6-substituted-tetrahydrobenz[cd]indoles

Abstract: The present invention involves certain 4-amino-6-substituted-tetrahydrobenz [cd] indoles and their use in treating disorders which can be benefited by modifying 5-HT A receptor function.

Description: Field of the Invention This invention relates to tetrahydrobenz[cd]indoles which are useful in treating conditions requiring regulation of the serotonin function in the body. Background of the Invention Over the last several years it has become apparent that the neurotransmitter serotonin (5-hydroxytryptamine --5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression, blood pressure lowering and hallucinogenic behavior [Glennon, R. A., J. Med. Chem. , 30 , 1 (1987)]. It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT 1 , 5-HT 2 , and 5-HT 3 receptors, with the former being further divided into the sub-classes 5-HT 1A , 5-HT 1B , 5-HT 1C , and 5-HT 1D . The binding affinity of a compound for one or more 5-HT receptors can provide a desirable physiological effect or minimize an undesirable effect. Therefore it is desirable to provide compounds which can bind to 5-HT receptors to act as serotonin agonists or antagonists. Flaugh in US-A-4,576,959 (issued 1986) and in EP-A-0153083 (published 1985) disclosed a family of 6-substituted-4-dialkylamino-1,3,4,5-tetrahydrobenz[cd]indoles which are described as central serotonin agonists. Leander in US-A-4,745,126 (1988) disclosed a method for treating anxiety in humans employing a 4-substituted-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide derivative. DE-A-3525564 relates to 4-amino-tetrahydrobenz[c,d]indole and tetrahydroazepine[3,4,5-c,d]indole derivatives. EP-A-0332968 discloses tetrahydrobenz[c,d]indole derivatives useful for the treatment of CNS disorders. EP-A-0392768 relates to 4-amino-6-substituted-tetrahydrobenz[c,d]indole derivatives for use as pharmaceuticals. It has now been found that certain 6-acyl substituted-4- amino-tetrahydrobenz[cd]indoles are useful in treating conditions which can be benefited by a modification of 5-HT 1 A receptor function in the body. It has been further found that certain of the instant compounds have substantial affinity for the 5-HT 1D receptor and can be useful in treating conditions which can be benefitted by modifying 5-HT 1A or 5HT 1A and 5-HT 1D receptor function in the body. Summary of the Invention This invention relates to compounds of the Formula wherein: R 1 is hydrogen, C 1 -C 4 alkyl, cyclopropylmethyl, or phenyl substituted C 1 -C 4 alkyl; R 2 is hydrogen, C 1 -C 4 alkyl, or cyclopropylmethyl; R 3 is hydrogen, C 1 -C 4 alkyl or a blocking group; R 4 is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy or C 1 -C 3 thioalkyl, phenyl or phenyl substituted with one or two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy, C 1 -C 3 thioalkyl, C 1 -C 3 alkyl or trifluoromethyl ; or a pharmaceutically acceptable salt thereof. The invention also provides a pharmaceutical formulation comprising a compound of Formula I and a pharmaceutically acceptable excipient therefor. A further embodiment of the invention is a method for effecting a biological response at a 5-HT receptor by administering an effective amount of a compound of Formula I. Further embodiments involve the treatment of disease states with require regulation of serotonin function in the body. Detailed Description of the Invention As used herein, the term "alkyl" represents a straight or branched alkyl chain having the indicated number of carbon atoms. For example, "C 1 -C 4 alkyl" groups are methyl, ethyl, n -propyl, isopropyl, n -butyl, sec .-butyl, isobutyl and tert -butyl. "C 1 -C 8 alkyl" groups include these listed for C 1 -C 4 alkyl as well as n -pentyl, 2-methylbutyl, 3-methylbutyl, n -hexyl, 4-methylpentyl, n -heptyl, 3-ethylpentyl, 2-methylhexyl, 2,3-dimethylpentyl, n -octyl, 3-propylpentyl and, 6-methyl-heptyl. The tern "C 1 -C 3 alkyl" means any of methyl, ethyl, n -propyl, and isopropyl; the term "C 1 -C 3 alkoxy" means any of methoxy, ethoxy, n-propoxy, and isopropoxy; the term "halo" means any of fluoro, chloro, bromo, and iodo; and the term "C 1 -C 3 thioalkyl" means any of methylthio, ethylthio, n -propylthio, and isopropylthio. Examples of substituted C 1 -C 8 alkyl are methoxymethyl, trifluoromethyl, 6-chlorohexyl, 2-bromopropyl, 2-ethoxy-4-iodobutyl, 3-hydroxypentyl and methylthiomethyl. Examples of substituted phenyl are p -bromo-phenyl, m -iodophenyl, n -tolyl, o -hydroxyphenyl, p -(methylthio)phenyl, m -trifluoro- methylphenyl, and 2-chloro-4-methoxyphenyl. The term "blocking group" is used as it is frequently used in synthetic organic chemistry, to refer to a group which can bond to a nitrogen such as in an amino group and prevent the nitrogen from participating in a reaction carried out on some other functional group of the molecule, but which can be removed from the nitrogen when it is desired to do so. Such groups are discussed by T. W. Greene in chapter 7 of Protective Groups in Organic Synthesis , John Wiley and Sons, New York, 1981, and by J. W. Barton in chapter 2 of Protective Groups in Organic Chemistry , J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include those of the formula -COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1- phenylethyl, isobutyl, t -butyl, t -amyl, vinyl, allyl, phenyl, benzyl, p -nitrobenzyl, o -nitrobenzyl, and 2,4-dichlorobenzyl, benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o -nitrobenzyl, and triphenylmethyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p -methoxybenzoyl; and other groups such as methanesulfonyl, p -toluenesulfonyl, p -bromobenzenesulfonyl, p -nitrophenylethyl, and p -toluenesulfonylaminocarbonyl. Preferred blocking groups are benzyl (-CH 2 C 6 H 5 ), triphenylmethyl (trityl), acyl [C(O)R] or SiR 3 where R is C 1 -C 4 alkyl, halomethyl, 2-halo-substituted alkoxy, or phenyl. Particularly preferred blocking groups are -CO 2 CH 2 CCl 3 and triphenylmethyl. The compounds of the instant invention have at least one chiral center and therefore at least two stereoisomers can exist for each. A chiral center exists at position 4 as in Formula I. If a substituent group contains a chiral center, then additional stereoisomers can of course exist. Racemic mixtures as well as the substantially pure stereoisomers of Formula I are contemplated as within the scope of the present invention. By the term "substantially pure", it is meant that at least about 90 mole percent, more preferably at least about 95 mole percent and most preferably at least 98 mole percent of the desired stereoisomer is present compared to other possible stereoisomers. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" refers to "right" and refers that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" or "left" refers to that configuration of a chiral center with a counterclockwise relationship of group priorties (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (heaviest isotope first). A partial list of priorities and a discussion of stereo chemistry is contained in the book: The Vocabulary of Organic Chemistry, Orchin, et al. , John Wiley and Sons Inc., publishers, page 126. While all of the compounds of the invention are useful for the purposes taught herein, certain of the present compounds are preferred for such uses. Preferably R 1 and R 2 are both C 1 -C 4 alkyl, and especially n -propyl. R 3 is preferably hydrogen, R 4 is preferably C 1 -C 4 alkyl or substituted C 1 -C 4 alkyl. Compounds containing a CHOH or C≡C group, instead of the C=O group of the compounds of formula I, are intermediates in the preparation of compounds of formula I. Other preferred aspects of the present invention are noted hereinafter. As pointed out above, this invention includes the pharmaceutically-acceptable salts of the compounds of Formula I. Since the compounds of this invention are amines, they are basic in nature and accordingly react with any number of inorganic and organic acids to form pharmaceutically acceptable salts such as hydro-chloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and others, as well as salts derived from non-toxic organic acids such as aliphatic mono and dicarboxylic acids, amino acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acid, 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, tartrate isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, hippurate, benzoate, chlorobenzoate, methylbenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mesylate. The following list illustrates representative compounds of the present invention: 4-(di- n -propylamino)-6-acetyl-1,3,4,5-tetrahydrobenz[cd]indole; 4-(di- n -propylamino)-6-(2,2-dimethylpropanoyl)-1,3,4,5-tetrahydrobenz[cd]indole; 