CA2107009A1 - 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd] indoles for treating motion sickness and vomiting - Google Patents

Abstract

Abstract The present invention provides a method of treating emesis and motion sickness using certain 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indoles and pharmaceutical formulations suitable therefor. Certain of the compounds utilized in the instantly claimed method are novel and, accordingly, such compounds, processes for preparing same, methods for using same and pharmaceutical formulations thereof are also provided.

Description

21~7~

6-HETEROCYCLIC-4-AMINO-1,2,2a.3,4 S-HExAHyDRosENz~ CD lINDOLES FQR TREATING
MOTION SICKNESS AND VOMITING

The present invention relates a method of treating emesis and motion sickness and pharmaceutical formulations suitable therefor.
Flaugh in U.S. Patent No. 4,576,959 (issued 1986) disclosed a family of 6-substituted-4-dialkylamino-1,3,4,5-tetrahydrobenz[cd]indoles which are described as central serotonin agonists. Leander in U.S. Patent 4,745,126 (1988) disclosed a method for treating anxiety in humans employing a 4-substituted-1,3,4,5-tetrahydrobenz[cd3indole-6-carboxamide derivative.
European Patent Application 399,982 discloses certain heterocyclic-substituted aminotetralins. These compounds are disclosed as being serotonin agonists, partial agonists or antagonists.
Despite the progress of science as represented above, many mammals, both human and animals, continue to be afflicted with emesis and motion sickness.
Accordingly, the need continues for safer, more selective, drugs which can be used to treat such diseases. As such, it is an object of the present invention to provide a method for treating emesis and motion sickness. A further object of the present invention is to provide novel formulations suitable for the instantly claimed method, as well as novel compounds which can be used in such method.

2107~9 The present invention provides a method of treating emesis or motion sickness in mammals comprising administering to a mammal in need of such treatment an effective amount of a compound, or pharmaceutically acceptable salt thereof, of the Formula 1 HET
¢~NR1 R2 wherein:
Rl is hydrogen, Cl-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl(Cl-C4 alkyl), -(CH2)nS(Cl-C4 alkyl), -C(o)R4, -(CH2)nC(o)NR5R6;
R2 is hydrogen, Cl-C4 alkyl, cyclopropylmethyl or C3-C4 alkenyl;
R3 is hydrogen, Cl-C4 alkyl or an amino-blocking group;
n is 1-4;
R4 is hydrogen, Cl-C4 alkyl, Cl-C4 haloalkyl, Cl-C4 alkoxy or phenyl;
R5 and R6 are independently hydrogen, a Cl-C4 alkyl, or a Cs-Cg cycloalkyl, with the proviso that when one of R5 or R6 is a cycloalkyl the other is hydrogen;
HET is a tetrazolyl ring, a substituted tetrazolyl ring or an aromatic 5- or 6-membered heterocyclic ring, said ring having from one to three heteroatoms which are the same or different and which are selected from the group consisting of sulfur, oxygen, and nitrogen X-8266A -3- 2107~

with the proviso that the 6-membered heterocyclic ring can only contain carbon and nitrogen and with the further proviso that the 5-membered ring may contain no more than one oxygen or one sulfur but not both oxygen and sulfur.
Compounds of Eormula 1 have not heretofore been used to treat emesis or motion sickness. Accordingly, a further embodiment of this invention is a pharmaceutical formulation adapted for the treatment of emesis or motion sickness comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.
Certain compounds of Formula 1, i.e., those compounds wherein HET is a tetrazolyl ring or a substituted tetrazolyl ring and Rl, R2 and R3 are as defined for Formula 1, are novel. Accordingly, a final embodiment of the present invention is such novel compounds, processes for preparing such compounds and methods of using same.
As used herein, the term "alkyl" represents a straight or branched alkyl chain having the indicated number of carbon atoms. For example, "Cl-C4 alkyl~l groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl and ert-butyl. "Cl-Cg alkyl~
groups include those listed for Cl-C4 alkyl as well as n-Pentyll 2-methylbutyl, 3-methylbutyl, n-hexYl, ~-methylpentyl, n-heptyl, 3-ethylpentyl, 2-methylhexyl, 2,3-dimethylpentyl, n-octyl, 3-propylpentyl, 6-methylheptyl, and the like.

-: :

