containing DMAP as a catalyst. Heating the 5-ethoxycarbonyloxy compound results in elimination to produce l-ethoxycarbonyl-6-bromo-1,2,2a,3- tetrahydrobenz[c,d]indole (XXV). Epoxidation of the double bond using, conveniently, m-chlorbperbenzoic acid or other peracid, then rearrangement of the epoxide on heating with ZnI2 in benzene yields the 4-oxo derivative (XXVII). Reaductive amination with R5NH23, e.g. n-propyl amine, and NaCNBH3 yields (j)-l-ethoxycarbonyl-4-n- propylamio-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XXVIII). This secondary amine can then be acylated with (R7-CO)2O, e.g. propionic anhydride, and the N-propionyl group reduced with a reducing agent, such as BH3 in THF or NaCNBH3 in TFA to-yield the 4-di-n-propyl compound, (i )-l-ethoxycarbonyl-4-di-n- propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]- indole (XXS). Similarly, the secondary amine can be acylated with formic anhydride, acetic anhydride, or mixed anhydrides and then reduced to yield (XXX). Alternatively, the secondary amine (XXVIII) can be alkylated as with n-propyliodide in the presence of an organic base to yield formula XXX directly. Also, the secondary amine (XXVIII) can be reductively alkylated to yield formula XXX. Finally, hydrolysis of the Z2 -CO moiety, e.g. 1-ethoxycarbonyl amide, yields formula XXXI, oxidation of which with MnO2 or with NCS reagent yields a 2,2a-didehydro derivative (XXXII). Reaction of the thus-formed 6-bromo-4-di-alkyl derivative (XXXIIa) with cuprous cyanide or an alkali or alkaline earth cyanide and cuprous iodide in l-methyl2-pyrrolidone solution yields the 6-cyano-4-di-alkyl derivative (XXXIII), hydrolysis of which with a hydroxide base (KOH, NaOH) in a C1-C4 alkanol yields (i)-4-di- alkylamino-6-carboxamido-1,3,4,5-tetrahydrobenz[c,d]- indole (XXXIV). The 6-alkyloxy compounds can be prepared by reacting the 6-bromo compound (XXXIIa) with sodium methoxide, cuprous iodide and DMF to provide compounds of formula XXXV where X2is O(C1-C3 alkyl) and R14 and R are individually ethyl, n-propyl or allyl. The 6-benzyloxy derivatives are prepared in similar fashion. The 6-acyloxy derivatives are prepared analogously with, for example, cuprous acetate or sodium acetate and cuprous iodide. The 6-hydroxy derivatives are obtained by reacting X2 with a de-etherifying agent, for example by basic hydrolysis. Alternatively, the 5-keto compounds of formula XXI are reacted with Z2COC1, e.g EtO-CO-Cl, in pyridine to provide the correspondingly protected compound of formula XXIa. Subsequent reduction with, for example NaBH4, yields the 5-hydroxy derivative of formula XXIb. Bromination in TFA with a base wash provides the 6-bromo derivative of formula XXIc. Dehydration provides the compounds of formula XXV. Preparation of the compounds of formula IV wherein X is OH is also accomplished by acylating a compound of the formula EMI22.1 with C H CH2OCOCl to form the corresponding 4-secondary carbamate. After removing the l-protecting groups (by Zn and HOAc), the reaction scheme proceeds analogously as described for compounds of formula XXXIa to XXXV to XXXVI wherein the 4-position is NCO2 CH C H and the 1-position is hydrogen. The protecting group is then removed by catalytic hydrogenation to yield the compounds of formula IV where X is OH and R1 and R2 are both hydrogen. Subsequent alkylation as-previously described provides the compounds of formula IV where X is OH and RÚ and Rê are individually methyl, ethyl, n-propyl or allyl, or one of RÚ and Rê may be hydrogen. The above reaction sequence has been illustrated with respect to the preparation of a 4-di-npropyl derivative. It will be apparent to those skilled in the art that substitution of methyl, ethyl or allyl amine for n-propylamine in the preparation of XXVIII would yield a 4-methyl, ethyl or allyl amino group. Likewise the thus formed secondary amine could be acylated (XXVIII where the amine group could be methyl, ethyl, n-propyl or allyl) with formic, acetic, acrylic or propicnic acid and the N-acyl group reduced to an alkyl or allyl group to form a compound of the formula EMI23.1 wherein X3 is NO2, C1 or Br, and R5 and R6 are individually methyl, ethyl, n-propyl or allyl. It will be noted that the above procedure provides an easy route to unsymmetrically substituted C-4 tertiary amines. Alternatively, the secondary amine (XXVIII where the amine group could be methyl, ethyl, n-propyl or allyl) can be directly alkylated with CH3I, C2H5I, n-propyl iodide or allyl bromide to yield the same tertiary amine (XXXa). The 6-chloro derivatives can be prepared in a fashion similar to the preparation of the 6-bromo derivative but chlorine is more resistant to replacement with a cyano radical, and the chloro compound is thus not as useful as an intermediate. Compounds of formula IV wherein X is F, Cl1 or O(C1-C3 alkyl) can be prepared according to the following reaction scheme. Reaction Scheme 2 EMI25.1 Reaction Scheme 2 cont'd. EMI26.1 Reaction Scheme 2 cont'd. EMI27.1 In Reaction Scheme 2, 22 is defined as before; X1is F, C1 or O(C1-C3 alkyl); 4 is H, CH3 or C2H5; R1 and R are defined as before. According to Reaction Scheme 2, where X1 is methoxy, R4 is ethyl and R1 and R2 are n-propyl for the sake of convenience only, a benzyl 3-(5-methoxy-3indolyl)propionate or the like ester (V) is reduced with sodium cyanoborohydride to the corresponding 2,3-dihydro compound. With the saturation of the 2,3 double bond, the 1-amino group becomes sufficiently basic to enable it to be protected with a standard amine protecting group such as an acyl group; i.e., ZOC1 as a benzoyl derivative or ethoxy carbonyl. This protective group is formed by reacting the 2,3-dihydro compound with an acyl halide or anhydride; for example, benzoyl chloride in the presence of pyridine, to yield VI. The free acid (VII) is then prepared from the benzoyl ester (VI) by hydrogenation over a noble metal catalyst in an inert solvent. The noble metal catalyst of choice is palladiumon-carbon. The free acid thus produced -- 3-(5-methoxy l-benzoyl-2 , 3-dihydro-3-indolyl )propionic acid -- is cyclized with a dehydrating agent, preferably polyphosphoric acid (PPA). This reagent is a particularly convenient cyclizing agent since it can also serve as a solvent for the cyclization reaction. Alternatively, the acid chloride can be prepared and cyclized in the presence of a Lewis acid, preferably AlCl3 -- see Kornfeld et al., J.A.C.S., 78, 3087 (1956) -- to yield the desired benz[c,d]indole. The cyclized product -(VIII) is t-benzoyl-5-oxo-6-methoxy-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole. Reduction of the oxo group with sodium borohydride in a C1-C4 alkanol such as ethanol yields the corresponding 5-oxy derivative (IX). This 5-oxy derivative can be dehydrated by heating in the presence of an acidic catalyst (p-toluenesulfonic acid for example) in an inert solvent to yield l-benzoyl-6 methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole (X). Preferrably, however, an acidic ion exchange resin is used as the acid catalyst. The 4,5 double bond is then epoxidized with a reagent such as m-chloroperbenzoic acid in an inert solvent to yield a 4,5-epoxy derivative (XI). Rearrangement of the epoxide by heating in the presence of zinc iodide yields an isomeric ketone, (isomeric with VIII), l-benzoyl-4-oxo-6-methoxy 1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XII). Next, the hydroxylamine derivative of this isomeric ketone (XIII) is formed and the resulting oxime reduced with Raney nickel to yield a mixture of amino derivatives, trans-dl and cis-dl-l-benzoyl-4 amino-6-methoxy-l,2,2a,3,4,5-hexahydrobenz[c,d]indole (XIV and XIVa). When R1 and R2 are both H in the final product, no further alkylation reaction of (XIV) is required. When R1 and R2 are other than H, alkylation of the primary amine group by standard procedures, for example reductive alkylation with an aldehyde, R4CHO, and sodium cyanoborohydride in acetonitrile, to which an equivalent of glacial acetic acid has been added, yields the symmetrical di-alkylamine; (XV and XVa). Treatment of the mixture of these cis-dl and trans-dl tertiary amines with aqueous acid yields a mixture comprising trans-dl-4-dialkylamino-6-methoxy-l, 2, 2a, 3,4, 5-hexa- hydrobenz(c,d]indole and the corresponding cis-dl compound. Oxidation of this mixture with, for example, NCS reagent, yields (i)-4-dialkylamino-6-methoxy 1,3,4,5-tetrahydrobenz[c,d]indole (XVII and XVIIa represent the two enantiomers). The racemic mixture can readily be converted to the salt form (XVIII and XVIIIa) by standard procedures. The preferred procedure for preparing the final products of formula IV wherein X is F, C1 or O(C1-C3 alkyl) and R1 and R2 are both hydrogen consists of a modification of Reaction Scheme 2. A compound of formula XIV or XIVa is protected at the 4amino group by acylation (e.g. CC13CHCO moiety) to provide a secondary amine, followed by oxidation (as before described) to provide the indole ring The Z2 -CO group (e.g. benzyl) is then cleaved to form the corresponding l-unsubstituted compound. The 4-acyl protecting group is then removed by acidic cleavage, e.g. zinc in acetic acid, to provide the 4-amino final product. Obviously, the 4-amino product can then be alkylated by conventional methods to obtain the other products of formula IV where RÚ and Rê individually are methyl, ethyl, n-propyl or allyl or one of RÚ and Rê may be hydrogen. While the above procedure has been illustrated with reference to the preparation of a 6-methoxy derivative, the procedure is equally applicable to the preparation of other 6-(C1-C3 alkyl)oxy compounds or of 6-halo compound; i.e., 6-chloro, or 6-fluoro. The procedure represented in Reaction Scheme 1 is particularly useful for preparing compounds according to IV in which the 6-derivative (X group) is alkyloxy. When R1 and R2 are other than n-propyl, a different synthetic route is preferably employed which prepares the compounds of formula IV where X is C1, Br, CN, CONH2, NH2 O(C1-C3 alkyl), OH, O-acyl or O-benzyl and R and R individually are hydrogen, methyl, ethyl, or n-propyl. This alternate route also prepares compounds of formula IV where both R1 and R2 are n-propyl. This alternate route is shown in the following reaction scheme. Reaction Scheme 3 EMI31.1 Reaction Scheme 3 cont'd. EMI32.1 In Reaction Scheme 3, R is hydrogen, methyl, ethyl or n-propyl; R is methyl, ethyl or n-propyl; Y is hydrogen, methyl, ethyl, or chloromethyl (this latter group is hydrolyzed from LV-LVI); Im2CO is bis-imidazole carbonyl. Compound LIV when R8 is hydrogen is selectively hyarolyzed to remove the COY moiety (e.g. basic hydrolysis such as MeOH, KOH). The product has the C-4 group a primary amine. The primary amine is then reductively alkylated with an aldehide R10 CHO where R10 is H, methyl, ethyl or vinyl to yield compounds of formula IV where R1 and R2 are individually methyl, ethyl or n-propyl and X is C1, Br or CN. The CN groups (LVI) can then be hydrated with base, i.e. KOH in C1-C4 alkanol to yield the carboxamide (LVII). Reducing agents useful in converting LV to LVI are borane complex reagents such as BH3-(CH3)2S, BH3pyridine, BH3-N(CH3)2, BH3-THF, or B2 in an inert solvent, such as THF. In Reaction Scheme 3, the step from formula L to LI utilizes similar chemistry to that in Reaction Scheme I (XXVII to XXVIII), except that in Reaction Scheme 3 acetic acid and NH3 can be used to produce a 4-moiety of NH2. The 4-amino group is converted to the benzyloxycarbonyl derivative by conventional methods. The C13C-CH2-O-CO moiety is used as a l-position protecting group since it is readily removed by reductive cleavage with Zn and acetic acid, which reaction does not affect the C-4 carbamate function present (LII). The C-4 amine function (LI) is acylated with a formic, acetic or propionic acid using Im2CO, bisimidazolcarbonyl, to aid the acylation. Other condensing agents which can be employed include N,N'disubstituted carbodiimide, and bis-imidazolyl sulfone. The reductive cleavage of the N-l protecting group (LIt) does not affect the C-4 amide. Other N-l protecting groups which are subject to reductive cleavage can also be used. The oxidation step (LIII to LIV) is the same as Reaction Scheme I (XXXI to XXXII). Alternatively, the 6-CN derivative (LV) is hydrolyzed to the 4-NHR8-6-carboxylic acid derivative, then alkylated with R1 halide to yield the 4-R1R8 - 6-carboxylic acid derivative. The 6-carboxylic acid moiety is coupled with NH3 and a peptide coupling agent (e.g. Im2CO, DCC and others) to provide the compounds of formula IV where X is CONH2 and R1 and R2 are individually methyl, ethyl, n-propyl or allyl, provided that only one of RÚ and Rê is allyl. Similarly, the 6-CN-4-(-NR8COY) derivative (LV) is reduced to provide the 6-CN-4-(NR8R1) derivative, which then has the 6-CN hydrolyzed to 6-COOH. The reaction then proceeds as described in the previous paragraph to yield the same 6-CONH2 product of formula IV. Compounds according to IV above have a single asymmetric center at C-4 and occur commonly as a racemate However, compounds according to VIII through XVI and XVIa have an additional asymmetric center at C-2a, which center is removed by the oxidative procedures. Thus, compounds IX, XIV, XIVa, XV, XVa, XVI and XVIa each have two asymmetric centers (at C-2a and C-4) and exist as two racemic pairs conveniently designated as the trans-dl and the cis-dl racemates. Compounds of formula IV wherein X is NO2 or NH2 can be prepared according to the following reaction scheme. Reaction Scheme 4 EMI35.1 In Reaction Scheme 4, R1 and R2 are defined as before. In Reaction Scheme 4, for example, a l-benzoyl 4-dialkylamino-1,2,2a,3,4,5-hexahydrobenz[c,d]indole can be nitrated to yield, after removal of the benzoyl protecting group and oxidation of the indoline to a indole, compounds according to IV in which X is NO2. This 6-nitro derivative is a particularly useful intermediate in that the nitro group can be reduced to a 6-amino function and thus produces compounds according to IV above in which X is NH2 The 6-nitro compound can be prepared analogously by nitrating the 5-hydroxy derivative (XXII). However, the 4-oxo compound (XXI or 6-unsubstituted XXVII) can also be nitrated at C-6 if desired. This invention is further illustrated by the following specific examples of the preparation of starting materials, intermediates, and final products. In the examples and application some terms are defined as follows: HOAC = acetic acid brine = an aqueous, saturated NaCl