4-(diethylamino)-6-propanoyl-1,3,4,5-tetrahydrobenz[cd]indole; 4-(di- n -propylamino)-6-benzoyl-1,3,4,5-tetrahydrobenz[cd]indole; 4-( n -propylamino)-6-(2-methylpropanoyl)-1,3,4,5-tetrahydrobenz[cd]indole; 4-(N- n -propyl-N-cyclopropylmethyl)amino-6-propanoyl-1,3,4,5-tetrahydrobenz[cd]indole. Scheme 1 depicts a process for preparing compounds of the present invention wherein R 1 , R 2 and R 4 are as defined above and Z is an amino-blocking group as defined hereinabove. According to one route of this process, a 4-amino-6-bromotetrahydrobenz[cd]indole 1 is combined with an equimolar to slight excess amount of potassium hydride in diethyl ether. The reagents are generally combined at a cold temperature, typically in the range of -20°C to 10°C, preferably at about 0°C. The resulting mixture is cooled to a temperature in the range of -100°C to -60°C, preferably at about -78°C, and combined with a lithiating reagent, preferably in at least a two molar excess amount. Suitable lithiating reagents include sec -butyllithium, the preferred t -butyllithium, and other similar organolithium compounds is preferred. The reaction is preferably conducted at a temperature in the range of -100°C to -20°C, more preferably at -60°C to -40°C. The 4-amino-6-lithiotetrahydrobenz[c,d]indole 2 thus prepared is then contacted with an appropriate electrophile such as L-C(O)R 4 wherein R 4 is defined above and L is a good leaving group such as chlorine bromine, methoxy and phenoxy. Typically, a solution of the compound 2 at a temperature in the range of -100°C to -60°C, preferably at about -80°C, is added to a solution of this reagent in a mutual solvent. If an excess amount of the electrophile is employed in the reaction, the 1-amino group is also acylated (ie Z is the acyl group R 4 C(O) in compound 3a ) and a subsequent hydrolysis reaction is required to provide the free indole, I . A 1:1 ratio of electrophile to lithiated indole (compound 2 ) can be used to minimize acylation of the 1-nitrogen. The reaction is preferably conducted at a temperature in the range of -40°C to 10°C. The desired compound is purified by quenching the reaction mixture with, for example, ice water when a 1:1 ratio is used. With a higher ratio in which significant 1-acylation is obtained, the product is hydrolyzed using an acid such as phosphoric acid or a base such as sodium carbonate or sodium hydroxide. The mixture is then washed with a water-immiscible organic solvent. The organic phase is extracted with acid; the aqueous phases are combined and made basic; and the desired compound is extracted with a water immiscible organic solvent. The organic solvent is then concentrated, typically under vacuum, and the desired compound I is further purified, if necessary, by standard procedures. lithiating reagent, preferably in at least a two molar excess amount. Suitable lithiating reagents include sec -butyllithium, the preferred t -butyllithium, and other similar organolithium compounds is preferred. The reaction is preferably conducted at a temperature in the range of -100°C to -20°C, more preferably at -60°C to -40°C. The 4-amino-6-lithiotetrahydrobenz[c,d]indole 2 thus prepared is then contacted with an appropriate electrophile such as L-C(O)R 4 wherein R 4 is defined above and L is a good leaving group such as chlorine bromine, methoxy and phenoxy. Typically, a solution of the compound 2 at a temperature in the range of -100°C to -60°C, preferably at about -80°C, is added to a solution of this reagent in a mutual solvent. If an excess amount of the electrophile is employed in the reaction, the 1-amino group is also acylated (ie Z is the acyl group R 7 C(O) in compound 3a ) and a subsequent hydrolysis reaction is required to provide the free indole, I . A 1:1 ratio of electrophile to lithiated indole (compound 2 ) can be used to minimize acylation of the 1-nitrogen. The reaction is preferably conducted at a temperature in the range of -40°C to 10°C. The desired compound is purified by quenching the reaction mixture with, for example, ice water when a 1:1 ratio is used. With a higher ratio in which significant 1-acylation is obtained, the product is hydrolyzed using an acid such as phosphoric acid or a base such as sodium carbonate or sodium hydroxide. The mixture is then washed with a water-immiscible organic solvent. The organic phase is extracted with acid; the aqueous phases are combined and made basic; and the desired compound is extracted with a water immiscible organic solvent. The organic solvent is then concentrated, typically under vacuum, and the desired compound I is further purified, if necessary, by standard procedures. In an alternative route, the 1-nitrogen can be "blocked" or "protected" before initiating the metallation reaction. A blocking group (depicted as "Z") such as SiR 3 or CH 2 (C 6 H 5 ) where R is C 3 -C 4 alkyl, preferably triisopropyl or phenyl (C 6 H 5 ) is preferably used for indole reactants, with a trityl group preferably used for indoline reactants. Compound 1a is then reacted with a lithiating agent as described above to provide compound 2a . Compound 2a can then be acylated by contacting with a suitable electrophile as described hereinabove. The resulting compound 3a is then deprotected by treatment with a fluoride salt when Z is SiR 3 , or when Z is benzyl compound 3a can be subjected to hydrogenolysis over a catalyst such as palladium to remove the benzyl group. The desired compound is isolated by standard conditions and purified by crystallization from common solvents or column chromatography over solid supports such as silica gel or alumina. An alternative synthesis of the compounds I is depicted in Scheme 2 and involves treatment of the 6-lithio derivatives 2 and 2a (depicted in Scheme 1) with an aldehyde, R 4 CHO, to form an alcohol 4 or 4a . Oxidation of the alcohol can be accomplished with oxidants known to those skilled in the art for such purposes such as pyridinium chlorochromate, dimethylsulfoxide and oxalyl chloride, an aqueous solution of chromic acid and sulfuric acid. Deprotection of the 1-amino group provides the free amine compounds I. In the processes depicted in Schemes 1 to 8, indoline analogues can serve as intermediates with the indole being subsequently formed by an oxidation reaction. The use of indolines or indoles is represented by the dashed line between carbons 2 and 2a in these Schemes. The oxidation can be effected at any stage which is appropriate in the scheme although normally the oxidation is accomplished as the final step using oxidizing agents as described hereinabove. As indicated hereinabove when indolines are used as reactants in Schemes 1 to 8, Z is preferably trityl whereas triisopropylsilyl is preferably used with indole reactants. The alcohol intermediates 4 and 4a can alternatively be prepared as depicted in Scheme 3 by addition of an organometallic reagent (R 4 M) such as an alkyl lithium R 4 Li or a Grignard reagent R 4 MgX to aldehyde 5 and 5a , respectively. Various routes can be used to prepare aldehydes 5 and 5a . The methods disclosed herein are not intended to be exhaustive and other procedures may be apparent to those skilled in the art. One route involves reacting 6-lithioderivatives 2 and 2a with dimethylformamide followed by aqueous work up. Another method depicted in Scheme 4 involves the preparation of the 6-nitrite derivative 6 followed by reduction and hydrolysis. The 1-benzoyl-6-bromo-derivative 1 is contacted for example with a mixture of cuprous cyanide and cuprous iodide in dimethylformamide at about 140°C or with cuprous cyanide and N-methylpyrrolidone at about 200°C. The resulting 6-nitrile 6 is hydrogenated over a catalyst such as palladium on carbon in the presence of semicarbazide to provide 6-semicarbazone compound 7. This is hydrolyzed using sulfuric acid to provide aldehyde 5 . In a preferred method of preparation, depicted in Scheme 5, the 6-nitrile derivative 6 (where Z is a blocking group such as benzyl) is contacted with a reducing agent [H] such as diisobutylaluminum hydride. The resulting aldehyde 5a can be contacted with an organometallic reagent such as a Grignard reagent, R 4 MgBr, to provide alcohol 4a which is oxidized as described hereinabove to the 1-blocked-6-acyl derivative 3a . Alternatively, certain compounds of Formula I can be prepared using the 6-iodo derivative 9 as depicted in Schemes 6 and 7 wherein R 1 , R 2 and Z are as defined hereinabove. In Scheme 6 a method is shown in which a 6-alkyne derivative is prepared. This method provides 6-acyl compounds in which there is a methylene group adjacent to the carbonyl group. In this method the 1-nitrogen can be protected with a group (represented by Z) such as a benzoyl group, although the unprotected 1-nitrogen is preferred, ie Z is hydrogen. This compound 9 is contacted with a palladium catalyst Pd(PPh 3 ) 4 [where Ph is phenyl] and the tin alkyne compound R 4a -C≡C-Sn(CH 3 ) 3 . R 4a is a C 1 -C 7 alkyl or C 1 -C 7 alkyl substituted with one or two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy or C 1 -C 3 thioalkyl. This reaction is normally conducted in a solvent such as toluene at an elevated temperature, for example at about 100°C. Typically an excess of the tin alkyne is used along about 0.25 equivalents of the palladium compound based on compound 9 . The 6-alkyne 10 is then contacted with HgSO 4 in water to provide the ketone 11 . The 1-blocking group can be removed by hydrolysis with base as described above to provide compound I. In another preparation method depicted in Scheme 7, the 6-iodo derivative 9 can be used to prepare certain 6-acyl compounds directly. This is accomplished by contacting the 6-iodo compound with a trialkyltinalkyl complex and carbon monoxide in the presence of a palladium catalyst Pd(PPh 3 ) 4 [where Ph is phenyl] as described in the literature for arylhalides. [A. Schoenberg and R. F. Heck, J. Org. Chem. , 39 , p. 3327 (1974); and A. Schoenberg, I. Bartoletti, and R. F. Heck, J. Org. Chem. , 39 , p. 3318 (1974)]. Although a blocking group Z such as diethylcarbamoyl can be used for this method, the method can also be accomplished when Z is hydrogen. In Scheme 8 a preparative method is depicted in which a vinyl ether is reacted with the 6-iodo derivative 9 . R 1 , R 2 and Z are as defined hereinabove. This method provides a 6-(1-alkoxyalkenyl)derivative 81 which can then be hydrolyzed and deprotected to provide the desired compound of Formula I. Alternatively the derivative 81 can be deprotected, with for example butyl lithium, and then the vinyl group hydrolyzed. In this method the 1-amino group is protected with an amino protecting group, preferably a benzoyl group. This compound 9 is then contacted with a palladium catalyst and the desired vinyl ether. The vinyl ethers useful in this method include those in which RC is a C 1 -C 4 alkyl and Q is hydrogen or an alkyl tin, alkyl or alkoxy boron, zinc halide, or magnesium halide, for example tributyltin. when Q is zinc halide or magnesium halide, it is preferred that Z be a group such as trityl. R a and R b can independently be hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, whereby the substituents are defined such that the possible end products can be prepared. The palladium catalyst used can be palladium powder (black) or Pd(PPh 3 ) 4 [where Ph is phenyl]. The Pd(PPh 3 ) 4 is commonly used with toluene at reflux. The Pd-black can be used with triphenylphosphine in toluene at reflux or in a mixture of acetonitrite and triethyl amine at about 100°C. Similar reactions are reported in Bull. Chem. Soc. Jpn. (1987), 60 , 767-768. The processes depicted in Schemes 1-8 can result in a mixture of products which require purification by standard methods of purification, for example, crystallization or chromatographic techniques as appropriate. Scheme 9 illustrates a preparation of the starting material for reaction Scheme 1. Epoxides of formula 13 are known in the art or can be prepared from compounds such as ketone 12 , which is known to the art, using common reagents and techniques. For example, Flaugh, et al. , J. Med. Chem. , 31 , 1746 (1988); Nichols et al. , Org. Prep. and Proc., Int. , 9 , 277 (1977); and Leanna et al. , Tet. Lett. , 30 , No. 30, 3935 (1989), teach methods of preparation of various embodiments of compounds of formula 13 . Those skilled in the art of organic chemistry will recognize that there are four stereoisomers of formula 13 : Formulae 13a and 13b are herein referred to collectively as the exo-isomers; similarly, formulae 13c and 13d are the endo-isomers. Leanna et al. , supra , teach the preparation of epoxides of formula 13 which are substantially exo or substantially endo, as desired. A preferred starting material is the compound of formula 13 wherein R 3 is benzoyl; the most preferred starting material is the mixture of substantially the exo-isomers thereof. Amino alcohols of formula 14 are formed by reacting an epoxide of formula 13 with an amine of formula R 5 NH 2 , where R 5 can be hydrogen, a C 1 -C 4 alkyl, or a C 1 -C 4 alkyl substituted with one to three groups selected from halogen, nitro or phenyl. Such amines are readily available. Opening of the epoxide ring proceeds substantially regiospecifically with the amino group at the 5-position and the hydroxyl group at the 4-position. The reaction is also stereospecific in the sense that stereoisomers of formulae 14 a-d are predictably formed from, respectively, stereoisomers of formulae 13 a-d. A stereoselective synthesis of the amino alcohol of formula 14 , and hence of all the subsequent intermediates and products of Scheme 9, can be effected by using a substantially pure enantiomer of an amine of the formula R 5 NH 2 , wherein R 5 contains at least one chiral center. A particularly preferred amine is (+) or (-) 1-phenylethyl amine. The diastereomers of the resulting amino alcohol can then be separated by a number of means known in the art, for example by chromatography or crystallization. Suitable solvents for recrystallization include those such as diethyl ether, butanol, and mixtures of hexane and ethyl acetate. An alternative method of achieving a stereospecific synthesis comprises conversion of all the diastereomers of formula 14 to corresponding diastereomers of formula 15 , followed by the separation of said diastereomers of formula 15 ; that alternative method is discussed below. If a stereoselective synthesis is not desired, then separation of the stereoisomers of the amino alcohol of formula 13 is not required and the amine R 5 NH 2 need not be optically active. A particularly efficient stereoselective process for a highly preferred compound of formula 14 , 1-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole, comprises the reaction of a mixture of substantially the exo-isomers of the corresponding epoxide of formula 13 , or a mixture of substantially the endo-isomers of the corresponding epoxide of formula 13 , with a substantially pure enantiomer of 1-phenethylamine in the solvent butanol and the subsequent selective crystallization of one of the two isomers of the amino alcohol. The temperature of the reaction is preferably from 50° to 150°C, more preferably in the range of 80° to 100°C. After the reaction is complete, as determined for example by thin layer chromatography or liquid chromatography, the desired amino alcohol is crystallized at -20° to 40°C; the preferred temperature for the crystallization is 0° to 15°C. Therefore this process has the valuable attribute that the reaction and the separation of stereoisomers occur efficiently in a single step. By the proper selection of the epoxide isomers, exo or endo, and the enantiomer of 1-phenylethylamine, R or S, one can determine which of the stereoisomers of the compound of formula 14 precipitates from the reaction mixture. For example, a preferred stereoisomer of 1-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole, the (2a-S,4-R,5-R)-isomer can be selectively prepared by reacting the exo-epoxides with S-1-phenylethylamine. A number of methods of forming aziridines such as those of formula 15 from amino alcohols such as those of formula 14 are known to the art. Two examples are the use of diethyl azodicarboxylate and triphenylphosphine (O. Mitsunobu, Synthesis , January, 1981, page 1), and the use of bromine and triphenylphosphine (J. P. Freemer and P. J. Mondron, Synthesis , December, 1974, page 894). A particularly efficient alternative to the above methods involving treating a compound of formula 14 with a tertiary amine in an inert solvent followed by the addition of methanesulfonyl chloride. The stereoisomers 15 a-d of the aziridine 15 arise respectively from the stereoisomers of formula 14 a-d with retention of configuration at any chiral center in the substituents R 3 or R 5 as well as at position 2a: Suitable tertiary amines include those of the formula (R 6 ) N, where the R 6 groups are independently C 1 -C 4 alkyl. Suitable solvents are chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and the xylenes; and ethers such as tetrahydrofuran, diethyl ether, and methyl t -butyl ether. The reaction can be conducted at a temperature from -35° to 45°C. In the preferred embodiment, the amino alcohol is treated with triethylamine in methylene chloride at -20° to 0°C, then the reaction mixture is warmed to 15° to 35°C for the completion of the reaction. If desired, the product, an aziridine of formula 15 , can be crystallized from an appropriate solvent such as acetonitrile or isopropanol after an aqueous