solution DCC = dicyclohexylcarbodiimide DMAP = 4-(N,N-dimethylamino)pyridine DMF = dimethylformamide DMSO = dimethylsulfoxide EtOH = ethanol EtOAc = ethyl acetate ether = dimethyl ether HPLC = high performance liquid chromatography Im2CO = bis-imidazole carbonyl = l,l-carbonyl- diimidazole MeOH = methanol NCS = N-chlorosuccinimide NCS reagent = NCS, dimethylsulfide and triethylamine PPA = polyphosphoric acid TFA = trifluoroacetic acid THF s = tetrahydrofuran TLC = thin-layer chromatography. Ratios are by volume when the substance is a liquid and by weight when the substance is a solid. Temperatures are in C. Example A Preparation of (i)-4-Di-n-propylamino-6-bromo 1,2,2a,3,4,5-hexahydrobenz[c,d]indole A mixture containing 5.0 g. of 5-oxo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 100 ml. of ethanol was treated with 1.63 g. of sodium borohydride in portions. The resulting mixture was stirred for about four hours after which time the bulk of the ethanol was removed in vacuo. The resulting residue was taken up in water, and the aqueous mixture acidified with 3M hydrochloric acid. The aqueous solution was filtered, and the filtrate treated with dilute aqueous sodium hydroxide. (i)-5 Hydroxy-l,2,2a,3,4,5,-benz[c,d]indole formed in the above reaction was insoluble in the basic medium and precipitated. The precipitate was collected, washed with water and then dried. Four and seventy-two hundredths grams of (i)-5-hydroxy-1,2,2a,3,4,5-hexahydro- benz[c,d]indole (93% yield) were obtained. The material was one spot by TLC; m.p. = 2050C. Analysis Calculated: C, 75.83; H, 6.94; N, 8.04 Found: C, 75.75; H, 7.16; N, 7.89 A solution of 35 g. of (i)-5-hydroxy-1,2,2a,- 3,4,5-hexahydrobenztc,dlindole in 900 ml. of cold glacial acetic acid was treated with 22 g. of bromine dissolved in 100 ml. of glacial acetic acid. After the bromine color had been discharged, the acetic acid was removed in vacuo. The residue, comprising a mixture of (i)-5-hydroxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]- indole and the corresponding 6,8-dibromo derivative was diluted with water and the aqueous mixture made basic with 5M aqueous sodium hydroxide. The hexahydrobenz [c,djindoles, being insoluble in base, precipitated, and the precipitate was collected. Recrystallization of the precipitate from methanol yielded about 3 g. of the dibromo derivative plus about 12.5 g. of the monobromo derivative and a considerable quantity of a crystal fraction which was a 1:1 mixture of starting material and monobromo derivative. (i ) -5-Hydroxy-6-bromo-l, 2, - 2a,3,4,5-hexahydrobenz[c,d3indole thus formed melted at about 1720C. with decomposition. Twenty-four and one tenth grams (47% yield) of the 6-bromo derivative were obtained by recrystallization of various fractions. The product as obtained still contained a small amount of the dibromo impurity. A reaction mixture was prepared by dissolving 27.43 g. of (i)-5-hydroxy-6-bromo-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole in 100 ml. of pyridine and then adding in dropwise fashion 25 ml. of ethyl chloroformate over a 20 minute period. About 0.5 g. of 4-(N,N dimethylamino)pyridine (DMAP) were added, and the resulting reaction mixture stirred at room temperature for about four hours The reaction mixture was then quenched by pouring into 1 liter of an ice-water mixture. cAn oil which separated crystallized almost immediately. The crystals were collected and washed thoroughly with water. The dried ester amide was a faintly pink solid melting above 215 C. with decomposition; yield = 40.48 g. (94%). Analysis indicated that some 6,8-dibromo compound continued as a contaminate. Forty and one tenth grams of (i)-1-ethoxy- carbonyl-5-ethoxycarbonyloxy-6-bromo-l, 2, 2a, 3,4, 5-hexa- hydrobenzfc,d]indole were pyrolized in four different ten gram runs at 215-2200C. under a nitrogen atmosphere. Each run required 25-30 minutes of heating. The four dark oily residues were combined, and the combined residues taken up in toluene. The toluene solution was chromatographed over silica. One and four tenths grams of starting material were recovered from fractions containing it but the main product--l-ethoxycarbonyl 6-bromo-1,2,2a,3-tetrahydrobenz[c,d]indole--was recrystallized from a hexane/toluene solvent mixture containing predominantly hexane to yield 19.36 g including a second crop, from hexane alone. Yield = 65% corrected for recovered starting material. The compound melted at 122-1230C. Analysis Calculated: C, 54.56; H, 4.58; N, 4.55; Br, 25.93 Found: C, 54.59; H, 4.61; N, 4.41; Br, 25.84 The unsaturated product from the above step was oxidized as follows: A solution of 7.5 g. of l-ethoxycarbonyl-6 bromo-1,2,2a,3-tetrahydrobenzfc,d3indole in 250 ml. of chloroform was cooled to about OOC. with an ice/salt mixture. Six grams of 85% of m-chloroperbenzoic acid were added. The reaction mixture was stirred at about 0 C. for one hour and was then kept at refrigerator temperature overnight. The reaction mixture was washed successively with 1N aqueous sodium hydroxide, saturated aqueous sodium bisulfite, again with IN aqueous sodium hydroxide and finally with brine. The organic solution was dried, and the solvent removed in vacuo. The resulting solid residue was recrystallized from a toluene/hexane solvent mixture. The first crop material obtained weighed 7.33 g. and melted at 126-8 C.; total yield (2 crops) = 98%. Analysis Calculated: C, 51.87; H, 4.35; N, 4.32; Br, 24.65 Found: C, 51.83; H, 11.33; N, 4.16; Br, 24.31 A solution of 7.5 g. of l-ethoxycarbonyl-4,5 epoxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole obtained as above in 50 ml. of benzene was added slowly to a refluxing solution of 1 g. of zinc iodide in 450 ml. of benzene which had been dried by distilling off 50 ml. of the benzene-water azeotrope. Reflux under a nitrogen atmosphere was continued for one hour after the addition had been completed. The reaction mixture was cooled. The supernate was decanted, and the decanted solution washed with water and then with brine. The solution was dried and the solvent removed therefrom in vacuo. The residue, comprising l-ethoxycarbonyl-4 oxo-6-bromo-1,2,2a,3,4, 5-hexahydrobenz[c,d]indole formed in the above reaction, was crystallized from a toluene/hexane solvent mixture. Five and thirty-six hundredths grams (71% yield) of crystalline product melting at 186-80C. were obtained. Analysis Calculated: C, 51.87; H, 4.35; N, 4.32; Br, 24.65 Found: C, 51.75; H, 4.29; N, 4.50; Br, 24.80 A reaction mixture was prepared from 14 g. of l-ethoxyCarbonyl-4-oxo-6-bromo-1,2,2a,3,4,5-hexahydro- benz[c,d]indole, 28.3 g. of n-propylamine, 4.9 ml. of glacial acetic acid and 300 ml. of acetonitrile. The reaction mixture was stirred under a nitrogen atmosphere for about one hour. 3A molecular sieves were added to absorb water. Next, 5.6 g. of sodium cyanoborohydride were added followed by 14 ml. of glacial acetic acid. This new reaction mixture was stirred for an additional two hours at which time 7 ml. of glacial acetic acid were added. The reaction mixture was stirred for another two hours, and another 7 ml. of glacial acetic acid added. Finally, the supernate was decanted from the molecular sieves, and the bulk of the volatile constituents were removed in vacuo. The residual solution was poured into cold 2N aqueous sodium hdyroxide. The alkaline mixture was extracted with methylene dichloride. The methylene dichloride extract was washed with 0.5N aqueous sodium hydroxide and then with brine. The solvent was removed in vacuo. The resulting residue was dissolved in 1N aqueous hydrochloric acid to which methanol had been added. This acidic solution was washed with ether, and the ether wash discarded. The acidic solution was then made basic with 5N aqueous sodium hydroxide, and the now insoluble ( ethoxycarbonyl-4-n-propylamino-6-bromo-1,2,2a, 3,4,5-hexahydrobenz[c,d]indole formed in the above reaction separated and was extracted into methylene dichloride. The methylene dichloride extract was separated, and the solvent removed therefrom to yield 16.7 g. of an orange oil which was used in the next step without further purification. The above crude product was dissolved in 50 ml. of acetonitrile, 3 ml. of n-propyl iodide and 2 ml. of diisopropylethylamine. This solution was allowed to remain in the dark for about three weeks. At this point in time, the solvent was removed under reduced pressure, and the residual mixture partitioned between ether and 0.5N aqueous sodium hydroxide. The organic layer was separated, and the aqueous alkaline layer extracted several times more with ether. The ether extracts were combined and the combined extracts washed with brine and then dried. The ether was removed in vacuo to yield a residue. Xylene was added to the residue and removed by evaporation to remove any remaining diisopropylethylamine. The unpurified residue slowly crystallized. The crystals were dissolved in 20 ml. of methylene dichloride and 1 ml. of acetic anhydride Was added thereto. After about an hour, the volatile constituents were removed in vacuo and the resulting residue dissolved in methylene dichloride. The methylene dichloride solution was stirred with aqueous saturated sodium carbonate to remove any excess acetic anhydride. The methylene dichloride layer was separated, and the methylene dichloride removed by evaporation. The residue was dissolved in a mixture of dilute hydrochloric acid and methanol. The resulting cloudy solution was washed with ether and the ether was discarded. The acidic layer was then made basic with SN aqueous sodium hydroxide and the now insoluble base which separated was extracted into methylene dichloride. Evaporation of the solvent gave a moist crystalline residue. The residue was treated with hexane, and the hexane solution separated from hexane-insoluble brown oil by decantation. The hexane was evaporated in vacuo, and the residue chromatographed over 25 g. of silica gel using ethyl acetate as the eluant. Fractions containing the desired material were combined and the solvent removed therefrom in vacuo. The white/ crystalline residue was transferred to a filter paper using cold isooctane. A total yield of 2.39 g. of (i )-l-ethoxycarbonyl-4-di-n-propylamino-6-bromo- 1,2,2a,3,4,5-hexahydrobenz[c,d]indole was obtained in two crops. m.p. = 90-940C. Analysis Calculated: C, 58.68; H, 7.14; N, 6.84; Br, 19.52 Found: C, 58.98; H, 6.88; N, 6.59; Br, 18.74. Alternatively, a solution of 15.7 g. of the crude secondary amine. (f)-l-ethoxycarbonyl-4-n-propyl- amino-6-bromo-1,2,2a,3,4,5-hexahydrobenzfc,d]indole in 80 ml. of pyridine was cooled to about OOC. Sixteen ml. of propionic anhydride were added slowly. The solution was allowed to remain at ambient temperature overnight. The bulk of the pyridine solvent was removed under vacuum, and the residual solution was stirred with an excess of aqueous sodium carbonate for several hours to remove any unreacted proponic anhydride and any by-product propionic acid. The aqueous mixture was extracted with methylene dichloride, and the methylene dichloride extract separated and washed with 0.5M aqueous sodium hydroxide, IN hydrochloric acid and brine. The organic solution was dried and the solvent removed therefrom in vacuo leaving a viscous oil. The oil was dissolved in 50 ml. of ThF and this solution added over about a 15 minute period to 85 ml. of lM diborane in ThF kept at about 0 C. After the addition had been completed, the cooling bath was removed, and the reaction mixture heated to reflux temperature for about 1.5 hours. The reaction mixture was then cooled to about 0 C. and 50 ml. of methanol were added cautiously. The resulting reaction was stirred overnight at room temperature. The methanol was removed in vacuo. Additional methanol was added and again removed by evaporation. The resulting residue began to solidify. The semisolid residue was partitioned between dimethyl ether and 1M hydrochloric acid containing added methanol. The solid which precipitated as a result of these operations was collected by filtration. The filtrate was made basic by the addition of aqueous sodium hydroxide, and the alkaline mixture extracted with methylene dichloride. The above ether layer, the methylene chloride extract and the separated solid were combined and the solvent evaporated. The residue was heated with wet DMSO, and this solution was then diluted with water plus sufficient 1M aqueous sodium hydroxide to maintain basic conditions. The alkaline mixture was extracted with ether. The ether extract was in turn extracted with 1M hydrochloric acid containing some methanol. The acidic extract was again made basic, and the resulting alkaline mixture extracted with methylene dichloride. The methylene dichloride extracts were combined. Upon evaporation of the solvent, fifteen and fifty-nine hundredths grams of crude salmon colored compound were obtained. The solid was dissolved in ethyl acetate and chromatographed over silica gel. Fractions containing the desired material were combined and the solvent removed therefrom in vacuo. Recrystallization of the resulting solid from isooctane gave (i)-1-ethoxycarbonyl- 4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz- [c,d]indole melting 87-90C.; yield = 14.8 g. (94%). A solution of 1 g. of the above tertiary amine in 10 ml. of 6N hydrochloric acid was heated to reflux temperature under nitrogen overnight. TLC indicated that only a trace of starting material re mained and that the chief product was (i)-4-di-n-propyl amine-6-br,omo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole. The acidic solution was poured into dilute aqueous sodium hydroxide, and the resulting alkaline layer extracted with methylene dichloride. The methylene dichloride extract was separated and the separated extract washed with brine and then dried. Evaporation of the solvent yielded a viscous oil which crystallized upon cooling. Recrystallization of the precipitate from isooctane gave 0.683 g. (83% yield) of (i)-4-di-n propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]- indole melting at about 62-30C. Analysis Calculated: C, 60.53; H, 7.47; N, 8.31; Br, 23.69 Found: C, 60.71; H, 7.57; N, 8.30; Br, 23.78 A run on a larger scale (14.8 g. of starting material) gave an 88% yield of the desired hydrolysis product - Example B Preparation of (i ) -4-Di-n-propylamino-6- nitro-1,2,2a,3,4,5-hexahydrobenz[c,d]indole One-half gram of (i) -l-benzoyl-4-di-n-propyl- amino-1,2,2a,3;4,5-hexahydrobenz[c,d]indole from United States Patent 4,110,339, column 3, line 