workup. In the event that R 5 contains at least one chiral center in substantially a single stereoconfiguration, the individual stereoisomers of the aziridine of formula 15 can be separated by methods such as chromatography and crystallization, thereby providing a stereospecific synthesis of the aziridine of formula 15 and subsequent products. The aziridine ring can be opened to form an intermediate secondary amine of formula 16 . A number of methods of opening aziridines are commonly known. It is, however, crucial that the method used for opening the aziridine to form a secondary amine of formula 16 be substantially regiospecific, i.e., the aziridine must be opened to form substantially the 4-amino compound rather than the 5-amino compound. One such method is catalytic hydrogenolysis as taught by Y. Sugi and S. Mitsui, Bull. Chem. Soc. Jap. , 43 , pp. 1489-1496 (1970). Catalysts which are suitable are the usual hydrogenation and hydrogenolysis catalysts, such as the noble metal catalysts; the preferred catalyst is palladium. Suitable solvents include hydrocarbons such as hexanes and heptanes; aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, and t- butylbenzene; alcohols such as methanol, ethanol, and isopropanol; and mixtures of solvents such as acetic acid mixed with said alcohols. Preferred solvents for preparing the compound of formula 16 , wherein R 3 is benzoyl, and R 5 is 1-phenylethyl, include glacial acetic acid or a mixture of methanol and phosphoric acid. The source of hydrogen can be an atmosphere of hydrogen supplied at a pressure of about 1 atmosphere or higher, or the source of hydrogen can be compounds which are suitable to serve as hydrogen donors in a catalytic transfer hydrogenolysis reaction, such as formic acid or hydrazine. The preferred hydrogen source is an atmosphere of hydrogen gas supplied at 1 to 10 atmospheres pressure. The temperature of the reaction may be from -20° to 80°C; the preferred temperature for the hydrogenolysis of the aziridine wherein R 3 is benzoyl and R 5 is 1-phenylethyl is -20° to 0°C. The conversion of compounds of formula 15 to compounds of formula 16 proceeds without disturbing the stereochemical configuration of the chiral centers at the 2a-or 4- positions of the formula 16 or of the chiral centers that may be present in any of the substituents. If desired, the compound of formula 16 can be isolated by the usual methods such as crystallization. The secondary amine at position 4 of formula 16 can be converted to a primary amine of formula 17 by a number of methods known to the art of organic chemistry, or alternatively the secondary amine itself can be isolated. However, a preferred method is to convert the secondary amine of formula 16 to the primary amine of formula 17 without isolating the secondary amine, but rather by simply continuing without interruption the hydrogenolysis reaction that produced the compound of formula 16 . Therefore, the preferred solvent and catalyst are the same as those for the preparation of the secondary amine of formula 16 . It may be desirable to conduct the hydrogenolysis of the secondary amine of formula 16 at a different temperature or a different pressure or different temperature and pressure than the hydrogenolysis of the aziridine of formula 15 . For the hydrogenolysis of the preferred compound of formula 16 wherein R 3 is benzoyl and R 5 is 1-phenylethyl, the preferred temperature and pressure are 50° to 60°C and 1 to 20 atmospheres. Under these conditions, the hydrogenolysis of compounds of formula 16 to compounds of formula 17 proceeds without disturbing the stereochemical configuration of the chiral center at the 4-position. The isolation of the compound of formula 17 can be accomplished by the usual methods such as crystallization. If desired, the compound of formula 17 can be further purified, for example by recrystallization. The compound of formula 17 can be halogenated to provide, for example, the 6-bromo or 6-iodo derivative 18 . Iodination of compound 17 can be accomplished by using iodine and orthoperiodic acid in the presence of an acid such as sulfuric acid or trifluoroactic acid, in a solvent such as acetic acid. Another method of iodination involves the use of N- iodosuccinimide in the presence of trifluoroacetic acid. The 6-bromo derivative can be prepared using bromine in acetic acid or using N-bromosuccinimide. The formation of the indole by oxidation of the indoline can be effected as depicted in Scheme 9, ie as the final step to form structure 19 , or it can be accomplished earlier in the process. Appropriate oxidizing agents include MnO 2 , palladium on carbon, dimethylsulfoxide and oxalyl chloride. Compounds of Formula I can be prepared from the appropriate compound of formula 19 , whether it exists as a mixture of stereoisomers or as a substantially pure enantiomer using common reagents and methods well known in the art. A preferred intermediate to the compounds of the instant invention is the 6-bromo-derivative of 19 although the 6-iodo derivative is preferred if the carbonylation reaction of Scheme 7 is used. Preferably R 3 is a blocking group such as benzoyl. Amino blocking groups can be added, if desired, to the 4-amino substituent using such methods as those disclosed by Greene, supra , and Barton, supra . Alkyl groups can be added, if desired, to the 4-amino substituent using such common methods as reaction of the 4-amine with the appropriate halide as discussed by Morrison and Boyd, Chapter 22, Organic Chemistry , Third Edition, Allyn and Bacon, Boston, 1973. If desired, the benzoyl group can be removed from the 1-position using known methods and optionally replaced with other amino-protecting groups. The amino-protecting groups and alkyl groups can be added either before or after the bromination, as desired. The 4-amino-6-bromotetrahydrobenz[cd]indole starting materials used to prepare the compounds of the invention can be readily prepared by other processes such as disclosed in US-A-4,576,959 and EP-A-0153083 of Flaugh. The following examples further illustrate the preparation of the compounds of this invention. The examples are provided for purposes of illustration. The terms and abbreviations used in the instant examples have their normal meaning unless otherwise designated, for example, "°C" refers to degrees celsius; "N" refers to normal or normality; "mmol" referes to millimole; "g" refers to gram; "ml" or "mL" means milliliter; "M" refers to molar; "min" refers to minutes; "Me" refers to methyl; "Pr" refers to propyl; "Et" refers to ethyl; "THF" refers to tetrahydrofuran; "EtOAc" refers to ethyl acetate; "mp" means melting point; "TLC" refers to thin layer chromatography; "hr" refers to hours; "NMR" refers to nuclear magnetic resonance; "IR" refers to infrared spectroscopy; "U.V." refers to ultraviolet spectroscopy; and "m.s." refers to mass spectrometry. Example 1 Preparation of ( )-6-(2,2-Dimethylpropanoyl)-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A. Preparation of ( )-6-Bromo-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]-indole. To a suspension of 1.25 g (7.50 mmol) of potassium hydride (24% dispersion in mineral oil) in 50 mL of THF at 0°C was added a solution of 2.00 g (5.97 mmol) of 6-bromo-4-(di- n - propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 2 mL of THF. After stirring for 40 min, an addition of 1.90 mL (7.18 mmol) of triisopropylsilyl triflate was made. Stirring was continued for another hour. The mixture was then poured into cold NaHCO 3 solution, and the product was extracted into CH 2 Cl 2 . This extract was washed with Nacl solution and dried over Na 2 SO 4 . Evaporation of the CH 2 Cl 2 left a brown oil which was chromatographed over 50 g of silica gel using toluene followed by 1:3 EtOAc/toluene. The silylated product from the column was isolated as a light brown oil in quantitative yield. The product slowly crystallized upon standing. B. Preparation of ( )-6-(2,2-Dimethylpropanoyl)-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.50 g (1.02 mmol) of the above 1-silylated compound of 20 mL of diethyl ether was stirred at -65°C as 1.50 mL (2.31 mmol) of 1.54 M t -butyllithium (in pentane) was added. After stirring at -70°C for another 30 minutes, a rapid addition of 0.50 mL (4.00 mmol) of 2,2-dimethylpropionyl chloride was made. The mixture was allowed to warm to -10°C. It was then shaken with 50 mL of cold NaHCO 3 solution for several minutes, and the product was extracted into diethyl ether. This extract was washed with Nacl solution and dried over Na 2 SO 4 . Evaporation of the ether left an oil which was chromatographed over 7 g of silica gel using 1:19 EtOAc/toluene and then 1:9 EtOAc/toluene. The product from the column was a viscous oil