49, in 5 ml. of 18M sulfuric acid was prepared in the cold and the resulting solution kept at ice bath temperature. Seven hundredths ml. of 90% nitric acid were added thereto in dropwise fashion via a pipette. The solution was stirred in the cold for about one hour and then poured over ice. The acidic mixture was neutralized by the careful addition of solid sodium carbonate. (t Benzoyl-4-di-n-propylamino-6-nitro-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole formed in the above reaction, being insoluble in the alkaline layer, separated and was extracted into methylene dichloride. The methylene dichloride layer was separated, washed with water and then dried. The solvent was removed in vacuo, and the crude residue chromatographed over Florisil using toluene containing increasing amounts (2-5%) of ethyl acetate as the eluant. Fractions shown by TLC to contain the desired material were combined and the solvent evaporated therefrom to yield a viscous red oil weighing 0.35 g. (61% yield). The red oil was used without further purification since the nmr was in agreement with the proposed structure. The above material was dissolved in 7 ml. of 6N hyrochloric acid, and the resulting solution heated to reflux temperature under a nitrogen atmosphere for about two hours. At this point, TLC indicated no more starting material remained. The reaction was quenched with cold SN aqueous sodium hydroxide. The free base was extracted with methylene dichloride. The methylene dichloride extract was washed with brine and then dried. TLC indicated only one mobile spot. The solvent was removed, and the residue chromatographed over Florisil using ethyl acetate as the eluant. Fractions containing the desired product were collected, the solvent removed therefrom and the residue recrystallized from isooctane. ( 4-Di-n-propylamino-6-nitro-1,2,2a,3,4,5-hexahydro- benz[c,d]-indole thus prepared melted at 97-1000C,; weight = 0.194 g. (69% yield). Analysis Calculated: C, 67.30; H, 8.31; N, 13.85 Found: C, 67.47; H, 8.21; N, 13.71 Example C Preparation of (f)-l-Benzoyl-4-di-n-propyl- amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole A solution was prepared by dissolving 26 g. of benzyl 2-(5-methoxy-3-indolyl)propionate in 500 ml. of glacial acetic acid. The solution was cooled and stirred. Twenty-six grams of sodium cyanoborohydride were added. The resulting reaction mixture was stirred at ambient temperature for about 3.5 hours at which time TLC showed no peak corresponding to starting material, indicating the reaction had gone substantially to completion. The reaction mixture was then poured into 2 1. of water and the aqueous mixture extracted with several portions of methylene dichloride. The methylene dichloride extracts were combined, the combined extracts washed with dilute aqueous sodium bicarbonate and then dried. Removal of the solvent in vacuo yielded 25.5 g. of a viscous oil comprising benzyl 2-(5-methoxy-3indolinyl)propionate formed in the above reaction. The oil was dissolved in chloroform and 8 ml. of pyridine were added to the chloroform solution. Next, 13.9 g. of benzoylchloride were added while the solution was being cooled in an ice-water bath. After the addition had been completed, the acylation mixture was stirred for about one hour and was then washed once with water, twice with 1N aqueous hydrochloric acid, twice with dilute aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride. The aqueous washes were all discarded. The organic layer was dried and the solvent removed in vacuo. The resulting residue was dissolved in ethyl acetate and the ethyl acetate solution passed over a short Florisil column. Ethyl acetate was removed from the eluate. Benzyl 2-(1- benzoyl-5-methoxy-3-indolinyl)propionate thus prepared crystallized on standing overnight. The crystals were washed with cyclohexane. Recrystallization from a toluene-hexane solvent mixture yielded 30.2 g. of benzyl 2-(1-benzoyl-5-methoxy-3-indolinyl )propionate melting at about 102-30C. The compound had the following physical properties: Ultraviolet spectrum; Amax (MeOH) 274 nm (g = 11,900); NMR (CDCl3) 6 = 2.0 (mult, 2H, a-CH2), 2.4 (mult, 2H, p-CH2), 3.3 (mult, 1H, 3-H), 3.7 (mult, 1H, 2B-H), 3.8 (s, 3H, OCH3), 4.2 (qt, 1H, 2a-H), 5.1 (s, 2H, PhCH2), 6.7 (mult, 1H, 7-H), 6.9 (brs, 1H, 4-H), 7.3 (mult, 1H, 8-H), 7.4 (s, 5H, Ph), 7.5 (s, 5H, Ph-CO). Analysis Calculated: C, 75.16; H, 6.07; N, 3.37 Found: C, 74.96; H, 5.88; N, 3.19 Thirty grams of benzyl 2-(1-benzoyl-5-methoxy 3-indolinyl)propionate were hydrogenated over palladiumon-carbon in ethanol to remove the -benzyl ester group. 2- (l-Benzoyl-5-methoxy-3-indolinyl )propionic acid thus formed crystallized on cooling in the hydrogenation bomb and separated with the catalyst on filtration. The desired product was dissolved away from the catalyst by washing with hot ethanol. Ethanol was removed from the combined filtrate and washings by evaporation. The resulting residue was dissolved in tetrahydrofuran (THF). The THF solution was filtered and the THF removed from the filtrate in vacuo. The resulting residue was crystallized from about 500 ml. of ethanol; yield = 21.2 g. of 2-(1 benzoyl-5-methoxy-3-indolinyl)propionic acid melting at 169-700C. Ultraviolet spectrum: Amax (MeOH) 274 nm (± = 12,200) Analysis Calculated: C, 70.14; H, 5.89; N, 4.31 Found: C, 70.42; H, 5.99; N, 4.62 A repeat hydrogenation on 17 g. of ester starting material in 125 ml. of THF and 125 ml. of ethanol using 0.5 g. of 10% Pd/C and a hydrogen pressure of 2.74 x 10 dynes/cmê gave a 94% yield of the desired acid. Five grams of 2-(l-benzoyl-5-methoxy-3indolinyl)propionic acid were cyclized in 100 g. of polyphosphoric acid (PPA) at 800C. TLC after one hour of reaction time indicated little or no starting material present. The reaction mixture was therefore poured over ice. The resulting aqueous mixture was extracted several times with methylene dichloride. The methylene dichloride extracts were combined and the combined extracts washed with sodium bicarbonate until the washings remained basic to litmus. The extracts were then concentrated in vacuo and the resulting residue recrystallized from a toluene/hexane solvent mixture to yield crystalline l-benzoyl-5-oxo-6-methoxy 1,2,2a,3,4,5-hexahydrobenz[c,d]indole formed in the above cyclization. Recrystallization yielded about 4.5 g. of compound melting at about 147.5-1490C. The compound had the following physical characteristics: Infrared spectrum (KBr): 1634, 1672 cm NMR (DMSO-d6) 6 = 1.81 (quintet, lH, 3B-H), 2.18 (brd, lH, 3a-H), 2.53 (mult, 2H, 4-CH2), 3.33 (mult, 1H, 2a-H), 3.61 (mult, 1H, 2a-H), 3.80 (s, 3H, OCH3), 4.14 (mult, 1H, 2a-H), 6.97 (mult, 1H, 7-H), 7.59 (mult, 5H, Ph), 8.11 (mult, 1H, 8-H). Analysis Calculated: C, 74.25; H, 5.58; N, 4.56 Found: C, 73.99; H, 5,84; N, 4.37 A second large-scale run using 18.95 g. of free acid starting material gave a crude product which, when combined with the product from the first reaction, yielded, after recrystallization, 29.9 g. (84% yield) of cyclized product melting at about 152-30C. A suspension of 4.2 g. of 1-benzoyl-5-oxo-6 methoxy-1,A,2a,3,4,5-hexahydrobenz[c,d]indole in 50 ml. of ethanol was prepared. A solution of 0.77 g. of sodium borohydride in 25 ml. of ethanol was added thereto in dropwise fashion with stirring. The suspended ketone slowly dissolved to produce a greenish solution After about four hours of stirring at room temperature, the now homogeneous reaction mixture was concentrated in vacuo. Fifty ml. of water were added to the residue and the resulting basic aqueous solution neutralized with 3N aqueous hydrochloric acid to pH = 7. This neutral aqueous layer was extracted several times with methylene dichloride. The methylene dichloride extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Removal of the solvent by evaporation left a viscous oil. Chromatography of this oil over silica gel using ethyl acetate as the eluant yielded 3.83 g. (90% yield) of (i)-l-benzoyl-5-hydroxy-6-methoxy-l,2,2a,3,4,.5- hexahydrobenz[c,d]indole. Recyrstallization from ethyl acetate of a 100 mg. sample of the crystalline product gave 68 mg. of the mixture of epimeric alcohols. Infrared spectrum (CHCl3): 1632 cm Ultraviolet spectrum: Amax (MeOH) 273 nm (s = 7900), 302 nm (sh) (s = 6000) Analysis Calculated: C, 73.77; H, 6.19; N, 4.53 Found: C, 73.71; H, 6.03; N, 4.43 A reaction mixture was prepared'from 3.7 g. of (i)-l-benzoyl-5-hydroxy-6-methoxy-l,2,2a,3,4,5-hexa- hydrobenz[c,d]indole, 1 g. of a macroreticular dehydration catalyst (AMBERLYST-15 resin) and 50 ml. of toluene. The reaction mixture was heated to reflux for about one hour in an apparatus equipped with a Dean Stark trap. The amount of water collected in the trap plus TLC on the reaction mixture indicated that dehydration was complete at this time. (i)-1-Benzoyl-6-methoxy- l,2,2a,3-tetrahydrobenz [c, djindole was formed in the above dehydration. The reaction mixture was filtered through filter cell. Evaporation of the filtrate to dryness yielded a viscous oil, which crystallized on trituation with hexane to give 3.34 g. of (i)-1-benzoyl- 6-methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole (96% yield). Recrystallization of a 100 mg. sample from a toluene/hexane solvent mixture yielded 85 mg. of compound melting at about 125.5-1270C. Ultraviolet spectrum: Xmax (MeOH) 271 nm (± = 13,300), 320 nm (sh) (E = 3500). Analysis Calculated: C, 78.33; H, 5.88; N, 4.81 Found: C, 78.09; H, 5.68; N, 4.65 A solution of 3.2 g. of (i)-1-benzoyl-6- methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole in 120 ml. of chloroform was cooled to about 0 C. with stirring. Three and sixty-one hundredths grams of 80-85% m-chloroperbenzoic acid were added thereto. The resulting solution was stirred in the 0-50C. range for about five hours after which time TLC showed no remaining starting material. The reaction mixture was then washed twice with cold lN aqueous sodium hydroxide, twice with dilute aqueous sodium bisulfite and again with 1N aqueous sodium hydroxide. The washings were discarded. The remaining organic layer was then dried and the solvent removed in vacuo. The residual oil crystallized to yield l-benzoyl-4,5-epoxy-6-methoxy-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole. The compound melted at l74-1750C. after recrystallization from toluene. Ultraviolet spectrum: Amax (MeOH) 273 nm ( & = 10,700), 300 nm (sh) (± = 7700). Analysis Calculated: C, 74.25; H, 5.58; N, 4.51 Found: C, 73.98; H, 5.70; N, 4.37 A solution of the epoxidized product in benzene solution was, without further purification, added to a suspension of 1.8 g. of zinc iodide in 150 ml. of benzene. (The suspension was dried by distillation of about 30 ml. of benzene containing some benzene-water azeotrope.) The addition was made in dropwise fashion over a ten minute period at a temperature of about 500C. The reaction mixture was heated to refluxing temperature for about 50 minutes and was then cooled. The cooled reaction mixture was washed with dilute aqueous hydrochloric acid in order to decompose any reaction complex present. The organic solution was next washed with saturated aqueous sodium bicarbonate. The solvent was removed from the organic layer in vacuo and the resulting residue was recrystallized fromoethyl acetate. (+)-l-Benzoyl-4-oxo-6- methoxy-l,2,2a,3, -4,5-hexahydrobenz [c, d]indole thus prepared melted at about 188-1890C. after two recrystallizations (yield = 72%). The compound had the following physical characteristics: Infrared spectrum (CHCl3): 1636, 1717 cm 1; NMR (CDC13): 6 = 2.34 (qt, 1H, 3B-H), 2.90 (brd, 1H, 3a-H), 3.31 (d, 1H, 5B-H), 3.66 (d, 1H, 5a-H), 3.8 (mult, 2H, 2a-H and 2ss-H), 3.80 (s, 3H, OCH3), 4.33 (mult, 1H, 2a-H), 6.75 (mult, 1H, 7-H), 7.54 (mult, 5H, Ph), 7.96 (mult, 1H, 8-H). Analysis Calculated: C, 74.23; H, 5.58; N, 4.56 Found: C, 74.24; H, 5.37; N, 4.50 A reaction mixture was prepared from 207 mg. of (i)-l-benzoyl-4-oxo-6-methoxy-1,2,2,3,4,5-hexa- hydrobenz-[c,d]indole and 200 mg. of hydroxylamine hydrochloride in 5 ml. of ethanol plus 1 ml. of pyridine. The reaction mixture was heated to reflux temperature for about 15 minutes and then was cooled. An equal volume of water was added. At this point, the oxime formed in the above reaction began to crystallize. Crystallization was allowed to proceed to completion. The reaction mixture was filtered. Additional water added to the filtrate produced a second crop of crystals; total yield = 0.21 g. (98% total yield). The crystalline product, a mixture of syn and anti-(i)-1-benzoyl-4- oximino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole formed in the above reaction, melted at about 189-1900C. Recrystallization yielded material melting at about l930C. Mass spectrum: 322 (mass peak). Analysis Calculated: C, 70.79; H, 5.63; N, 8.69 Found: C, 70.86; N, 5.47; N, 8.46 A mixture of syn and anti-oximes (2.46 g.) was hydrogenated over Raney nickel in ethanolic ammmonia at about 1000C. for about 10 hours. The hydrogenation solution was filtered to remove the catalyst. The filtrate was evaporated to dryness leaving a viscous oil comprising (t benzoyl-4-amino-6-methoxy-1,2,2a, (i)-l-benzoyl-4-amino-6-methoxy-l,2 ,2a, 3,4,5-hexahydrobenz[c,d]indole formed in the above hydrogenation. The product was a mixture of two racemates named as the cis-(i) and trans-(i)-racemate for convenience. (Optical centers are at C-2a and C-4.) The viscous oil was dissolved in 25 ml. of lN aqueous hydrochloric acid and the acidic solution washed several times with methylene dichloride. These washings were discarded. The aqueous solution was then made basic (pH = about 12) with aqueous sodium hydroxide and then extracted with chloroform. The chloroform layer was filtered to remove an insoluble material. The chloroform was removed from the filtrate in vacuo. Recrystal lization of the resulting residue from a mixture of toluene and hexane yielded 1.48 g. of crystals melting at 140-1440C. An additional 0.63 g. of a pale yellow glass was obtained from the filtrate; total yield = 2.11 g. (90%). It was determined that the crystaline material was one @acemic mixture in which the minime group and the ring junction hydrogen were on Opposite sides of the hexahydrobenz[c,d]indole ring system, designated as.the trans-(i) racemate, and the yellow oil respresented a raceKic mixture in which the amine group and the 2a-hydrogen were on the same side of the benz[c,d]indole ring system, designated as the cisracemate. The trans-(+)-racemate, trans-(#)-1-benzoyl- 