weighing 0.375 g (74% yield). C. A solution of 0.345 g (0.70 mmol) of the above ketone in 7.0 mL of THF at 0°C. was treated with 1.5 mL of 1 M tetrabutylammonium fluoride in THF. After strirring for 30 minutes, the solution was poured into 25 mL of water containing 0.5 g of tartaric acid. This solution was washed with CH 2 Cl 2 , and these washings were extracted with fresh dil. tartaric acid solution. The combined aqueous solutions were basified with 5 N NaOH solution, and the product was extracted with CH 2 Cl 2 . After drying the extracted over Na 2 SO 4 , the solvent was evaporated and the residual oil was chromatographed over 7 g of silica gel using 1:9 EtOAc/toluene. The product from the column crystallized when triturated with hexane. Recrystallization from hexane afforded 0.175 g (88% yield) of ( )-6-(2,2-dimethylpropanoyl)-4-(di- n -propylamino) -1,3,4,5-tetrahydrobenz[cd]indole, mp 92°C. Analysis for (C 22 H 32 N 2 O): Theory: C, 77.60; H, 9.47; N, 8.23 Found: C, 77.89; H, 9.37; N, 8.17 NMR: (300 MHz, CDCl 3 ) δ 0.89 (t, 6H, CCH 3 of NPr), 1.31 (s, 9H, CCH 3 of Bu t ), 1.45 (sextet, 4H, CH 2 Me), 2.53 (t, 4H, CH 2 Et), 2.79 (dd, 1H, 3α-H), 2.94 (mult, 2H, 5-CH 2 ), 2.95 (dd, 1H, 3β-H), 3.21 (mult, 1H, 4β-H), 6.87 (s, 1H, 2-H), 7.09 (d, 1H, 8-H), 7.19 (d, 1H, 7- H), 7.91 (s, 1H, 1-H). Example 2 Preparation of ( )-6-Acetyl-4-(di- n -propylamino)-1,3,4,5- tetrahydrobenz[cd]indole. A. Preparation of ( )-6-Cyano-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. To a suspension of 1.00 g (6.0 mmol) of potassium hyride (24% dispersion in mineral oil) in 25 mL of THF at 0°C. was added 0.90 g (3.20 mmol) of 6-cyano-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[c,d]-indole. After stirring for 30 min, an addition of 1.00 mL (3.72 mmol) of triisopropylsilyl triflate was made. The mixture was then stirred at room temp. for 15 hours. It was then poured into cold water, and the product was extracted into CH 2 Cl 2 . This extract was washed with NaCl solution and dried over Na 2 SO 4 . Evaporation of the CH 2 Cl 2 left a brown oil which was chromatographed over 15 g of silica gel using successively 1:1 hexane/toluene, toluene, and then 1:19 EtOAc/toluene. The silylated product from the column was a light brown oil weighing 0.85 g (61% yield). The product slowly crystallized upon standing. B. Preparation of ( )-6-Acetyl-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.30 g (0.69 mmole) of the above nitrile in 10 mL of benzene was treated with 2.0 mL of 1.0 M methylmagnesium bromide in diethyl ether. This mixture was heated at 65°C for 15 hours. After cooling, the excess Grignard reagent was decomposed with ice chips. The mixture was then stirred for an hour with 10 mL of saturated NH 4 Cl solution. The benzene layer was separated, and the aqueous layer was extracted with fresh benzene. The combined organic solutions were dried over Na 2 SO 4 then evaporated to a viscous oil. Chromatography of this oil over 5.0 g of silica gel using 1:9 EtOAc/toluene followed by 1:1 EtOAc/toluene afforded 0.29 g (93% yield) of 6-acetyl compound as a pale yellow oil which slowly crystallized upon standing. C. A solution of 0.10 g (0.22 mmol) of the above ketone in 2.5 mL of THF at 0°C. was treated with 0.5 mL of 1M tetrabutylammonium fluoride in THF. After stirring for 30 minutes, the solution was poured into 10 mL of water containing 0.2 g of tartaric acid. This solution was washed with CH 2 Cl 2 , and these washings were extracted with fresh dil. tartaric acid solution. The combined aqueous solutions were basified with 1 N NaOH solution, and the product was extracted with CH 2 Cl 2 . After drying the extract over Na 2 SO 4 , the solvent was evaporated leaving a crystalline residue. Recrystallization from toluene/hexane afforded 0.045 g (68% yield) of ( )-6-acetyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole, mp 148.5-150°C. Analysis for (C 19 H 26 N 2 O) : Theory: C, 76.47; H, 8.78; N, 9.39 Found: C, 76.24; H, 8.85; N, 9.58 NMR: (300 MHz, CDCl 3 ) δ 0.90 (t, 6H, CCH 3 of NPr),1.48 (sextet, 4H, CH 2 Me), 1.57 (s, 3H, COCH 3 ), 2.58 (sextet, 4H, CH 2 Et), 2.78 (dd, 1H, 3α-H), 2.97 (dd, 1H, 3β-H), 3.07 (dd, 1H, 5α-H), 3.20 (mult, 1H, 4β-H), 3.71 (dd, 1H, 5β-H), 6.89 (s, 1H, 2-H), 7.15 (d, 1H, 8-H), 7.66 (d, 1H, 7-H), 8.00 (s, 1H, 1-H). Example 3 Preparation of (±)-6-propanoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.52 g (1.19 mmol) of (±)-6-cyano-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 25 mL of benzene was treated with 0.83 mL (1.66 mmol) of 2.0 M ethylmagnesium bromide in diethyl ether as in Example 2, part B. Chromatography of the 1-silylated product over silica gel using 1:9 EtOAc/toluene afforded 0.40 g (72% yield) of this material as a light oil. Treatment of this oil in 15 mL of THF with 1.2 mL of 1 M tetrabutylammonium fluoride (in THF) as in Example 2, part C gave, after silica gel chromatography (3:7 EtOAc/toluene) and recrystallization from toluene/hexane, 0.157 g (59% yield) of (±)-6-propanoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole, mp 149-150° C. Analysis (C 20 H 28 N 2 O) Theory: C, 76.88; H, 9.03; N, 8.96 Found: C, 76.60; H, 9.27; N, 8.96 NMR: (300 MHz, CDCl 3 ) δ 0.91 (t, 6H, CCH 3 of NPr),1.25 (t, 3H, CCH 3 of EtCO), 1.48 (sextet, 4H, CH 2 Me of NPr), 2.58 (sextet, 4H, CH 2 Et of NPr), 2.78 (dd, 1H, 3α-H), 3.00 (mult, 3H, 3β-H and CH 2 Me of EtCO), 3.08 (dd, 1H, 5α-H), 3.20 (mult, 1H, 4β-H), 3.70 (dd, 1H, 5β-H), 6.90 (s, 1H, 2-H), 7.16 (d, 1H, 8-H), 7.68 (d, 1H, 7-H), 8.01 (s, 1H, 1-H). Example 4 Preparation of (±)-6-butanoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.53 g (1.21 mmol) of (±)-6-cyano-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 25 mL of benzene was treated with 0.61 mL (1.70 mmol) of 2.8 M propylmagnesium chloride in diethyl ether as in Example 2, part B. Chromatography of the 1-silylated product over silica gel using 1:9 EtOAc/toluene afforded 0.38 g (65% yield) of this material as a light oil. Treatment of this oil in 15 mL of THF with 1.3 mL of 1 M tetrabutylammonium fluoride (in THF) as in Example 2, part C gave, after silica gel chromatography (3:7 EtOAc/toluene) and recrystallization from toluene/hexane, 0.149 g (58% yield) of (±)-6-butanoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole, mp 151-153° C. Analysis (C 20 H 28 N 2 O) Theory: C, 77.26; H, 9.26; N, 8.58 Found: C, 77.09; H, 9.39; N, 8.44 NMR: (300 MHz, CDCl 3 ) δ 0.91 (t, 6H, CCH 3 of NPr),1.03 (t, 3H, CCH 3 of PrCO), 1.48 (sextet, 4H, CH 2 Me of NPr), 1.80 (sextet, 2H, CH 2 Me of PrCO), 2.59 (sextet, 4H, CH 2 Et of NPr), 2.78 (dd, 1H, 3α-H), 2.97 (mult, 3H, 3β-H and CH 2 Et of PrCO), 3.08 (dd, 1H, 5α-H), 3.20 (mult, 1H, 4β-H), 3.68 (dd, 1H, 5β-H), 6.90 (s, 1H, 2-H), 7.16 (d, 1H, 8-H), 7.67 (d, 1H, 7-H), 8.03 (s, 1H, 1-H). Example 5 Preparation of (±)-6-(2-methylpropanoyl)-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.52 g (1.19 mmol) of (±)-6-cyano-1-triisopropylsilyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 25 mL of benzene was treated with 0.85 mL (1.70 mmol) of 2.0 M isopropylmagnesium chloride in diethyl ether as in Example 2, part B. Chromatography of the 1-silylated product over silica gel using 1:9 EtOAc/toluene afforded 0.40 g (70% yield) of this material as an oil. Treatment of 0.39 g of this oil in 15 mL of THF with 1.3 mL of 1 M tetrabutylammonium fluoride (in THF) as in Example 2, part C gave, after silica gel chromatography (3:7 EtOAc/toluene) and recrystallization from toluene/hexane, 0.106 g (40% yield) of (±)-6-(2-methylpropanoyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. mp 127.5-128°C. Analysis (C 21 H 30 N 2 O) Theory: C, 77.26; H, 9.26; N, 8.58 Found: C, 77.03; H, 9.02; N, 8.53 NMR: (300 MHz, DMSO- d 6 ) δ 0.87 (t, 6H, CCH 3 of NPr), 1.07 (d, 3H, CCH 3 of i-PrCO), 1.12 (d, 3H, CCH 3 of i-PrCO), 1.41 (sextet, 4H, CH 2 Me of NPr), 2.51 (mult, 4H, CH 2 Et of NPr), 2.70 (dd, 1H, 3α-H), 2.87 (dd, 1H, 3β-H), 2.95 (dd, 1H, 5α-H), 3.03 (mult, 1H, 4β-H), 3.43 (d, 1H, 5β-H), 3.57 (septet, 1H, CHMe 2 ) 7.04 (s, 1H, 2-H), 7.18 (d, 1H, 8-H), 7.60 (d, 1H, 7-H), 10.92 (s, 1H, 1-H). Example 6 Preparation of (±)-6-benzoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. Substituting 0.48 mL (4.14 mmol) of benzoyl chloride for the dimethylpropanoyl chloride, the acylation procedure (part B) of Example 1 was repeated. Silica gel chromatography using toluene followed by 1:9 EtOAc/toluene afforded the 1-silylated product as an oil. Treatment of this oil in 15 mL of THF with 2.5 mL of 1 M tetrabutylammonium fluoride (in THF) as in Example 2, part C gave, after silica gel chromatography (3:7 EtOAc/toluene) and recrystallization from toluene/hexane, 0.046 g (11% yield) of (±)-6-benzoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole, mp 149.5-150.5° C. Analysis (C 24 H 28 N 2 O) Theory: C, 79.96; H, 7.83; N, 7.77 Found: C, 79.77; H, 7.79; N, 8.02 NMR: (300 MHz, CDCl 3 ) δ 0.87 (t, 6H, CCH 3 ), 1.44 (sextet, 4H, CH 2 Me), 2.50 (t, 4H, CH 2 Et), 2.82 (dd, 1H, 3α-H), 3.00 (mult, 2H, 3β-H and 5α-H), 3.22 (mult, 1H, 4β-H), 3.28 (dd, 1H, 5β-H), 6.93 (s, 1H, 2-H), 7.14 (d, 1H, 8-H), 7.36 (d, 1H, 7-H), 7.46 (t, 2H, Ph), 7.56 (t, 1H, Ph), 7.82 (d, 2H, Ph), 8.02 (s, 1H, 1-H). Example 7 Preparation of (4R)-(+)-6-acetyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A. A mixture of 1-benzoyl-4,5-(endo)epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]-indole (21g, 0.076 mol) and (+)-R-1-phenethylamine (18g, 0.15mol) in 400ml of n-butanol was refluxed under N 2 for 16h. The reaction was concentrated in vacuo to provide 30g of an oil as an equal mixture of two diastereomeric amino alcohols. The mixture of amino alcohols was dissolved in 300ml of CH 2 Cl 2 and Et 3 N (30g, 0.225mol) was added at once under N 2 . The reaction mixture was cooled to -10°C then MsCl(12.9g, 0.011) was slowly added dropwise. The rate of addition was such as to maintain a reaction temperature between -10° and 5°C. Upon complete addition of MsCl, the reaction mixture was stirred for an additional 30min at -5°C and then 30 min at ambient temperature. To the reaction mixture was added 200ml of water and the mixture was stirred. The CH 2 Cl 2 solution was separated and washed successively sat'd NaHCO 3 sol and brine sol. The organic sol was dried (MgSO 4 ) and concentrated to dryness to provide a mixture of two diastereomeric aziridines. The mixture was separated by preparative HPLC (silica gel; hexanes/EtOAc gradient). The first diastereomer of the aziridines to be eluted was designated isomer 1 ; 6.6g, mp 162-163°C from i-PrOH. The second diastereomer to be eluted was designated as isomer 2 ; 7.4g, mp 144-145°C from isopropyl alcohol. B. (2aR,4R)-4-amino-1-benzzyl-1,2,2a,3,4,5-hexahydrobenzl[cd]indole A solution of aziridine isomer 1 (9.4g,0.025mol) in 90ml of glacial acetic acid was hydrogenated at 60psi and at 60°C over 5% Pd/C for 16h. The reaction mixture was filtered and the filtrate was evaporated to a residual oil. The residue was dissolved in 1N HCI and the acidic mixture was extracted once with EtOAC. The acidic solution was made alkaline with addition of concentrated NH 4 OH. The basic mixture was extracted with CH 2 Cl 2 . The CH 2 Cl 2 solution was washed with brine solution and dried (MgSO 4 ). The organic solution was evaporated to dryness to provide 2aR,4R-4-amino-1-benzoyl-1,2,2a,3,4,5-hexhydrobenz[cd] indole; 5.2g as an oil. C. (2aR, 4R) -4-amino-1-benzoyl-6-bromo-1,2,2a,3,4,5-hexahydrobenz[cd]indole A solution of (2aR, 4R)-4-amino-1-benzoyl-1,2,2a,3,4,5-hexahydro-benz[cd]indole(5.2g,0.019mol) and sodium acetate (6.2g,0.076) in 40mL glacial acetic acid (HOAc) and 10mL of MeOH was cooled to 10°C. to the reaction mixture was added dropwise a solution of bromine(3g, 0.019mol) in 10mL of glacial HOAc. The reaction temperature was maintained at 10°C during addition of the bromine. The reaction was then stirred at ambient temperature for 1h. The solvents were evaporated and the residue was dissolved in water. The acidic solution was made alkaline with cold 50% aqueous NaOH. The basic mixture was extracted twice with CH 2 Cl 2 . The organic solution was washed with brine solution, dried (MgSO 4 ) and concentrated in vacuo to provide 6.8g (2aR,4R)-6-bromo compound as an oil. D. (2aR, 4R)-1-benzoyl-6-bromo-4(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A reaction mixture of (2aR, 4R)-4-amino-1-benzoyl-6-bromo-1,2,2a,3,4,5-hexahydrobenz[cd]indole(6.8g, 0.019mol), K 2 CO 3 (8.28g, 0.06mol) and n-propyliodide(10.2g, 0.06mol) in 200mL of CH 3 CN was stirred at reflux temperature for 16h. The reaction mixture was filtered and solvent was evaporated. The residue was dissolved in EtOAc and the solution was extracted with dilute HCl. The acidic solution was made alkaline with concentrated NH 4 OH. The basic mixture was extracted with EtOAc. The organic solution was washed with brine solution and dried (MgSO 4 ). The EtOAc was evaporated to provide a residual oil. Chromatography (silica gel-EtOAc) gave product, 2.4g. E. (2aR,4R)-1-Benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole To a solution of (2aR,4R)-1-Benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexa-hydrobenz[cd]indole (2.4g;5mmol) in 100mL of dimethyl formamide (DMF) was added CuCN (1.34g,15mmol) and CuI (2.85g, 15mmol). The reaction mixture was stirred at reflux under a N 2 atmosphere for 16hr. The reaction mixture was poured into 500mL of water. The ppt was collected and washed several times with water. The ppt was suspended in dil NH 4 OH and slurried with EtOAc. The whole mixture was filtered thru a celite pad. The EtOAc sol was separated and washed with brine sol. The EtOAc sol was dried(MgSO 4 ) and conc to dryness to provide 1.7g of nitrile as an oil. F. (2aR,4R)-6-Cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole To a stirred solution of 1.7g (4.4mmol) of (2aR,4R)-6-Cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 25mL of THF cooled to -78°C under a N 2 atmosphere was added 5.5mL (8.8mmol) of 1.6M solution of n-BuLi in hexane. The reaction mixture was stirred at -78°C for 30 min. and then allowed to warm to -20°C. To the reaction mixture was added 20mL of 1N HCl. The mixture was extracted once with Et 2 O. The acidic solution was made alkaline with the addition of cold 5N NaOH. The basic mixture was extracted twice with CH 2 Cl 2 . The combined organic solution was washed with sat'd NaCl solution. The CH 2 Cl 2 solution was dried over MgSO 4 and evaporated to give 1.3g of an oil. Chromatography of this oil over silica gel with EtOAc as eluent gave 1g (80%) of product as an oil. G. (2aR,4R)-1-Trityl-6-Cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole To a sol of (2aR,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1g, 3.5mmol) and Et 3 N (354mg, 3.5mmol) in 50mL of methylene chloride was added a sol of triphenylmethyl chloride (trityl chloride)(0.98g,3.5mmol) in 10mL of methylene chloride dropwise at RT. The reaction mixture was stirred for 16hr at RT. The reaction mixture was extracted with water and cold 1N HCl. The organic sol was washed with sat'd NaHCO 3 sol and with sat'd brine sol. The organic sol was dried (MgSO 4 ) and conc to dryness in vacuo to give a residue. The residue was slurried with warm hexanes, cooled and filtered to remove insolubles. The filtrate was conc to an oil. The oil was chromatographed (silica gel, 20% EtOAc in hexanes) to provide 1.5g of (2aR,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole. H. (2aR,4R)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole A solution of 1.6g(3mmol) (2aR,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100ml of THF was treated with 20mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16hr. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of sat'd NH 4 Cl solution. The reaction mixture was extracted with EtOAc. The organic solution was evaporated to an oil. The oil was dissolved in 25mL of 5N HCl and the solution was stirred at room temperature for 30 min. The acidic solution was made alkaline with the addition of excess conc NH 4 OH solution. The basic mixture was extracted twice with EtOAc. The combined organic solution was washed once with sat'd Nacl solution and dried over MgSO 4 . The EtOAc solution was evaporated to yield 0.9g of an oil. Chromatography of this oil over silica gel with EtOAc as eluent gave 600mg of product. Recryst from hexanes to yield 228mg (-) ketone. mp 85-86°;[α] D = -4.94°(CH 3 OH) I. Formation of the Tetrahydrobenz[cd]indole A solution of 0.11 g (0.37 mmol) of (2aS,4R)-(+)-6-acetyl-4-(di- n -propylamino)-1,2,2a,3,4,5-hexahydrobenz[c,dlindole and 0.12 g (1 mmol) of indole in 5.0 mL of THF was stirred at 0° C. as 0.075 g (0.21 mmol) of benzeneseleninic anhydride was added. The solution was stirred at 25° C. for 4 hours. It was then poured into dil. tartaric acid solution and washed with CH 2 Cl 2 . The aqueous solution was basified with 1 N NaOH and extracted with CH 2 Cl 2 . An NMR spectrum of the oil obtained upon evaporation of the CH 2 Cl 2 revealed that the oxidation had proceded only to the extent of about 30%. The treatment with benzeneseleninic anhydride was repeated. TLC indicated that a small amount of starting material still remained. The treatment with benzeneseleninic anhydride was carried out a third time, this time with half as much oxidant. The crude product was chromatographed over 3 g of silica gel using 1:9 EtOAc/toluene followed by 1:4 EtOAc/toluene, then recrystallized from toluene/hexane. The purified product weighed 0.033 g (30% yield), mp 