4-amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole, had the following elemental analysis: Analysis Calculated: C, 74.00; H, 6.54; N, 9.08 Found: C, 74.21; H, 6.57; N, 8.81 Ultraviolet spectrum: Amax (MeOH) 275 nm (± = 11,500), 300 nm (sh) (#= 9000); Mass spectrum: 308 (mass peak) A reaction mixture was prepared from 0.55 g. of the cis-racemate, 0.75 ml. of propionaldehyde and 5 ml. of acetonitrile. Eighteen hundredths grams of sodium cyanoborohydride were added thereto. The pH of the reaction mixture was adjusted to about 7 with a few drops of glacial acetic acid, at which point a vigorous reaction ensued. The reaction mixture was stirred under a nitrogen atmosphere for about three hours with the occasional addition of a drop of glacial acetic acid. At this point in time, TLC indicated there was no longer any peak corresponding to starting material and only one major spot. The solvent was removed from the reaction mixture and the residue treated with 5N aqueous sodium hydroxide. The alkaline layer was extracted with methylene dichloride. The methylene .dichloride extracts were combined and the combined extracts dried. Removal of the solvent left a viscous pale yellow oil as a residue. Chromatography of this residual oil over silica gel in an HPLC preparative column using a 1:1 ethyl acetate/toluene solvent mixture as the eluant produced fractions containing cis-(#)-1-benzoyl-4-di- n-propylamino-6-methoxy-l, 2, 2a, 3,4, 5-hexahydrobenz- [c,d]indole relatively free of contaminating materials according to TLC. Elemental analysis indicated, however, that the product was slightly impure (weight = 0.56 g.). In a later run at twice the scale, the free base obtained in ether solution, as above, was converted to the hydrochloride salt using a slight excess of 2.4 M ethereal HC1; yield = 63%. The hydrochloride salt had the following elemental analysis. Analysis Calculated: C, 69.99; H, 7.75; N, 6.53; C1, 8.26 Found: C, 69.92; H, 7.67; N, 6.47; C1, 8.03 Ultraviolet spectrum: hmax (MeOH) 274 nm (± = 10,500), 300 nm (sh) (± = 7200); Mass spectrum: 392 (mass peak) Example D Preparation of cis-(i )-1-Benzoyl-4-dimethyl- amino-6-methoxy-1, 2, 2a, 3 ,, 5-hexahydrobenz [c, d] indole Following the procedure of Example C, 2.41 g. of cis-(#)-1-benzoyl-4-amino-6-methoxy-1,2,2a,3,4,5 hexahydrobenz[c,d]indole in 25 ml. of acetonitrile was reacted with 5.2 ml. of 37% formalin and 0.78 g. of NaBH3CN at pH = 7. The reaction mixture was poured into 2N aqueous sodium hydroxide and the alkaline mixture extracted with ether. The ethereal extract was in turn extracted with 1N aqueous hydrochloric acid. The acidic solution was then made basic with 2N aqueous sodium hydroxide and l-benzoyl-6-methoxy-4-dimethylaminohexahydrobenz[c,d]indole formed in the above reaction, being insoluble in alkali, separated and was extracted into methylene dichloride. Removal of the methylene dichloride yielded a residue which was purified by chromatography over silica gel using ethyl acetate as the eluant. Fractions containing the desired amine base were combined. An excess of 3.2 M ethereal hydrogen chloride was added to the combined fractions and the solvent removed by evaporation to leave 1.99 g. of cis-(i)-l-benzoyl-4-dimethylamino-6-methoxy-1,2,2a, 3,4,5-hexahydrobenz[c,d]indole hydrochloride. The salt had the following physical characteristics: Ultraviolet spectrum: h (EtOH) 274 nm (± = 12,200), 300 nm (sh) ( & = 9300); Mass spectrum: 335 (M-1 peak). Analysis Calculated: C, 67.64; H, 6.76; N, 7.51 Found: C, 67.77; H, 6.87; N, 7.5 Example E Preparation of trans- (i ) -l-Benzoyl-4-di-n- propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenzfc,d]- indole The procedure of Example C was repeated with the crystalline fraction comprising trans-(i)-l-benzoyl- 4-amino-6-methoxy 1,2,2a,3,4,5-hexahydrobenz[c,d3indole. One and sixty-three hundredths grams of this racemate were dissolved in 12.5 ml. of acetonitrile and 1.85 ml. of propionaldehyde were added. Forty-five hundredths grams of sodium cyanoborohydride were then added followed by the dropwise addition of sufficient acetic acid to bring the pH to about 7. The reaction mixture was stirred for about three hours while occasionally adding a drop of glacial acetic acid. At the end of this time, TLC indicated absence of starting material. The reaction mixture was therefore poured into 2N aqueous sodium hydroxide solution and the alkaline mixture extracted with ether. The ether extracts were combined and the combined extracts washed with water. The ether solution was then contacted with IN aqueous hydrochloric acid thereby extracting trans-(i)-l- benzoyl-4-(di-n-propyl)amino-6-methoxy-L,2,2a,3,4,5- hexahydrobenz[c,dindole formed in the above reaction. The acidic aqueous layer was extracted with ether and the ether extract discarded. The acidic aqueous layer was then made basic with sodium hydroxide and the free base extracted into methylene dichloride. Methylene chloride was removed by evaporation and the free base remaining was dissolved in dilute aqueous hydrochloric acid containing some methanol. The procedure of taking the free base into acidic solution, extracting the acidic solution with ether, making the acidic solution alkaline and reextracting the free base into methylene dichloride was repeated. Evaporation of ethylene dichloride from the final base extract yielded a viscous oil weighing 1.07 g. (63% yield). TLC indicated essentially single spot material. The compound was converted to the hydrochloride salt by standard procedures. Trans-(i)-l-benzoyl-4-di-n-propylamino-6- methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole hydrochloride thus prepared had the following analysis. Analysis Calculated: C, 69.99; H, 7.75; N, 6.53; C1, 8.26 Found: C, 69.92; H, 7.52; N, 6.26; C1, 8.02 Ultraviolet spectrum: Amax (MeOH) 274 nm (± = 10,800), 300 nm (sh) (± = 8400); Mass spectrum: 392 (mass peak) Trans-(i)-l-benzoyl-4-dimethylamino-1,2,2a,3,- 4,5-hexahydrobenz[c,d]indole can be prepared in similar fashion by reductive alkylation of the 6-amino derivative with HCHO and NaBH3CN. Example F Preparation of cis- (i ) -4-Di-n-propylamino-6- methoxy-1,2,2a,3,4,5-hexahydrobenz[c,dlindole Cis- (i ) -1-benzoyl-4-di-n-propylamino-6- methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (0.507 g.) and 5 ml. of 6N aqueous hydrochloric acid were refluxed under a nitrogen atmosphere for three hours. TLC at the end of this time indicated that hydrolysis of the benzamide group was complete. The aqueous solution was therefore diluted with water. Benzoic acid formed in the hydrolysis crystallized on cooling and was separated by filtration. The acidic aqueous layer was extracted twice with equal volumes of ether to remove the last traces of benzoic acid. The ether extracts were discarded. The acidic aqueous layer was then made basic by addition of 5N aqueous sodium hydroxide. The alkaline layer was extracted several times with methylene dichloride. The methylene dichloride extracts were combined and dried. Evaporation of the methylene dichloride yielded an oil that was purified by passage over a short silica gel column using ethyl acetate as the eluant. The purified product was crystallized from isooctane. Cis- (i ) -4-di-n-propylamino-6-methoxy- 1,2,2a,3,4,5-hexahydrobenz[c,dlindole thus prepared melted at 75-780Cl The compound had the following physical characteristics. Ultraviolet spectrum: #max (EtOH) 237 nm (E = 7400), 299 nm (± = 3000); NMR (CDCl3) 6 = 0.87 (t, 6H; C-CH3), 1.45 (mult, 5H, CH2Me and 3ss-H), 2.20 (sextet, 1H, 3&alpha;-H), 2.49 (mult, 5H, CH2Et and 5ss-H), 2.91 (qt, 1H, 5a-H), 3.12 (mult, 2H, 2B-H and 4-H), 3.26 (mult, 1H, 2a-H), 3.64 (t, 1H, 2a-H), 3.77 (s, 3H, OCH3), 6.48 (qt, 2H, 7-H and 8-H). Analysis Calculated: C, 74.96; H, 9.79; N, 9.71 Found: C, 75.24; H, 9.55; N, 9.60 Example G Preparation of cis-(#)-4-Dimethylamino-6- methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole Following the procedure of Example F, 1.90 g. of cis-(#)-1-benzoyl-4-Dimethylamino-6-methoxy- 1,2,2a,3,4,5-hexahydrobenz[c,d]indole was debenzoylated by treatment of the hydrochloride salt with acid (20 ml. of 3 M aqueous sulfuric acid). After cooling, the reaction mixture was extracted twice with ether to remove benzoic acid formed as a by-product in the above reaction. The reaction mixture was then made basic with 5 M aqueous sodium hydroxide. Cis-(i)-4-dimethylamino6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole formed in the above reaction separated and was extracted into methylene dichloride. Removal of the solvent from the extract left a dark oil which was purified by chromatography over silica gel using 1:19 methanbl-ethyl acetate solvent mixture as the eluant. Removal of the solvent from fractions containing the desired compound yielded 1.D6 g. of cis- (i) -4-dimethylamino-6-methoxy- 1,2,2a,3,4,5-hexahydrobenzEc,d]indole having the following elemental analysis. Analysis Calculated: C, 72.38; H, 8.68; N, 12.06 Found: C, 72.18; H, 8.72; N, 11.83 The compound had the following physical characteristics: Infrared spectrum: Xmax (EtOH) 239 nm (# = 7400), 300 nm (g = 3100); Mass spectrum: 232 (mass peak) Example H Preparation 6 f trans- of trans-(i)-4-Di-n-propylamino- 6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole Trans-(#)-1-benzoyl-4-(di-n-propyl)amino-6- methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole was hydrolyzed by the procedure of Example F to yield (79%) trans-(i)-4-(di-n-propyl)amino-6-methoxy-1,2,2a,3,4,5- hexahydrobenz[c,d]indole melting at 71-30C. after recrystallization from isooctane. The compound had the following physical characteristics: Infrared spectrum: #max (EtOH) 239 nm (E = 7100), 299 nm =3100); NMR (CDCl3) 6 = 0.89 (t, 6H, C-CH3), 1.41 {quintet, 1H, 3ss-H), 1.49(sextet, 4H, CH2Me), .2.16(brd, 1H, 3&alpha;-H), 2.47 (mult, 5H, CH2Et and 5p-H), 2.83 (qt, 1H, 5a-H), 3.14 (mult, 3H, 2a-H and 2ss-H) and 4-H), 3*48 (brs, 1H, N-H), 3.62 (t, 1H, 2&alpha;-H), 3.77 (s, 3H, OCH3), 6.46 {g't, 2H, 7-H and 8-H). Analysis Calculated: C, 74.96; H, 9.79; N, 9.71 Found: C, 74.72; H, 9.57; N, 9.54 Example I Preparation of (#)-4-Di-n-propylamino-6- bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole A mixture containing 5.0 g. of 5-oxo 1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 100 ml. of ethanol-was treated with 1.63 g. of sodium borohydride in portions. The resulting mixture was stirred for about four hours after which time the bulk of the ethanol was removed in vacuo. The resulting residue was taken up in water, and the aqueous mixture acidified with 3M hydrochloric acid. The aqueous solution was filtered, and the filtrate treated with dilute aqueous sodium hydroxide. (i)-5-Hydroxy-1,2,2a,3,4,5,-benz- [c,d]indole formed in the above reaction was insoluble in the basic medium and precipitated. The precipitate was collected, washed with water and then dried. Four and seventy-two hundredths grams of (i)-5-hydroxy 1,2,2a,3,4,5-hexahydrobenz[c,d]indole (93% yield) were obtained. The material was one spot by TLC; m.p. = 2050C. Analysis Calculated: C, 75.83; H, 6.94; N, 8.04 Found: C, 75.75; H, 7.16; N, 7.89 A solution of 35 g. of (i)-5-hydroxy-1,2,2a,- 3,4,5-hexahyrobenz[c,d]indole in 900 ml. of cold glacial acetic acid was treated with 22 g. of bromine dissolved in 100 ml. of glacial acetic acid. After the bromine color had been discharged, the acetic acid was removed in vacuo. The residue, comprising a mixture of (#)-5-hydroxy-6-bromo--1,2,2a,3,4,5-hexahydrobenz[c,d]- indole and the corresponding 6,8-dibromo derivative was diluted with water and the aqueous mixture made basic with 5M aqueous sodium hydroxide. The hexahydrobenz tc,d]indoles, being insoluble in base, precipitated, and the precipitate was collected. Recrystallization of the precipitate from methanol yielded about 3 g. of the dibromo derivative plus about 12.5 g. of the monobromo derivative and a considerable quantity of a crystal fraction which was a 1:1 mixture of starting material and monobromo derivative. (i ) -5-Hydroxy-6-bromo-1 , 2, - 2a,3 ,4, 5-hexahydrobenz [c,d] indole thus formed melted at about 1720C. with decomposition. Twenty-four and one tenth grams (47% yield) of the 6-bromo derivative were obtained by recrystallization of various fractions. The product as obtained still contained a small amount of the dibromo impurity. A reaction mixture was prepared by dissolving from 27.43 g. of (i)-5-hydroxy-6-bromo-1,2,2a,3,4,5- hexahydrobenztc,d]indole in 100 ml. of pyridine and then adding in dropwise fashion 25 ml. of ethyl chloroformate over a 20 minute period. About 0.5 g. of dimethyl aminopyridine were added, and the resulting reaction mixture stirred at room temperature for about four hours. The reaction mixture was then quenched by pouring into 1 liter of an ice-water mixture. An oil which separated crystallized almost immediately. The crystals were collected and washed thoroughly with water. The dried ester amide was a faintly pink solid melting above 2150C. with decomposition; yield = 40.48 g. (94%). Analysis indicated that some 6,8dibromo compound continued as a contaminate. Forty and one tenth grams of (i)-l-ethoxy carbonyl-5-ethoxycarbonyloxy-6-bromo-l, 2, 2a, 3,4, 5-hexa- hydrobenz[c,d]indole were pyrolized in four different ten gram runs at 215-2200C. under a nitrogen atmosphere. Each run required 25-30 minutes of heating. The four dark oily residues were combined, and the combined residues taken up in toluene. The toluene solution was chromatographed over silica. One and four tenths grams of starting material were recovered from fractions containing it but the main product--1-ethoxycarbonyl 6-bromo-1,2,2a,3-tetrahydrobenz[c,d]indole--was recrystallized from a hexane/toluene solvent mixture containing predominantly hexane to yield 19.36 g including a second crop, from hexane alone. Yield = 65% corrected for recovered starting material. The compound melted at 122-1230C. Analysis Calculated: C, 54.56; H, 4.58; N, 4.55; Br, 25.93 Found: C, 54.59; H, 4.61; N, 4.41; Br, 25.84 The unsaturated product from the above step was epoxitized as follows: A solution of 7.5 g.