135.5-136° C. Analysis (C 19 H 26 N 2 O) Theory: C, 76.47; H, 8.78; N, 9.39 Found: C, 76.31; H, 8.97; N, 9.40 NMR: Identical to racemate [α] D = +118° (c=5mg/ml,CH 3 OH) Example 8 Preparation of (4S)-(-)-6-acetyl-4- (di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of about 0.15 g (0.50 mmol) of (2aR,4S)-(-)-6-acetyl-4-(di- n -propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 10 mL of CH 2 Cl 2 was sonicated (50-55 kHz) in the presence of 1.0 g of MnO 2 for 5 hours. The oxidant was removed by filtration through Celite, and the sonication was repeated with 1.0 g of fresh MnO 2 . The crude product obtained after filtering and removing the solvent was chromatographed over 3 g of silica gel using 1:9 EtOAc/toluene, then recrystallized from toluene/hexane. The purified (4S)-(-)-6-acetyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole weighed 0.020 g (13% yield), mp 133-134.5° C. Analysis (C 19 H 26 N 2 O) Theory: C, 76.47; H, 8.78; N, 9.39 Found: C, 76.30; H, 9.05; N, 9.39 NMR: Identical to racemate [α] D = -121° (c=10mg/ml, CH 3 OH). Example 9 Preparation of (4R)-(+)-6-(2-methylpropanoyl)-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.50 g (1.52 mmol) of (2aS,4R)-(+)-6-(2-methylpropanoyl)-4-(di- n -propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 50 mL of hexane was sonicated (50-55 kHz) in the presence of 2.0 g of MnO 2 for 6.5 hours. The crude product obtained after filtering and removing the solvent was chromatographed over 3 g of silica gel using 3:7 EtOAc/toluene, then recrystallized from toluene/hexane. The purified (4R)-(+)-6-(2-methylpropanoyl)-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole weighed 0.120 g (24% yield), mp 148-150° C. Analysis (C 21 H 30 N 2 O) Theory: C, 77.26; H, 9.26; N, 8.58 Found: C, 77.15; H, 9.28; N, 8.69 NMR: Identical to racemate [α] D = +87° (c=1, CH 3 OH). Example 10 Preparation of (4R)-(+)-6-benzoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole. A solution of 0.15 g (0.41 mmol) of (2aS,4R)-(+)-6-benzoyl-4-(di- n -propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 15 mL of hexane was sonicated (50-55 kHz) in the presence of 0.60 g of MnO 2 for 4.5 hours. Another 0.15 g of MnO 2 was added and the sonication was continued another 2 hours. The crude product obtained after filtering and removing the solvent was chromatographed over 3 g of silica gel using 3:7 EtOAc/toluene, then recrystallized from toluene/hexane. The purified (4R)-(+)-6-benzoyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole weighed 0.050 g (34% yield), mp 132.5-134° C. Analysis (C 24 H 28 N 2 O) Theory: C, 79.96; H, 7.83; N, 7.77 Found: C, 79.81; H, 7.68; N, 7.60 NMR: Identical to racemate [α] D = +122° (c=1, CH 3 OH). The present compounds of Formula I have been found to have selective affinity for the 5HT receptors in the brain with much less affinity for other receptors. Because of their ability to selectively bind to 5HT receptors, the compounds of Formula I are useful in treating disease states in which alteration of 5HT 1A receptor function is beneficial but without the side effects which may be associated with less selective compounds. Certain of the instant compounds have been found to also have substantial affinity for the 5-HT 1D receptor and are useful in treating disease states which can be benefitted by alteration of these receptors. The alteration of the particular receptor can involve mimicking (an agonist) or inhibiting (an antagonist) the function of serotonin. The disease states involved include anxiety, depression, excess gastric acid secretion, hypertension, nausea, sexual dysfunction, consumptive disorders such as appetite disorders, alcoholism and smoking, cognition, and senile dementia. The foregoing conditions are treated with a pharmaceutically effective amount of a compound of Formula I. The term "pharmaceutically effective amount", as used herein, represents an amount of a compound of the invention which is capable of diminishing the adverse symptoms of the particular disease. The particular dose of compound administered according to this invention of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar con- siderations. The compounds can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes. A typical single dose for prophylactic treatment, however, will contain from 0.01 mg/kg to 50 mg/kg of the active compound of this invention when administered orally. Preferred oral doses are 0.01 to 3.0 mg/kg, more preferably 0.1 to 1.0 mg/kg. When the compound is given orally it may be necessary to administer the compound more than once each day, for example about every eight hours. For IV administration by bolus, the dose is from 10 µg/kg to 300 µg/kg, preferably 20 µg/kg to 50 µg/kg. The following experiments were conducted to demonstrate the ability of the compounds of the present invention to interact with the serotonin 1A and/or 1D receptors. The affinities of the compounds at the central 5-binding assay described by Taylor, et al. , ( J. Pharmacol. Exp. Ther. 236:118-125, 1986). Membranes for the binding assay were prepared from male Sprague-Dawley rats (150-250 g). The animals were killed by decapitation, and the brains were rapidly chilled and dissected to obtain the hippocampi. The hippocampi were either prepared that day or stored frozen (-70°C) until the day of preparation. Membranes were prepared by homogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at 22°C) using a Techmar Tissumizer (setting 65 for 15 sec), and the homogenate was centrifuged at 39800xg for 10 min. The resulting pellet was then resuspended in the same buffer, and the centrifugation and resuspension process was repeated three additional times to wash the membranes. Between the second and third washes the resuspended membranes were incubated for 10 mm at 37°C to facilitate the removal of endogenous ligands. The final pellet was resuspended in 67mM Tris-HCl, pH 7.4, to a concentration of 2 mg of tissue original wet weight/200 µl. This homogenate was stored frozen (-70°C) until the day of the binding assay. Each tube for the binding assay had a final volume of 800 µl and contained the following: Tris-HCl (50 mM), pargyline (10 µM), CaCl 2 (3 mM), [ 3 H]8-OH-DPAT (1.0 nM), appropriate dilutions of the compound being evaluated, and membrane resuspension equivalent to 2 mg of original tissue wet weight, for a final pH of 7.4. The assay tubes were incubated for 10 min at 37°C, and the contents were then rapidly filtered through GF/B filters (pretreated with 0.5% polyethylenimine), followed by four one-mL washes with ice cold buffer. The radioactivity trapped by the filters was quantitated by liquid scintillation spectrometry, and specific [ 3 H]8-OH-DPAT binding to the 5-HT 1A sites was defined as the difference between [ 3 H]8-OH-DPAT bound in the presence and absence of 10 µM 5-HT. The affinity of the particular compound at the 5-HT 1A receptor is expressed as IC 50 value, i.e., the concentration required to inhibit 50% of the binding. The IC 50 values were determined from 12-point competition curves using nonlinear regression (SYSTAT, SYSTAT, INC., Evanston, IL). The results from this determination are provided in Table I. The affinities of the compounds at the central 5-HT 1D binding sites were determined using a modification of the binding assay described by Heuring and Peroutka ( J. Neurosci. 7:894-903, 1987). Bovine brains were obtained from Pel-Freeze Biologicals, and the caudate nuclei were dissected out and frozen at -70°C until the time that the membranes were prepared for the binding assays. At that time the tissues were homogenized in 40 volumes of ice-cold Tris-HCl buffer (50mM, pH 7.4 at 22°C) with a Techmar Tissumizer (setting 65 for 15 sec), and the homogenate was centrifuged at 39,800g for 10 min. The resulting pellet was then resuspended in the same buffer, and the centrifugation and resuspension process was repeated three additional times to wash the membranes. Between the second and third washes the resuspended membranes were incubated for 10 min at 37°C to facilitate the removal of endogenous 5-HT. The final pellet was resuspended in Tris buffer to a concentration of 25 mg of original tissue wet weight/ml for use in the binding assay. Each tube for the binding assay had a final volume of 800 µl and contained the following: Tris-HCl (50mM), pargyline (10 µM), ascorbate (5.7 mM), CaCl 2 (3 mM), 8-OH-DPTA (100 nM to mask 5-HT 1A receptors), mesulergine (100 nM to mask 5-HT 1C receptors), [ 3 H]5-HT (1.7-1.9 nM), appropriate dilutions of the drugs of interest, and membrane suspension equivalent to 5 mg of original tissue wet weight, for a final pH of 7.4. The assay tubes were incubated for 10 min at 37°C, and the contents were then rapidly filtered through GF/B