-of l-ethoxycarbonyl-6- bromo-1s2,2a,3-tetrahydrobenz Ec,d3indole in 250 ml. of chloroform was cooled to about 0 C. with an ice/salt mixture. Six grams of 85% of m-chloroperbenzoic acid were added. The reaction mixture was stirred at about 0 C. for one hour and was then kept overnight at about 40C. The reaction mixture was washed successively with 1N aqueous sodium hydroxide, saturated aqueous sodium bisulfite, again with 1N aqueous sodium hydroxide and finally with brine. The organic solution was dried, and the solvent removed in vacuo. The resulting solid residue was recrystallized from a toluene/hexane solvent mixture. The first crop material obtained weighed 7.33 g. and melted at 126-8 C.; total yield (2 crops) 98%. Analysis Calculated: C, 51.87; H, 4.35; N, 4.32; Br, 24.65 Found: C, 51.83; H, 11.33; N, 4.16; Br, 24.31 A solution of 7.5 g. of l-ethoxycarbonyl-4,5- epoxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole obtained as above in 50 ml. of benzene was added slowly to a refluxing solution of I g. of zinc iodide in 450 ml. of benzene which had been dried by distilling off 50 ml. of the benzene-water azeotrope. Reflux under a nitrogen atmosphere was continued for one hour after the addition had been completed. The reaction mixture was cooled. The supernate was decanted, and the decanted solution washed with water and then with brine. The solution was dried and the solvent removed therefrom in vacuo. The residue, comprising l-ethoxycarbonyl-4 oxo-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole formed in the above reaction, was crystallized from a toluene/hexane solvent mixture. Five and thirty-six hundredths grams (71% yield) of crystalline product melting at 186-80C. were obtained. Analysis Calculated: C, 51.87; H, 4.35; N, 4.32; Br, 24.65 Found: C, 51.75; H, 4.29; N, 4.50; Br, 24.80 A reaction mixture was prepared from 14 g. of l-ethoxyCarbonyl-4-oxo-6-bromo-1,2,2a,3,4,5-hexahydro- benz[c,d]indole, 28.3 g. of n-propylamine, 4.9 ml. of glacial acetic acid and 300 ml. of acetonitrile. The reaction mixture was stirred under a nitrogen atmosphere for about one hour. A 3A molecular sieve was added to absorb water. Next, 5.6 g. of sodium cyanoborohydride were added followed by 14 ml. of glacial acetic acid. This new reaction mixture was stirred for an additional two hours at which time 7 ml. of glacial acetic acid were added. The reaction mixture was stirred for another two hours, and the process repeated again. Finally, the supernate was decanted from the molecular sieve, and the volatile constituents were removed in vacuo. A residual solution (mainly acetic acid) was poured into cold 2N aqueous sodium hdyroxide. The alkaline mixture was extracted with methylene dichloridR. The methylene dichloride extract was-washed with 0.5N aqueous sodium hydroxide and then with brine. The solvent was removed in vacuo. The resulting residue was dissolved in 1N aqueous hydrochloric acid to which methanol had been added. This acidic solution was washed with ether, and the ether wash discarded. The acidic solution was then made basic with 5N aqueous sodium hydroxide, and the now insoluble (f)-l-ethoxy- carbonyl-4-n-propylamino-6-bromo-1,2,2a,3,4,5-hexa- hydrobenzfc,d]indole formed in the above reaction separated and was extracted into methylene dichloride. The methylene dichloride extract was separated, and the solvent removed therefrom to yield 16.7 g. of an orange oil which was used in the next step without further purification. The above crude product was dissolved in 50 ml. of acetonitrile, 3 ml. of n-propyl iodide and 2 ml. of diisopropylethylamine. This solution was allowed to remain in the dark for about three weeks. At this point in time, the solvent was removed under reduced pressure, and the residual mixture partitioned between ether and 0.5N aqueous sodium hydroxide. The organic layer was separated, and the aqueous alkaline layer extracted several times more with ether. The ether extracts were combined and the combined extracts washed with brine and then dried. The ether was removed in vacuo to yield a residue. Xylene was added to the residue and removed by evaporation to remove any remaining diisopropylethylamine. The unpurified residue slowly crystallized. the crystals were dissolved in 20 ml. of methylene dichloride and 1 ml. of acetic anhydrideiwas added thereto. After about an hour, the volatile constituents were removed in vacuo and the resulting residue dissolved in methylene dichloride. The methylene dichloride solution was stirred with aqueous saturated sodium bicarbonate to remove any excess acetic anhydride. The methylene dichloride layer was separated, and the methylene dichloride removed by evaporation. The residue was dissolved in a mixture of dilute hydrochloric acid and methanol. The resulting cloudy solution was washed with ether and the ether was discarded. The acidic layer was then made basic with 5N aqueous sodium hydroxide and the now insoluble base which separated was extracted into methylene dichloride; TLC (1:9 MeOH/EtOAc). Evaporation of the solvent gave a moist crystalline residue. The residue was treated with hexane, and the hexane solution separated from hexane-insoluble brown oil by decantation. TLC indicated a single spdt. The hexane was evaporated in vacuo, and the resiude chromatographed over 25 g. of silica gel using ethyl acetate as the eluant. Fractions containing the desired material were combined and the solvent removed therefrom in vacuo. The white, crystalline residue was transferred to a filter paper using cold isooctane. A total yield of 2.39 g. of (i)-l-ethoxycarbonyl-4-di-n-propylamino-6-bromo 1,2,2a,3,4,5-hexahydrobenz[c,d]indole was obtained. m.p. = 90-940C. Analysis Calculated: C, 58.68; H, 7.14; N, 6.84; Br, 19.52 Found: C, 58.98; H, 6.88; N, 6.59; Br, 18.74. Alternatively, a solution of 15.7 g. of the crude amine product, (f)-l-ethoxycarbonyl-4-n-propyl- amino-6-bromo-l,2,2a,3,4,5-hexahydrobenz [c,d]indole in 80 ml. of pyridine was cooled to about OOC. Sixteen ml. of propionic anhydride were added slowly. The solution was allowed to remain at ambient temperature overnight. The bulk of the pyridine solvent was removed under vacuum, and the residual solution was stirred with an excess of aqueous sodium carbonate for several hours to remove any unreacted propionic anhydride and any by-product propionic acid. The aqueous mixture was extracted with methylene dichloride, and the methylene dichloride extract separated and washed with 0.5M aqueous sodium hydroxide, 1N hydrochloric acid and brine. The organic solution was dried and the solvent removed therefrom in vacuo leaving a viscous oil. The oil was dissolved in 50 ml. of THF and this solution added over about a 15 minute period to 85 ml. of 1M diborane in THF kept at about OOC. After the addition had been completed, the cooling bath was removed, and the reaction mixture heated to reflux temperature for about 1.5 hours. The reaction mixture was then cooled to about 0 C and 50 ml. of methanol were added cautiously. The resulting reaction was stirred overnight at room temperature. The methanol was removed in vacuo. Additional methanol was added and again removed by evaporation. The resulting residue began to solidify. The semisolid residue was partitioned between diethyl ether and 1M hydrochloric acid containing added methanol. The solid which preicipiated as a result of these operations was collected by filtration. The filtrate was made basic by the addition of aqueous sodium hydroxide, and the alkaline mixture extracted with methylene dichloride. The above ether layer, the methylene chloride extract and the separated solid were combined and the solvent evaporated. The residue was heated with wet DMSO, and this solution was then diluted with water plus sufficient 1M aqueous sodium hydroxide to maintain basic additions. The alkaline mixture was extracted with ether. The ether extract was in turn extracted with 1M hydrochloric acid containing some methanol. The acidic extract was again made basic, and the resulting alkaline mixture extracted with methylene dichloride. The methylene dichloride extracts were combined. TLC indicated that the chief product in this solution was (i)-l-ethoxycarbonyl-4-di-n-propyl- amino-6-bromo-1, 2, 2a, 3,4, 5-hexahydrobenz [c, d] indole formed in the above reactions. Fifteen and fifty-nine hundredths grams of crude salmon colored compound were obtained. The solid was dissolved in ethyl acetate and chromatographed over silica gel. Fractions containing the desired material were combined and the solvent removed therefrom in vacuo. Recrystallization of the resulting solid from isooctane gave (i)-l-ethoxycarbonyl 4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz- [c,d]indole melting 87-90C.; yield = 14.8 g. (94%). A solution of 1 g. of the above tertiary amine in 10 ml. of 6N hydrochloric acid was heated to reflux temperature under nitrogen overnight. TLC indicated that only a trace of starting material remained and that the chief product was (i)-4-di-n-propyl amine-6-bromo-1, 2, 2a, 3,4, 5-hexahydrobenz [c, d] indole formed in the above hydrolysis. The acidic solution was poured into dilute aqueous sodium hydroxide, and the resulting alkaline layer extracted with methylene dichloride. The methylene dichloride extract was separated and the separated extract washed with brine and then dried. Evaporation of the solvent yielded a viscous oil which crystallized upon cooling. Recrystallization of the precipitate from isooctane gave 0.683 g. (83% yield) of (i)-4-di-n-propylamino-6-bromo-1,2,2a, 3,4,5-hexahydrobenzc,dindole melting at about 62-30C. Analysis Calculated: C, 60.53; H, 7.47; N, 8.31; Br, 23.69 Found: C, 60.71; H, 7.57; N, 8.30; Br, 23.78 A run on a larger scale (14.8 g. of starting material) gave an 88% yield of the desired hydrolysis product. Example J Preparation of N-formyl (i ) -4-methylamino- 6-cyano-1,3,4,5-tetrahydrobenz[c,d]indole A solution of 16.8 g of (i)-5-oxo-1,2,2a,3,4,5- hexahydrobenz[c,d]indole in 100 ml of pyridine was stirred at ice bath temperature while 16 ml of 2,2,2trichloroethylchloroformate was added slowly over a 10 minute period. The reaction mixture was allowed to warm to room temperature under an N2 atmosphere at which temperature it was stirred for an ádditional 3 hours. A majority of the pyridine was removed in vacuo. The resulting residue was partitioned between toluene and water. The toluene layer was separated and the aqueous layer extracted twice more with equal volumes of toluene. The toluene extracts were combined and the combined extracts washed several times with 1N hydrochloric acid (until the separated aqueous layer was acid to litmus). The combined toluene extracts were evaporated in vacuo. The resulting residue was recrystallized from toluene/ hexane (1:1) to give 31.62 g (93% yield of (i)-(2,2,2 trichlorethoxycarbonyl-5-oxo-l, 2, 2a, 3,4, 5-hexahydrobenz- [c,d]indole melting at about 130-1320C. Following the procedure of Example A, 31.0 g of (#)-1-(2,2,2-trichlorethoxycarbonyl)-5-oxo-1,2,2a,3,4,5- hexahydrobenz[c,d]indole were reduced with NaBH4 in ethanol to yield (t)-1-(2,2,2-trichlorethoxycarbonyl)- 5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole; yield = 30.1 (97%); m.p. = 119-1210C (from ethanol). A solution was prepared by dissolving 23.41 g of (t)-l > ç2,2,2-trichlorethoxyzarbonyl)-5-hydroxy- 1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 190 ml of chilled (OOC) trifluoroacetic acid (TFA). When solution was complete, 9.58 g of bromocyanuric acid were added in small amounts (1.25 hr. addition time). The reaction mixture was stirred for 2 hours at about 0 C. TLC in 100% methylene chloride indicated that no starting material remained. The reaction mixture was chilled and then made basic (to litmus) by the addition of an excess of 5N aqueous sodium hydroxide. The alkaline mixture was extracted with two 200 ml portions of CH2C12. The combined CH2C12 extracts were washed with dilute aqueous sodium hydroxide. Two grams of tetrabutylammonium hydrogen sulfate were added to the dilute sodium hydroxide and the CH2C12 layer shaken with the NaOH solution until TLC indicated that all bi-product 5-trifluoroacetate had been hydrolyzed back to the 5hydroxy derivative. The CH2C12 was removed in vacuo and the residue chromatographed over silica gel using CH2C12 as the eluant. Fractions containing the desired 6-bromo derivative were combined and the solvent removed. Recrystallization of the residue from diethylether provided (#)-1-(2,2,2-trichlorethoxycarbonyl)- 5-hydroxy-6-bromo-1,2,2a,3,4,5-benz[c,d]indole and melted at about 123-1250C; yield (2 crops) = 18.74 g (65%). Analysis Calculated: C, 39.15; H, 3.05,- N, 3.26; Br, 18.60 Found: C, 39.34; H, 3.85; N, 3.44; Br, 18.38. Mass spectrum: M+ = 429 A reaction mixture was prepared by placing 18.74 g of the above 6-bromo derivative, 475 ml of toluene, 8 g of Amberlyst 15, an ion exchange resin known to catalyze dehydration, in a 1 1. round-bottom flask equipped with magnetic stirrer, Dean-Stark trap, reflux condensor and drying tube. The reaction mixture was heated to reflux. After one hour, TLC revealed no remaining starting material. The solution was decanted from the Amberlyste beads, and then decolorized with carbon. The decolorizing solution was filtered through hyflo supercel. The filtrate was evaporated to dryness in vacuo. CH2C12 was added and the solvent again removed in vacuo. The residue was crystallized from hexane. Yellowish crystals of (i)-1-(2,2,2-trichlor ethoxyCarbonyl)-6-bromo-1,2,2a,3-tetrahydrobenz[c,d]- indole thus prepared melted at about .95-990C. Recrystallization from ether gave crystals melting at 98-1010C (96% yield). Following the procedure of Example A, the above A4,5 compound was epoxidized with m-chloroperbenzoic acid in CHC13 to yield (i)-1-(2,2,2-trichlor- ethoxyCarbonyl)-4,5-epoxy-6-bromo-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole. 11.8 g of epoxide was removed based on 17.64 g of starting olefin. The epoxide was rearranged to the corresponding 4-oxo derivative by the procedure of Example A (zinc iodide in benzene), 7.29 g (from 11.8 g of starting olefin) of (i)-1-(2,2,2-tri- chlorethoxycarbonyl)-4-oxo-6-bromo-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole were obtained (62% yield). A cold solution of 4.4 g of methylamine in 100 ml of acetonitrile was prepared. 1.9 ml of acetic acid were added followed by 1.5 g of sodium cyanoboro hydroxide followed by about 5 g of (+)-1-(2,2,2-tri- chlorethoxycarbonyl)-4-oxo-6-bromo-1,2,2a,3,4,5-hexa- hydrobenz(c,d]indole. The reaction mixture was continuously stirred and every two hours additional acetic acid was added in the following amounts--6.2 ml, 1.3 ml, and 1 ml, respectively. The reaction mixture was poured into ice-cold 2N aqueous NaOH. The alkaline mixture was extracted with CH2Cl2. The organic layer was separated and the solvent removed therefrom in vacuo. The residue was partitioned between 1N hydrochloric acid and ether. The ether layer was discarded. The acidic aqueous layer was made basic with NaOH and the now alkaline layer extracted with CH2C12. The organic extract was washed with brine and dried. 6.2 g of (i)-1-(2,2,2-trichlor- ,ethoxycarbonyl) -4-methyiamino-6-bromo-1,2,2a,3,4,5-hexa- hydrobenztc,d]indole, formed in the above reaction were obtained as a viscous oil. The oil was dissolved in 2.5 ml of THF and this solution added to a solution of 5 g of bis-imidazole carbonyl and 1.5 g of 98% formic acid in 100 ml of THF which had been stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 3 hours at room temperature, at which time the solvent was removed in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate. After standing overnight, a small amount of CH2C12 was added to dissolve residual solid. The alkaline aqueous phase was separated and the separated phase extracted with ether/CH2C12. The combined organic phases were washed with lN hydrochloric acid and then with brine. The combined phases were dried and the solvent removed in vacuo. 7.48 g of N-formyl ti)-1-(2, 2, 2-trichlorethoxycarbonyl-4-methyl- amino-6-bromo-l,2,2a,3,4, 5-hexahydrobenz [c,d]indole formed in the above acylation were obtained as a glass. The glassy residue was dissolved in 220 ml of glacial acetic acid and 25 ml of water. 23.4 g of zinc dust were added and the mixture stirred under N2 for 2 hours at room temperature. The suspension was filtered to remove unreacted zinc dust. The bulk of the acetic acid was then removed in vacuo. The oily residue was taken up in CH2C12 and saturated aqueous sodium bicarbonate added with care. A colorless zinc salt separated. The mixture was filtered through hyflo supercel. The organic layer was separated and the alkaline aqueous layer extracted with CH2C12. The combined CH2C12 extracts were washed with brine and then dried. Evaporation of the volatile constituents gave a glassy residue. The residue was dissolved in ethyl acetate. Crystals appeared. The bulk of the ethyl acetate was removed by decantation and toluene added. The mixture was chilled. Crystalline N-formyl (i )-4-methylamino-6- bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole thus prepared was collected by filtration; weight = 2.15 g; m.p. = 177-1790C. Analysis calculated: C, 52.90; H, 5.12; N, 9.49; Br, 27.07; Found: C, 52.65; H, 5.31; N, 9.23; Br, 27.20. Evaporation of the filtrate to dryness yielded an oil which was purified by chromatography over silica gel using ethyl acetate as the eluant, yield 1.22 g of the oil as the epimer of the above crystalline product; Analysis calculated: C, 52.90; H, 5.12; N, 9.49; Br, 27.07; Found: C, 53.14; H, 5.25; N, 9.21; Br, 27.02. Total yield of both epimers = 78%. Two grams of the crystalline epimer were dissolved in 100 ml of CH2C12. Eight grams of activated MnO2 were added and the resulting suspension sonicated at 50-55 K11z under N2 for 3 hours. The reaction mixture was filtered and the solvent evaporated to dryness in vacuo, leaving as a residue 1.63 g of N-formyl (t)-4- methylamino-6-bromo-1, 3, 4,'5-tetrahydrobenz [c, d] indole. The oily epimer, 1.15 g, was similarly oxidized to yield 1.02 g of N-formyl (+)-4-methylamino-6-bromo-1,3,4,5- tetrahydrobenz[c,d]indole. The two N-formyl products were combined, dissolved in hot ethyl acetate containing 5% methanol, and chromatographed over 50 g of silica gel using ethyl acetate as eluant. The product from the column was recrystallized affording 2.17 g (69%) of N-formyl (l)-4-methylamino-6-bromo-1,3,4,5-tetrahydro- benztc,d]indole. m.p. 204-2050C. Analysis Calculated: C, 53.26; H, 4.47; N, 9.56; Br, 27.26; Found: C, 53.00; H, 4.67; N, 9.28; Br, 27.06. A mixture of 0.70 g of cuprous cyanide, 1.00 g ofiN-formyl (+)-4-methylamino-6-bromo-1,3,4,5tetrahydrobenz[c,d]indole, and 10 ml of N-methyl-2-pyrrolidone was heated at 2000C under N2 for 4 hours. After cooling, the mixture was poured into water and CH2C12. The mixture was filtered, the aqueous phase was washed with CH2C12. The organic phase and CH2C12 washings were combined, washed with 1N HC1, then with NaCl solution, and dried over Na2 SO4. The solvent was removed in vacuo and the residue was chromatographed over silica gel using ethyl acetate as eluant. The fractions containing the desired product were combined and evaporated to yield 0.39 g (48%) of N-formyl (+)-4 methylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d]indole. m.p. 205-2070C. Analysis calculated: C, 70.28; H, 5.48; N, 17.56; Found: C, 70.56; H, 5.51; N, 17.30. Example 1 Preparation of (i ) -4-Di-n-propylamino-6- bromo-1,3,4,5-tetrahydrobenz[c,d]indole A suspension of 0.44 g. of N-chlorosuccinimide in 16 ml. of toluene was chilled to about OOC. Three tenths ml. of dimethylsulfide were added. After 15 minutes, the reaction mixture was cooled in a dry iceacetone bath to about -60 C. Six tenths grams of (i) 4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz- [c,d]indole (prepared in Example A) and 2 ml. of toluene were added over a 15 minute period. The reaction mixture was stirred at about -600C. for about two hours at which point 0.8 ml. of triethylamine were added. The cooling bath was removed and stirring continued for about 2 hours at ambient temperature. The reaction mixture was then poured into cold 1N aqueous sodium hydroxide and the now alkaline mixture extracted several times with toluene. The toluene extracts were combined, and the combined extracts washed with brine and then dried. The solvent was removed and the resulting residue chromatographed over 15 g. of Florosil using a 1:9 ethyl acetate/toluene solvent mixture as the eluant. Fractions containing the desired product were combined and rechromatographed over silica using the same eluant. Fractions containing the desired product were again combined and the solvent evaporated therefrom to leave a slightly greenish oil. This oil was dissolved in about 20 ml. of pentane and filtered to remove a colorless precipitate. The pentane was then removed by evaporation in vacuo. A yellow green oil weighing 0.303 g. (51% yield) was obtained comprising (i)-4-di n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,drindole formed in the above oxidation. The product crystallized upon standing; m.p. = 72-30C. Analysis Calculated: C, 60.90; H, 6.91; N, 8.36; Br, 23.83 Found: C, 60.77; H, 6.87; N, 8.28; Br, 23.61 Example 2 Preparation of (f)-4-Di-n-propylamino-6- bromo-1,3,4,5-tetrahydrobenz[c,d]indole A solution of 1 g. of (i)-4-di-n-propylamino 6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (prepared in Example A) and 50 ml. of hexane was prepared. Four grams of activated manganese dioxide were added and the resulting suspension sonicated 50-55 KHz under a nitrogen atmosphere for about one hour. TLC at this point indicated almost no starting material remaining. The reaction mixture was suction filtered, and the precipitate of magnese dioxide obtained was thoroughly washed with fresh hexane. The hexane was removed from the filtrate and the resulting residue chromatographed as before. Fractions containing the desired indole were combined and the solvent removed by evaporation. Recrystallization of the resulting residue from isooctane yielded 0.62 g. (62% yield) of (i)-4-di-n-propylamino-6- bromo-1,3,4,5-tetrahydrobenz[c,d]indole melting at 73-40C. Example 3 Preparation of (i )-4-Di-n-propylamino-6-cyano- 1,3,4,5-tetrahydrobenz[c,d]indole A solution was prepared by dissolving 0.7 g. of cuprous cyanide in 10 ml. of N-methyl-2-pyrrolidone (previously purged with nitrogen). One gram of (i)-4 di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenzEc,d]- indole waS added to the cuprous cyanide solution. The solution was heated under a nitrogen atmosphere at 2000 C. for one hour. The reaction mixture was then cooled and the cooled mixture partitioned between ethyl acetate and dilute aqueous ammonium hydroxide. The alkaline layer was extracted several times with ethyl acetate. The ethyl acetate layers were combined and the combined layers washed successively with dilute aqueous ammonium hydroxide, dilute aqueous ethylenediamine and brine. The ethyl acetate layer was then dried and the solvent removed therefrom. The residual oil was dissolved in ether, and the ether solution washed twice with brine. The ether layer was separated and the ether removed therefrom in vacuo. The residue was next dissolved in ether, and the ether diluted with several volumes of petroleum ether. The supernate was decanted and the dark residual oil treated with a mixture of ether and petroleum ether again. The combined supernates were evaporated yielding a viscous orange oil as a residue. Chromatography of this residue over silica gel using 1:10 ethyl acetate/toluene as the eluant yielded fractions containing the desired (i)-4 di-n-propylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d3- indole formed in the above reaction. Recrystallization of the solids thus obtained from a toluene/hexane solvent mixture yielded crystalline material melting at l32-30C.; yield = 44%. Analysis Calculated: C, 76.83; H, 8.24; N, 14.83 Found: C, 76.56; H, 8.09; N, 14.86 Example 4 Preparation of (f)-4-Di-n-propylamino-6- carbamoyl-1,3,4,5-tetrahydrobenztc,d]indole About 1.5 g. of powdered potassium hydroxide were suspended in 10 ml. of distilled t-butanol and 0.3 ml. of DMSO. Three tenths grams of (i)-4-di-n propylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d]indole were added. The mixture was heated to reflux temperature under a nitrogen atmosphere for about 72 hours. At this point, TLC indicated only partial reaction. Reflux was continued for another 24 hours. The reaction mixture was then quenched by the addition of cold water and the aqueous mixture extracted with methylene dichloride. The organic layer was separated and the separated layerwashed with brine and then dried. Evaporation of the solvent yielded a residue which was chromatographed over Florisil using ethyl acetate containing increasing amounts of methanol, up to 10%. The starting material was eluted with 5% methanol/95% ethyl acetate, and the desired product, (i ) -4-di-n-propylamino-6-carbamoyl- 1,3,4,5-tetrahydrobenz[c,d]indole, was eluated with the 10% methanol/90% ethyl acetate. Fourteen hundredths grams of product were obtained and about 0.17 g. of starting material. The recovered starting material was treated as above with powdered KOH in t-butanol and DMSO. The second hydration mixture was heated to reflux temperature for about four days. The reaction mixture was quenched as before, but TLC indicated that hydration reaction was still not complete. However, the 6 carbamoyl derivative obtained from the second run was about 0.5 t. Again, the recovered starting material was treated as before and refluxed with base for about one week and an additional quantity of the 6-carbamoyl derivative obtained. All the fractions containing (i)-4-di-n-propylamino-6-carbamoyl-1,3,4,5-tetrahydro- benztc,d]indole were combined and the combined fractions chromatographed over Florisil using ethyl acetate followed by 1:1 methanol/ethyl acetate as the eluant. The starting material was eluted with the ethyl acetate. The (i)-4-Di-n-propylamino-6-carbamoyl-1,3,4,5-tetra- hydrobenz[c,d]indole, thus isolated, melted at 163-50C. after successive recrystallizations from toluene/hexane and toluene. One hundred seventy-three thousands grams of the compound was obtained (54% yield). Analysis Calculated: C, 72.21; H, 8.42; N, 14.03 Found: C, 72.23; H, 8.27; N, 13.57 Example 5 Preparation of (f)-4-Di-n-propylamino-6- nitro-1,3,4,5-tetrahydrobenz[c,dgindole A solution was prepared by dissolving 0.15 g. of (t)-4-di-n-propylamino-6-nitro-1,2,2a,3,4,5-hexa- hydrobenz[c,d]indole (prepared in Example B) in 10 ml. of methylene dichloride. Six tenths grams of manganese dioxide were added and the mixture sonicated at 50-55 KHz under a nitrogen atmosphere for about ten hours. The mixture was filtered through supercel and the supercel washed with fresh methylene dichloride. The solvent wat removed from the filtrate, and the resulting residue was chromatographed over silica gel using toluene containing increasing amounts (5-10%) of ethyl acetate. Fractions containing (i ) -4-di-n-propylamino- 6-nitro-1,3,4,5-tetrahydrobenz[c,d]indole were combined to yield 0.102 g. of that product. Recrystallization from a toluene/hexane solvent mixture gave 0.087 g. (58% yield) of compound melting at 130-20C. Analysis Calculated: C, 67.75; H, 7.69; N, 13.94 Found: C, 67.74; H, 7.74; N, 13.81 Example 6 Preparation of (i )-4-Di-n-propylamino-6- methoxy-1,3,4,5-tetrahydrobenz[c,d]indole A solution of sodium methyl ate was prepared by dissolving 0.276 g. of sodium metal in 3 ml. of methanol. Ten ml. of DMF were addded followed by 0.3 g. of CuI. 0.20 g. of (i)-4-di-n-propylamino-6-bromo 1,3,4,5-tetrahydrobenz[c,d]indole were added to the resulting suspension. The reaction mixture was heated at about 1300C under N2 for about 5 hours. The reaction mixture was filtered, and the filter cake washed thoroughly with DMF. Cold water was added to the filtrate. The aqueous layer was extracted three times with ether. The combined ether extracts were washed with brine and dried. Removal of the ether in vacuo left a residue which was chromatographed over SiO2 using 1:1 ethyl acetate/toluene as the eluant. Late fractions containing the desired 6-methoxy derivative were combined and the solvent removed in vacuo. The viscous oily product was seeded with previously obtained crystals of the 6-methoxy derivative. Recrystallization from isooctane yielded (t)-4-di-n-propylamino-6-methoxy- 1,3,4,5-tetrahydrobenz[c,d]indole melting at 87-90C; yield = 80% Analysis Calculated: C, 75.48; H, 9.15; N, 9.78; Found: C, 75.64; H, 9.25; N, 9.62. Example 7 Preparation of {i)-4-Di-n-propylamino-6- methoxy-1,3,4,5-tetrahydrobenzEc,dlindole Cis-(i)-4-di-n-propylamino-6-methoxy-1,2,- 2a,3,4,5-hexahydrÏbenz[c,d]indole was oxidized to the tetrahydrobenz[c,dlindole by the following procedure. Three hundred twenty-one thousandths grams of the indoline free base and 0.12 ml. of dimethylsulfide were dissolved in 5 ml. of methylene dichloride. The solution was cooled to about -800C. in a dry ice-acetone bath. A solution of 0.175 ml. of t-butylhypochlorite in 3 ml. of methylene chloride was added to the reaction mixture over a 30 minute period. After the addition had been completed, the reaction mixture was stirred for two hours at dry ice-acetone temperatures. Next a solution of 0.13 g. of sodium and 3 ml. of ethanol was added, also in dropwise fashion. The