filters (pretreated with 0.5% polyethylenimine), followed by four one-mL washes with ice-cold buffer. The radioactivity trapped by the filters was quantitated by liquid scintillation spectrometry, and specific [ 3 H]5-HT binding to the 5-HT 1D sites was defined as the difference bewteen [ 3 H]5-HT bound in the presence and absence of 10 µM 5-HT. The affinities of compounds at the 5-HT1D receptor are expressed as IC 50 values, i.e., the concentration required to inhibit 50% of the binding. These values were determined from 12-point competition curves using nonlinear regression (SYSTAT, SYSTAT, Inc., Evanston, IL). The results from this determination are provided in Table I. Example No. 5HT 1A 5HT 1D 1 0.50 2.01 2 0.2 18.37 7 0.22 7.46 8 0.12 96.37 9 0.16 1.27 10 0.22 1.81 In another experiment certain compounds of the Examples were evaluated to determine ability to affect the 5-hydroxyindoles serotonin and 5-hydroxyindole acetic acid (5HIAA), and serum corticosterone, in vivo . Male albino rats were injected subcutaneously with an aqueous solution of the compound. The pH of the solution was adjusted as necessary to solubilize the compound. A control of the solution without the test compound was similarly injected into a control animal. The rats were decapitated one hour later. Trunk blood was collected and allowed to clot. After centrifugation, serum was stored frozen prior to analysis. The whole brain was removed and frozen on dry ice for storage prior to analysis. The serum corticosterone concentration was measured spectrofluorometrically using the procedure of Solem and Brinck-Johnson, "An Evaluation of a Method for Determination of Free Corticosteroids in Minute Quantities of Mouse Plasma", Scand. J. Clin. Lab. Invest. , Suppl. 80, p. 1-14 (1965). 5-Hydroxy-indoleacetic acid (5HIAA) concentration in whole brain was measured by liquid chromatography with electrochemical detection as reported by Fuller and Perry, "Effects of Buspirone and its Metabolite, 1-(2-pyrimidinyl)piperazine, on Brain Monoamines and Their Metabolites in Rats", J. Pharmacol. Exp. Ther. , 248 , p. 50-56 (1989) . The results of this procedure are provided in Table II. Example No (Dose mg/kg) Serotonin (nmoles/g) 5HIAA (nmoles/g) Serum Corticosterone (microg./100ml) Control 2.97 ± 0.27 1.55 ± 0.09 3.8 ± 0.6 Example 1 0.03 3.15 ± 0.13 1.58 ± 0.05 8.2 ± 3.2 0.3 3.45 ± 0.10 1.31 ± 0.03 36.0 ± 4.8 3.0 3.38 ± 0.08 1.23 ± 0.04 44.2 ± 1.5 Control 2.07 ± 0.08 1.62 ± 0.05 3.4 ± 0.5 Example 2 (0.03) 2.60 ± 0.09 1.27 ± 0.01 33.4 ± 3.7 (0.3) 2.54 ± 0.14 1.10 ± 0.06 39.1 ± 1.1 (3) 3.25 ± 0.01 2.04 ± 0.02 13.8 ± 0.6 Control 2.81 ± 0.15 2.18 ± 0.05 3.4 ± 0.2 Example 2 (0.0003) 2.71 ± 0.06 2.21 ± 0.05 3.8 ± 0.5 (0.003) 2.64 ± 0.11 1.79 ± 0.10 3.6 ± 0.1 (0.03) 3.23 ± 0.11 1.95 t 0.04 36.7 ± 1.2 Control 2.08 ± 0.06 2.06 ± 0.08 4.6 ± 1.0 Example 7 (0.03) 2.47 ± 0.07 1.43 ± 0.02 41.8 ± 1.7 (0.3) 2.59 ± 0.14 1.37 ± 0.07 41.5 ± 5.3 (3 ) - - Control 2.72 ± 0.10 1.81 ± 0.05 3.4 ± 0.2 Example 7 (0.0003) 2.68 ± 0.11 1.93 ± 0.07 4.1 ± 0.6 (0.003) 2.74 ± 0.07 1.80 ± 0.05 3.6 ± 0.1 (0.03) 3.00 ± 0.10 1.34 ± 0.07 21.8 ± 2.1 Control 2.08 ± 0.06 2.06 ± 0.08 4.6 ± 1.0 Example 8 (0.03) 2.58 ± 0.15 1.31 ± 0.06 47.0 ± 2.4 (0.3) 2.78 t 0.13 1.36 ± 0.04 47.3 ± 2.3 (3) 2.63 ± 0.12 1.35 ± 0.04 45.4 ± 1.3 Control 2.72 ± 0.10 1.81 ± 0.05 3.4 ± 0.2 Example 8 (0.0003) 2.91 ± 0.12 1.91 ± 0.08 3.4 ± 0.2 (0.003) 2.65 ± 0.13 1.47 ± 0.04 3.8 ± 0.2 (0.03) 3.30 ± 0.09 1.59 ± 0.10 40.3 ± 1.8 Control 2.55 ± 0.12 1.53 ± 0.04 - Example 8(c) (0.1) 2.77 ± 0.07 1.67 ± 0.04 - (0.3) 2.47 ± 0.07 1.60 ± 0.07 - (1) 2.86 ± 0.07 1.74 ± 0.05 - (3) 2.68 ± 0.11 1.31 ± 0.08 - Control 2.07 ± 0.08 1.62 ± 0.05 3.4 ± 0.5 Example 9 (0.03) 2.56 ± 0.07 1.38 ± 0.02 7.7 ± 1.8 (0.3) 2.94 ± 0.13 1.22 ± 0.04 40.8 ± 2.0 (3) 2.65 ± 0.07 1.38 ± 0.08 30.8 ± 4.5 Control 2.81 ± 0.15 2.18 ± 0.05 3.4 ± 0.2 Example 9 (0.0003) 2.76 ± 0.10 2.44 ± 0.06 4.1 ± 0.5 (0.003) 2.94 ± 0.11 2.23 ± 0.09 6.0 ± 1.3 (0.03) 3.08 ± 0.11 1.82 ± 0.08 9.1 ± 1.2 The compounds of the present invention are preferably formulated prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. when the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.5 to about 50 mg, more usually about 1 to about 10 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. The following formulation examples illustrate the invention. Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) (±)-6-(2,2-Dimethylpropanoyl)-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole 25 Starch, dried 425 Magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. Formulation 2 A tablet formula is prepared using the ingredients below: Quantity (mg/tablet) (±)-6-Acetyl-4-(di- n -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole 25 Cellulose, microcrystalline 625 Colloidal Silicon dioxide 10 Stearic acid 5 The components are blended and compressed to form tablets each weighing 665 mg. Formulation 3 A dry powder inhaler formulation is prepared containing the following components: Weight % 4-(diethylamino)-6-propanoyl-1,3,4,5-tetrahydrobenz[cd]-indole 5 Lactose 95 The active compound is mixed with the lactose and the mixture added to a dry powder inhaling applicance. Formulation 4 Tablets each containing 60 mg of active ingredient are made up as follows: 4-(di- n -propylamino)-6-(2-methyl-propanoyl)-1,3,4,5-tetrahydrobenz[cd]indole tartrate salt 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 4 mesh U.S. sieve. The granules so produced are dried at 50-60°C and passed through a No. 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formulation 5 Capsules each containing 20 mg of medicament are made as follows: 4-(di- n -propylamino)-6-(3-methylbutanoyl)-1,3,4,5- tetrahydrobenz[cd]indole 20 mg Starch 169 mg Magnesium stearate 1 mg Total 190 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 20mesh U.S. sieve, and filled into hard gelatin capsules in 190 mg quantities. Formulation 6 Suppositories each containing 225 mg of active ingredient are made as follows: 4-(di- n -propylamino)-6-benzoyl-1,3,4,5-tetrahydrobenz[cd]-indole 225 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Claims: A compound of the Formula I wherein: R 1 is hydrogen, C 1 -C 4 alkyl, cyclopropylmethyl, or phenyl substituted by C 1 -C 4 alkyl; R 2 is hydrogen, C 1 -C 4 alkyl, or cyclopropylmethyl; R 3 is hydrogen, C 1 -C 4 alkyl or a blocking group; R 4 is C 1 -C 4 alkyl, C 1 -C 6 alkyl substituted with one or two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy or C 1 -C 3 thioalkyl, phenyl or phenyl substituted with one or two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy, C 1 -C 3 thioalkyl, C 1 -C 3 alkyl or trifluoromethyl; and pharmaceutically acceptable salts thereof. The compound of Claim 1 wherein R 3 is hydrogen. The compound of Claim 2 wherein R 1 and R 2 are independently C 1 -C 4 alkyl or cyclopropylmethyl; and pharmaceutically acceptable salts thereof. The compound of Claim 3 wherein R 4 is C 1 -C 8 alkyl, C 1 -C 4 alkyl substituted with one to two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy or C 1 -C 3 thioalkyl, phenyl or phenyl substituted with one or two moieties selected from C 1 -C 3 alkoxy, halo, hydroxy, C 1 -C 3 thioalkyl, C 1 -C 3 alkyl or trifluoromethyl; The compound of Claim 4 wherein R 4 is C 1 -C 4 alkyl, trifluoromethyl, phenyl or halo-substituted phenyl; and pharmaceutically acceptable salts thereof. A compound of Claim 2 selected from the group consisting of 4-(di-n-propylamino)-6-acetyl-1,3,4,5-tetrahydrobenz[cd]indole; 4-(di-n-propylamino)-6-(2,2-dimethylpropanoyl)-1,3,4,5-tetrahydrobenz[cd]indole; 4-(diethylamino)-6-propanoyl-1,3,4,5-tetrahydrobenz[cd]indole; 4-(di-n-propylamino)-6-benzoyl-1,3,4,5-tetrahydrobenz[cd]indole; 4-(n-propylamino)-6-(2-methylpropanoyl)-1,3,4,5-tetrahydrobenz[cd]indole; 4-(N-n-propyl-N-cyclopropylmethylamino)-6-propanoyl-1,3,4,5-tetrahydrobenz[cd]indole; and pharmaceutically acceptable salts thereof. A substantially pure stereoisomer of the compound of Claims 2 to 6 and pharmaceutically acceptable salts thereof. A pharmaceutical formulation comprising as an active ingredient a compound as claimed in any one of Claims 2 to 7, associated with one or more pharmaceutically acceptable excipients. A compound as claimed in any of Claims 2 to 7 for use as a pharmaceutical. A process for preparing a compound as claimed in any one of Claims 2 to 7 which comprises deprotecting a compound of Formula I wherein R 3 is an amino blocking group.

Inventors: FLAUGH MICHAEL EDWARD, MARTINELLI MICHAEL JOHN, SCHAUS JOHN MEHNERT, FLAUGH, MICHAEL EDWARD, MARTINELLI, MICHAEL JOHN, SCHAUS, JOHN MEHNERT
Applicants: LILLY CO ELI, ELI LILLY AND COMPANY
Application year: 1991
Main classification: C07D209
IPC codes: A61P43, A61P25, A61P9, A61P15, A61K31, A61P13, A61P1, C07D209