resulting mixture was allowed to warm to room temperature and was stirred at that temperature for about one hour, at which time it was washedStwice with water and the water wash discarded. The solvent was removed from the organic layer to leave a dark brown residue which was chromatographed over silica gel. The chromatographic column was prepared in a solvent mixture comprising 10% triethylamine, 10% ethyl acetate and 80% toluene. The desired product was eluted with a 1:9 ethyl acetate/toluene solvent mixture. Chromatographic fractions containing this product were combined and the solvent removed therefrom in vacuo leaving a colored residual free base consisting of (i)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole formed in the above oxidation. The residual oil was converted to the hydrochloride salt which decomposed at about 1100C. The salt had the following analysis: Analysis Calculated: C, 66.96; H, 8.43; N, 8.68; C1, 10.98 Found: C, 66.84; H, 8.58; N, 8.44; C1, 10.76 NMR (CDC13) 6 = 1.02 (mult, 6H, 2-CH3), 1.99 (mult, 4H, CH2Me), 2.94 (mult, 1H, 56-H), 3.04 (qt, 1H, 5a-H), 3.17 (mult, 5H, CH2Et and 3a-H), 3.47 (mult, 1H, 3B-H), 3.80 (t, 1H, 4-H), 3.89 (s, 3H, OCH3), 6.85 (d, 1H, 8-H), 6.94 (s, 1H, 2-H), 7.19 (d, 1H, 7-H), 8.18 (s, 1H, N-H), 12.14 (brs, 1H, HC1); Mass spectrum: 286 (mass peak) The trans-(i)-racemate was oxidized in a slightly different fashion as follows. A solution of 0.35 g. of 98% N-chlorosuccinimide in 10 ml. of distilled methylene dichloride was cooled to about OOC. while 0.3 ml. of methylsulfide were added in dropwise fashion under a nitrogen atmosphere. After stirring at ice bath temperature for 15 minutes, the solution was cooled to dry ice-acetone temperature (-700C.). Next, a solution of 0.72 g. of trans-(i)-4-di-n-propylamino-6-methoxy-1,- 2,2a,3,4,5-hexahydrobenz[c,d]indole in 2 ml. of methylene dichloride was added in a dropwise fashion over a 30 minute period. The resulting reaction mixture was stirred for another 30 minutes after which time I ml. of triethylamine was added in dropwise fashion. This new reaction mixture was stirred at dry ice-acetone temperature for another 15 minutes and was then allowed to warm to room temperature. The reaction mixture was next washed three times with water and the water extracts reextracted with ether. The methylene dichloride solution and ether extracts were combined and the solvent removed therefrom in vacuo leaving a viscous brown oil. Chromatography over silica gel (as with the cis-racemate) gave 0.303 g. of (i)-4-di-n-propylamino 6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole formed in the above reaction. Two hundred thirty-five hundredths grams of free base were eventually obtained and converted to the hydrochloride salt using ethereal hydrogen chloride (2.38 molar). Example 8 Preparation of (i ) -4-Dimethylamino-6-methoxy- 1,3,4,5-tetrahydrobenzrc,dlindole Following the procedure of Example 7, a solution of 0.78 g. of N-chlorosuccinimide and 0.5 ml. of dimethylsulfide in 25 ml. of toluene was used to oxidize 1.6 g. of cis-(i)-4-dimethylamino-6-methoxy l,2,2a,3,4,5-hexahydrobenz[c,d]indole at dry ice-acetone temperatures. One and twenty-five hundredths ml. of triethylamine were added. The reaction mixture was worked up and the crude residue, comprising (i)-4- dimethylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]- indole formed in the above oxidation, was purified by chromatography over silica gel. Ethyl acetate containing increasing (0-5%) methanol was used as the eluant. Fractions containing the desired tetrahydrobenz[c,d]indole were combined to yield 0.15 g. of the compound. The free base in ethereal solution was converted to the hydrochloride salt with 4.5 M ethereal HC1, which salt had the following elemental analysis. Analysis Calculated: C, 63.03; H, 7.18; N, 10.50; C1, -13.29 Found: C, 62,83; H, 7.10; N, 10.29; C1, 13.14 The compound had the following physical characteristics: NMR (CDCl3) 6 = 2.86 (d, 3H, NCH3), 2.9 (mult, 1H, 5B-H), 2.97 (d, 3H, NCH3), 3.04 (qt, 1H, 5a-H), 3.18 (qt, lH, 3a-H), 3.51 (qt, 1H, 3ss-H), 3.71 (mult, 1H, 4-H), 3.90 (s, 3H, OCH3), 6.87 (d, 1H, 8-H), 6.96 (s, 1H, 2-H), 7.19 (d, 1H, 7-H), 8.00 (s, 1H, N-H), 12.79 (brs,.H, HCl); Mass spectrum: 230 (mass peak). Example 9 Preparation of (f)-4-Dimethylamino-6-cyano- 1,3,4,5-tetrahydrobenz[c.d]indole A mixture of 0.42 g of N-formyl (+)-4-methylamino-6-cyano-1,3,4,5-tetrahydrobenz[c.d]indole (prepared in Example J) and 12 ml of THF was treated with 1.9 ml of 2M borane-methyl sulfide complex in THF. After stirring the mixture for 2 hours at room temperature, the reaction was quenched with 1 ml of methanol, the solvents removed in vacuo, and the residue taken up in 2 ml of DMSO. To the solution was added a few drops of saturated NaHCO3 solution. The mixture as heated on a steam bath for 10 minutes, water added, and the product extracted with CH2Cl2. The extracts were washed with NaCl solution, dried over Na2SO4, and the solvents removed in vacuo. The crystalline residue was chromatographed over Florisil using ethyl acetate as eluant. The fractions containing product were evaporated, and the residue recrystallized from ethyl acetate/toluene to yield 0.24 g (60%) of (+)-4-dimethylamino-6-cyano 1,3,4,5-tetrahydrobenz[c,d]indole. m.p. 196-1980C. mass spectroscopy = 225 (parent peak) Example 10 Preparation of (+)-4-Dimethylamino-6-carbamoyl 1,3,4,5-tetrahydrobenzfc,d]indole To a suspension of 1.25 g of powered KOH in dry t-butanol was added 0.25 g of 18-crown-6-ether followed by 0.20 g of (+)-4-dimethylamino-6-cyano 1,3,4,5-tetrahydrobenz[c,d]indole. The mixture was refluxed for 48 hours under N2, then 0.3 ml of DMSO was added. The mixture was refluxed for another 72 hours. The mixture was then treated-with 0.25 ml of water then refluxed another 24 hours. The reaction was quenched with water and the product extracted with CH2Cl2. The extract was washed with brine, then dried over Na2SO4. The solvent was removed, and the residue was chromatographed over Florisil using 5% methanol/95% ethyl acetate followed by 10% methanol/90% ethyl acetate. (The former solvent gave starting material and the latter solvent gave the product.) The (+)-4-dimethyl amino-6-carbamoyl-1 '3,4, 5-tetrahydrobenz [c, d] indole thus isolated weighed 2 mg (1%); Rf = 0.10 (solvent system CH2Cl2/CH3OH/concentrated NH40H, 45:5:1). In the above procedure (Examples J and 9), use of ammonia in place of methyl amine in the reaction with (i)-1-(2,2,2-trichloroethoxycarbonyl)-4-oxo-6- bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole yields (i)-1-(2,2,2-trichlorethoxycarbonyl)-4-amino-6-bromo 1,2,2a,3,4,5-hexahydrobenz[c,d]indole. This primary amine can then be acylated with, for example, formic acid and bis-imidazolecarbonyl to yield an amide, which group is carried through the reductive (Zn and acetic acid) removal of the 1-(2,2,2-trichlorethoxycarbonyl) group to yield an indoline, oxidation with MnO2 to yield an indole, replacement of the 6-bromo formation with cyanide to yield a 6-tyano group and finally hydrolysis (3N hydrochloric acid/THF) to yield (i)-4-amino-6-cyano-l,3,4,5- tetrahydrobenzrc,dlindole. The primary amine group can then be reductively alkylated with an aldehyde (formaldehyde, acetaldehyde, propionaldehyde) and, for example, sodium cyanoborohydride or other suitable borohydride reducing agent, to yield the di alkyl amine function. The cyano group can then be hydrated to the carboxamide to yield a (i)-4-(C1-C3 alkyl) amino-4 aminocarbonyl-l, 3,4, 5-tetrahydrobenz [c, dJ indole. The central serotonergic action of drugs according to IV above was demonstrated in two ways. The first method was to show inhibition of tritiated serotonin uptake according to the following protocol. (Weak inhibition of tritiated spiperone uptake was also determined.) Several (i ) -4-di-n-propylamino-6-sub- stituted-1,3,4,5-tetrahydroindoles plus the corresponding drug from Bach-Kornfeld United States Patent 4,110,339 lacking a C-6 substituent were tested. Brain tissue was obtained from 150-200 g. male Wistar rats. The cerebral cortex was dissected out and then homogenized and centrifuged according to the method described by Nelson and coworkers, Mol. Pharmacol., 14, 983-995 (1978), using preincubation in buffer without added monoamine oxidase inhibitor in order to eliminate endogenous serotonin. For receptor binding, each sample contained 300-400 pg. of membrane protein and 10 pM pargyline in addition to the 3Hligand in 1 ml. of 0.05 M Tris buffer, pH = 7.4. The assay of serotonin binding was done following the method of Bennett and Snyder, Mol. Pharmacol., 12. 373-389 (1976), and that for tritiated spiperone according to Peroutka and Snyder, Mcl. Pharmacol., 16, 687-699 (1979). The samples were incubated for 15 minutes at 37 and were then filtered through GF/C glass fiber filter pads using a Brandel M-24 cell harvester modified for receptor binding. After two 5 ml. rinses, the filter discs were put into scintillation vials and counted in 10ml. of Amersham PCS scintillation fluid Nonspecific binding of 3H-serotonin (3H SHT) was determined in the presence of 10-5M serotonin and of 3H-spiperone in the presence of 10-6M LSD. Specific binding was calculated as the difference between total binding with no added nonradioactive compound and the nonspecific binding. IC50 values were determined where the IC50 is the amount of substance causing 50 percent inhibition of the specific binding using 10-12 concentration in the range of 10-9 to 10-4M. The concentration of 3H-ligands were: serotonin (Amersham, 11 Ci/mmol), 2-3 nM; LSD (Amersham, 1.8 Ci/mmol), 1.8-2.6 pM; spiperone (Amersham, 20 Ci/mmol), 0.6-0.7 pM The results obtained, are set forth in Table 1. TABLE 1 RECEPTOR BINDING 3H-Ligand-IC50* Name of Compound 3H-5HT 3H-SPIP (i)-4-di-n-propylamino- 60 4980 6-aminocarbonyl-1,3,4,5tetrahydrobenz[c,d]indole (i)-4-di-n-propylamino-6- 90 390 cyano-1,3,5,6-tetrahydro- benz[c,d]indole (i)-4-di-n-propylamino-6- 100 400 nitro-1,3,5,6-tetrahydrobenz[c,d]indole (i)-4-di-n-propylamino-6- 50 950 methoxy-1,3,4,5-tetrahydro benz[c,d]indole (i)-4-dimethylamino- 120 730 1,3,4,5-tetrahydrobenz [c,dlindole *Values are in nanomoles of inhibitor. Secondly, as a measure of- central serotonin agonist activity, the decrease of serotonin metabolites in brain was measured. Also the measure of dopamine agonist activity was indicated by changes in dopamine metabolites. The following protocol was employed. 150-200 g.Wistar rats were given 0.3 mg/kg subcutaneously of (+)-4-di-n-propylamino-6-substituted- 1,3,4,5-tetrahydrobenz[c,d]indole. Then, 60 minutes later each rat was decapitated and the hypothalamus and striatum were dissected out and extracted. The amounts of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and of 5-hydroxyindoleacetic acid (SHIAA) in the hypothalamus were measured by high-performance liquid chromatography, using electrochemical detection. Serum corticosteroids were also measured. Table 2 gives the results of this experiment. In the table, columns 1 and 2 give the substitution pattern in the compounds of formula IV, columns 3-5, the 5HT or dopamine metabolite concentrations, and column 6, the serum corticosteroids. TABLE 2 5HIAA In Dopamine Metabolites Serum Hypothalamus In Striatum, NMoles/G Corticosterone X RÚ and Rê NMoles/G DOPAC HVA MCG/100 ML OMe di-nPr 1.51#.05* 4.61#.10* 2.43#.18* 48#2* OMe di-Me 0.69#.07* 7.15#.23* 4.68#.21 41#4* CN di-nPr 0.34#.07 4.25#.25* 2.27#.16* 47#4* NO2 di-nPr 0.29#.03* 3.74#.11 2.02#.20* 49#2* CONH2 di-nPr 0.58#.03* 6.23#.56 4.12#.27 49#2* (Control) 2.59#.11 5.58#.38 4.24#.27 7#1 Compounds were injected at 0.3 mg/kg s.c. 1 hour before rats were killed. *statistically significant. For of the five compounds tested appear to have som Dopamine agonist activity. However, the fifth compound appears to have no significant dopamine agonist activity. All but the cyano compound showed significant serzrLani.n agonist activity at the same dose level. Thirdly, as a measure of central serotonin agonist activity, the test rats received (i)-4-di-n- propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole The decrease of serotonin turnover in brain was measured as a function of 5-hydroxytryptophane (5-HTP) accumulation whe the decarboxylation of 5-HTP is blocked by m-hyroxybenzylhydrazine, using the above protocol, except that thirty minutes after injection of the drug, m-hyroxybenzylhydrazine was injected at 100 mg./kg. i.p. Then , 40 minutes later each rat was decapitated, the hypothalamus dissected out and extracted. The amount of S-Rrp in each extract were measured by hight-performance liquid chromatography, using electrochemical detection. In normal rats, 5-HTP brain levels are so law as to be virtually undetectable. Thus, the control group received the same dose of m-hydroxybenzylhydrazine is the test rats but no drug. Table 3 gives the results of this experiment. TABLE 3 UPTAKE INHIBITION 5HTP Level in Nanomoles Dose of Drug Mg./Kg. of Hypothalamus i S.E. 0 1.81 i 0.11 0.01 1.85 i 0.06 0.03 1.72 i 0.07 0.10 1.16 t 0.05* 0.30 0.97 i 0.03* *Significant difference from zero dose group (P < .05). The above results indicate that certain dose levels of ( 4-di-n-propylamino-6-methoxy-1,3,4,5- (i)-4-di-n-propylamino-6-methoxy-l, 3,4,5- tetrahydrobenz [c, djindole significantly decreased 5HTP accumulation, thus indicating central serotonin agonist activity at those dosage levels or at higher dosage levels. Drugs which have central serotonin agonist activity are useful as antidepressants. The compounds of formula IV which have such central serotonergic activity to a marked degree with minimal agonist or antagonist actions toward NE or dopamine should be particularly useful in that their use would not be accompanied by side effects common to presently marketed antidepressants, particularly the antimuscarinic effect. Several of the marketed antidepressants are also monamine oxidase inhibitors, a nonspecific amine oxidase linked with metabolic degradation of both catecholamines and serotonin, which activity is also lacking in the drugs of formula IV. The novel drugs of formula IV can be administered patenterally as an isotonic solution of a pharmaceutically acceptable salt. Preferably, however, the drugs are administered orally. For such route of administration, the drug is mixed with one or more pharmaceutical excipients and loaded into empty telescoping gelatin capsules or compressed into tablets, each tablet or capsule to contain a unit antidepressant dosage of the drug.

Claims: CLAIM 9t A compound of the formula EMI102.1 wherein R1 and R2 are individually hydrogen, methyl, ethyl, n-propyl or allyl; X is F, Cl, Br, CN, CONH2, NH2, NO2, O(C1-C3 alkyl), OH, O-acyl or O-benzyl; or a pharmaceutically-acceptable salt thereof. 2. A compound of claim 1 wherein X is F, Cl, Br, CN, CONH2, NH2, or NO2 3. A compound of claim 2 wherein X is Br, CN, CONH2, or NO2 4. Any one of the following compounds or a pharmaceutically-acceptable salt thereof: (#)-4-Di-n-propylamino-6-bromo-1,3,4,5-tetra- hydrobenz[c,d]indole (#)-4-Di-n-propylamino-6-cyano-1,3,4,5-tetra- hydrobenz[c,d]indole (#)-4-Di-n-propylamino-6-carbamoyl-1,3,4,5- tetrahydrobenz[c,d]indole (#)-4-Di-n-propylamino-6-nitro-1,3,4,5-tetrafiydrabenz Ic, dl indole (#)-4-Di-n-propylamino-6-methoxy-1,3,4,5tetrahydrobenz [c, d] indole (i)-4-Dimethylamino-6-methoxy-1,3,4,5-tetra- hydrobenz[c,d]indole (#)-4-Dimethyl-6-cyano-1,3,4,5-tetra- hydrobenz[c,d]indole (#)-4-Dimethyl-6-carbamoyl-1,3,4,5-tetratetrahydrobenz [c, d] indole. 5. A process for preparing a compound of formula IV, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4, which comprises: a) reacting a compound of the formula EMI103.1 wherein X5 is F, Cl, Br, NO2, O(Cl-C3 alkyl), O-acyl or O-benzyl; R5 and R6 are individually methyl, ethyl, n-propyl or allyl, with an oxidizing agent to provide the compounds of formula IV wherein X is F, Cl, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl, and R1 and R2 are individually methyl, ethyl, n-propyl or allyl; or b) reacting a compound of the formula EMI104.1 wherein R14 and R13 are individually ethyl, n-propyl or allyl, with cuprous cyanide or an alkali or alkaline earth cyanide and cuprous iodide in l-methyl-2-pyrrolidone to provide the compounds of formula IV wherein X is CN and R1 and R2 are individually ethyl, n-propyl or allyl; or c) reacting a compound of the formula EMI104.2 wherein R14 and R13 are defined as before, with a hydroxide base in a C1-C4 alkanol to provide the compounds of formula IV wherein X is CONH2 and RI and R2 are individually ethyl, n-propyl or allyl; or reacting a compound of the formula EMI105.1 wherein R14 and R13 are defined as before, with NaX2 and CuI where X2is O-benzyl, O-acyl or O(C1-C3 alkyl) to provide the compounds of formula IV where X is O(C1-C3 alkyl), O-benzyl or O-acyl and R1 and R2 are individually ethyl, n-propyl or allyl; or e) reacting a compound of the formula EMI105.2 wherein X4is O-benzyl, or O(C1-C3 alkyl) and R14 and R13 are defined as before, with a de-etherifying agent to provide the compounds of formula IV wherein X is OH and R1 and R2 are individually ethyl, n-propyl or allyl; or f) reacting a compound of the formula EMI106.1 where R13 and R14 are defined as before, with a hydroxide or alkoxide base to provide the compounds of formula IV wherein X is OH and RÚ and Rê are individually ethyl, n-propyl or allyl; or g) reacting a compound of the formula EMI106.2 wherein R1 and R2 are defined as before, with a reducing agent to provide the compounds of formula IV wherein X is NH2; ; or h) reacting a compound of the formula EMI106.3 wherein X1 is F, Cl or O(C1-C3 alkyl), 27 is C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, or O-benzyl, and R15 is H or C1-C3 alkyl, with basic cleavage or when z is O-benzyl with catalytic hydrogenation to provide the compounds of formula IV wherein X is F, Cl or O(C1-C3 alkyl) and R1 is hydrogen and R2 is C1-C3 alkyl or hydrogen; or i) reacting a compound of the formula EMI107.1 wherein X5 and R15 are defined as before, with an alkylating agent or by reductive amination to provide the compounds of formula IV where X is F, Cl, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl, and R1 and R2 are individually methyl, ethyl, n-propyl, or allyl or one of RÚ and Rê may be hydrogen; or j) reacting a compound of the formula EMI107.2 where R8 is hydrogen, methyl, ethyl or n-propyl and Y is hydrogen methyl, ethyl or chloromethyl, with a borane complex to provide the compounds of formula IV where X is CN and R1 and R2 are individually hydrogen, methyl, ethyl or n-propyl; or k) reacting a compound of the formula EMI108.1 where R1 and R8 are defined as before, with a peptide coupling agent and ammonia to provide the compounds of formula IV where X is CONH2, R2 is H, methyl, ethyl or n-propyl and R1is defined as before; or 1) reacting a compound of the formula EMI108.2 wherein R8 is defined as before, with an R1 halide or by reductive amination with a hydrogen catalyst to yield the compounds of formula IV where X is CONH2, R2 is H, methyl, ethyl or n-propyl and R1 is defined as before; m) optionally salifying the compounds of formula IV. 6. A pharmaceutical formulation which comprises as an active ingredient a compound of formula IV, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4, associated with one or more pharmaceutically-acceptable carriers or excipients there for. 7. A pharmaceutical formulation of claim 6 adapted for oral administration. 8. A compound of formula IV, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4, for use as a central serotonin agonist in the chemotherapy of warm-blooded animals. 9. A compound of the formula EMI109.1 wherein R5 and R6 are individually methyl, ethyl, npropyl or allyl; X6 is NO2, O(C1-C3 alkyl), Br, Cl, or F; or an acid addition salt thereof. 10. A compound of the formula EMI110.1 wherein R5 and R6 are individually methyl, ethyl, n-propyl or allyl; X6 is NO2, O(C1-C3 alkyl), Br, Cl, or F; and Z is a protecting group; or an acid addition salt thereof. 11. A compound of the formula EMI110.2 wherein X6 in NO2, O(C1-C3 alkyl), Br, Cl, or F; and Z is a protecting group; or an acid addition salt thereof. CLAIMS 1. A process for preparing a compound of the formula EMI112.1 wherein R1 and R2 are individually hydrogen, methyl, ethyl, n-propyl or allyl, and X is F, Cl, Br, CN, CONH2, NH2 N02, O(Cl-C3 alkyl), O-acyl, OH or O-benzyl; or a pharmaceutically-acceptable salt thereof; which is characterized by: a) reacting a compound of the formula EMI112.2 wherein X5 is F, Cl, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl; R5 and R6 are individually methyl, ethyl, n-propyl or allyl, with an oxidizing agent to provide the compounds of formula IV wherein X is F, Cl, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl, and R1 and R2 are individually methyl, ethyl, n-propyl or allyl; or b) reacting a compound of the formula EMI113.1 wherein R14 and R13 are individually ethyl, n-propyl or allyl, with cuprous cyanide or an alkali or alkaline earth cyanide and cuprous iodide in l-methyl-2-pyrrolidone to provide the compounds of formula IV wherein X is CN and R1 and R2 are individually ethyl, n-propyl or allyl; or c) reacting a compound of the formula EMI113.2 wherein R14 and R13 are defined as before, with a hydroxide base in a C1-C4 alkanol to provide the compounds of formula IV wherein X is CONH2 and R1 and R2 are individually ethyl, n-propyl or allyl; or d) reacting a compound of the formula EMI114.1 wherein R14 and R13 are defined as before, with NaX2 and CuI where X2 is O-benzyl, O-acyl or O(C1-C3 alkyl) to provide the compounds of formula IV where X is O(C1-C3 alkyl), O-benzyl or O-acyl and RÚ and Rê are individually ethyl, n-propyl or allyl; or e) reacting a compound of the formula EMI114.2 wherein X4 is O-benzyl, or O(C1-C3 alkyl) and R14 and R13 are defined as before, with a de-etherifying agent to provide the compounds of formula IV wherein X is OH and R1 and R2 are individually ethyl, n-propyl or allyl; or f) reacting a compound of the formula EMI115.1 where R13 and R14 are defined as before, with a hydroxide or alkoxide base to provide the compounds of formula IV wherein X is OH and R1 and R2 are individually ethyl, n-propyl or allyl; or g) reacting a compound of the formula EMI115.2 wherein R1 and R2 are defined as before, with a reducing agent to provide the compounds of formula IV wherein X is NH2; or h) reacting a compound of the formula EMI116.1 wherein X1 is F, Cl or O(C1-C3 alkyl), Z7 is C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, or O-benzyl, and R15 is H or C1-C3aIkyl, with basic cleavage or when Z7 is O-benzyl with catalytic hydrogenation to provide the compounds of formula IV wherein X is F, Cl or O(C1-C3 alkyl) and R1 is hydrogen and R2 is C1-C3 alkyl or hydrogen; or i) reacting a compound of the formula EMI116.2 wherein X5 and R15 are defined as before, with an alkylating agent or by reductive amination to provide the compounds of formula IV where X is F, Cl, Br, NO2, O(C1-C3 alkyl), O-acyl or O-benzyl, and RÚ and Rê are individually methyl, ethyl, n-propyl, or allyl or one of RÚ and Rê may be hydrogen; or j) reacting a compound of the formula EMI117.1 where R8is hydrogen, methyl, ethyl or n-propyl and Y is hydrogen, methyl, ethyl or chloromethyl, with a borane complex to provide the compounds of formula IV where X is CN and R1 and R2 are individually hydrogen, methyl, ethyl or n-propyl; or k) reacting a compound of the formula EMI117.2 where R1 and R8 are defined as before, with a peptide coupling agent and ammonia to provide the compounds of formula IV where X is CONH2, R2 is H, methyl, ethyl or n-propyl and R is defined as before; or I) reacting a compound of the formula EMI118.1 wherein R8 is defined as before, with an R1 halide or by reductive amination with a hydrogen catalyst to yield the compounds of formula IV where X is CONH2, R2 is H, methyl, ethyl or n-propyl and R1 is defined as before; m) optionally salifying the compounds of formula IV. 2. A process of claim 1 characterized in that the compounds of formula IV have X equal F, Cl, Br, CN, CONH2, NH2 or NO2. 3. The process of claim 1(a) for preparing (#)-4-di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz- [c,d]indole which is characterized by reacting (i)-4 di-n-propylamino-6-bromo-1, 2, 2a, 3,4, 5-hexahydrobenz- [c,d]indole with N-chlorosuccinimide, dimethylsulfide and triethylamine. 4. The process of claim 1(a) for preparing (i)-4-di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz [c,d]indole which is characterized by reacting (i)-4 di-n-propylamino-6-bromo-1, 2, 2a, 3,4, 5-hexahydrobenz- [c,d]indole with manganese dioxide. 5. The process of claim l(b) for preparing (+)-4-di-nepropylamino-6-cyano-1,3,4,5-tetrahydrobenz- [c,d]indole which is characterized by reacting (+)-4- di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]- indole with cuprous cyanide. 6. The process of claim l(c) for preparing (i)-4-di-n-propylamino-6-carbamoyl-1,3,4,5-tetrahydrobenz[c,d]indole which is characterized by reacting (i) 4-di-n-propylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d]- indole with potassium hydroxide in t-butanol. 7. The process of claim l(a) for preparing (i)-4-di-n-propylamino-6-nitro-1,3,4,5-tetrahydrobenz [c,d]indole which is characterized by reacting (i)-4 di-n-propylamino-6-nitro-1,2,2a,3,4,5-hexahydrobenz- [c,d]indole with manganese dioxide. 8. The process of claim l(d) for preparing (i)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz [c,d]indole which is characterized by reacting (i)-4 di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]- indole with sodium methylate and cuprous iodide. 9. The process of claim l(a) for preparing (i)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole which is characterized by reacting cis (i)-4-di-n-propylamino-6-methoxy-l,2,2a,3,4,5- hexahydrobenz[c,d]indole with dimethylsulfide, t-butylhypochlorite, sodium and ethanol. 10. The process of claim l(a) for preparing (i)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole which is characterized by reacting trans (i)-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5- hexahydrobenz[c,d]indole with N-chlorosuccinimide, dimethylsurfide and triethylamine. 11. The process of claim 1(a) for preparing (i)-4-dimethylamino-6-methoxy-1,3,4,5-tetrahydrobenz [c,djindole which is characterized by reacting cis (#)-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydro- benz[c,d]indole with dimethylsulfide, N-chlorosuccinimide and triethylamine. 12. The process of claim l(c) for preparing (i)-4-dimethylamino-6-carbamoyl-1,3,4,5-tetrahydrobenz [c,djindole which is characterized by reacting (i)-4dimethylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d]indole with potassium hydroxide in t-butanol. 13. The process of claim 1(J) for preparing (#)-4-dimethylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d]- indole which is characterized by reacting N-formyl (#)-4-methylamino-6-cyano-1,3,4,5-tetrahydrobenz[c,d] indole with BH3-(CH3)2S in THF.

Inventors: FLAUGH, MICHAEL EDWARD
Applicants: ELI LILLY AND COMPANY
Application year: 1985
Main classification: C07D209
IPC codes: A61P25, A61P3, A61K31, C07D209