X-8266A -4- 2~ ~70~9 The term ~C3-C4 alkenyl~ refers to olefinically unsaturated alkyl groups such as -CH2CH=CH2, -CH2CH2CH=CH2, -CH(CH3)CH=CH2 and the like.
The term "aryl~ means an aromatic carbocyclic structure having six to ten carbon atoms. Examples of such ring structures are phenyl, naphthyl, and the like.
The term "cycloalkyl" means an aliphatic carbocyclic structure having the indicated number of carbon atoms in the ring. For example, the term ~C3-C7 cycloalkyl~ means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "aryl (Cl-C4 alkyl)" means an aryl structure joined to a Cl-C4 alkyl group. Examples of such groups are benzyl, phenylethyl, a-methylbenzyl, 3-phenylpropyl, a-naphthylmethyl, ~-naphthylmethyl, 4-phenylbutyl, and the like. Similarly the term "aryl (Cl-C3 alkyl)ll means an aromatic carbocyclic structure joined to a Cl-C3 alkyl.
The Cl-Cg alkyl, aryl, aryl (Cl-C4 alkyl) and aryl (Cl-C3 alkyl) groups can be substituted by one or two moieties. Typical aryl and/or alkyl substitutents are Cl-C3 alkoxy, halo, hydroxy, Cl-C3 thioalkyl, nitro, and the like. Moreover, the aryl, aryl (Cl-C4 alkyl) and aryl (Cl-C3 alkyl) groups can also be substituted by a Cl-C3 alkyl or a trifluoromethyl group.
In the foregoing, the term ~Cl-C3 alkyl~ means any of methyl, ethyl, g-propyl, and isopropyl; the term "Cl-C3 alkoxy" means any of methoxy, ethoxy, n-propoxy, and isopropoxy; the term "halo" means any of fluoro, chloro, bromo, and iodo; and the term "Cl-C3 thioalkyl"
means any of methylthio, ethylthio, B-propylthio~ and isopropylthio.

2 1 ~

Examples of substituted Cl-Cg alkyl are methoxymethyl, trifluoromethyl, 6-chlorohexyl, 2-bromopropyl, 2-ethoxy-4-iodobutyl, 3-hydroxypentyl, methylthiomethyl, and the like.
Examples of substituted aryl are ~-bromophenyl, iodophenyl, ~-tolyl, o-hydroxyphenyl, ~-(4-hydroxy)-naphthyl, ~-(methylthio)phenyl, _-trifluoromethylphenyl, 2-chloro-4-methoxyphenyl, a- (5-chloro)naphthyl, and the like.
Examples of substituted aryl (Cl-C4 alkyl) are ~-chlorobenzyl, Q-methoxybenzyl, _-(methylthio)-a-methylbenzyl, 3-(4~-trifluoromethylphenyl)propyl, o-iodobenzyl, ~-methylbenzyl, and the like.
The term "amino-blocking group~ is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an amino group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed from the amine when it is desired to do so.
Such groups are discussed by T. W. Greene in chapter 7 of Protective Groups in Orq~nic Svnthesis, John Wiley and Sons, New York, 1981, and by J. W. sarton in chapter 2 of Protective Grou~s in Organic Chemistrv, J
F. W. McOmie, ed., Plenum Press, New York, 1973, which are incorporated herein by reference in their entirety Examples of such groups include benzyl and substituted benzyl such as 3,4-dimethoxybenzyi, o-nitrobenzyl, and triphenylmethyl; those of the formula -COOR where R
includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, l-methyl-l-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, ~-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, 2107~9 X-~3266A -6-trichloroacetyl, trifluoroacetyl, benzoyl, and ~-methoxybenzoyl; and other groups such as methanesulfonyl, ~-toluenesulfonyl, p-bromobenzene-sulfonyl, ~-nitrophenylethyl, and ~-toluenesulfonylaminocarbonyl. Preferred amino-blocking groups are benzyl (-CH2C6Hs), acyl [C(O)R] or SiR3 where R is Cl-C4 alkyl, halomethyl, or 2-halo-substituted-(C2-C4 alkoxy).
The term '~aromatic 5- or 6-membered heterocyclic ring~ refers to a ring containing from one to three heteroatoms which can be nitrogen, oxygen or sulfur.
The 5-membered heterocyclic rings can contain carbon and nitrogen atoms and up to one oxygen or one sulfur but not one of each. In 5-membered rings not containing oxygen or sulfur, one nitrogen can be substituted with either a hydrogen, Cl-C3 alkyl, phenyl or (Cl-C3 alkyl)phenyl group. The 6-membered heterocyclic rings can contain carbon and nitrogen atoms only. The 5- or 6-membered rings can have one or two of the carbon atoms in the ring substituted independently with Cl-C3 alkyl, halogen, OH, Cl-C3 alkoxy, Cl-C3 alkylthio, NH2, CN or phenyl. Adjacent carbons in the heterocyclic ring may be connected with a -CH=CH-CH=CH- bridge to form a benzo-fused ring on the heterocycle.
These aromatic 5- or 6-membered heterocyclic rings can be either substituted or unsubstituted and include furan, thiophene, thiazole, oxazole, isoxazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, and triazole. The heterocyclic ring can be attached to the benzene ring by any carbon in the heterocyclic ring, for example, 2- or 3-furan.

2107~9 The term '~substituted tetrazolyl ring" refers to a tetrazolyl ring system which has a C1-C3 alkyl or phenyl substituent on the 2-position nitrogen atom of such ring system.
As used herein the following terms refer to the structure indicated and include all of the structural isomers:
~ S ~ F N ~ ~ ~ ~ N-O
N~fs~ N~S S~ ~ N~/

Thiazoles Isoxazoles r~ FN p~ //N--O N--N F\ FN
O~N o~N N~N N~ O~ N~N N~

Oxadiazoles Imidazoles gN 6~ N~

Pyridines Pyrazine Pyrroles R--N--N
\\ where R is hydrogen, ~ C1-C3 alkyl or phenyl Tetrazole 21~7~;3~

/~N NF\O ,Nj~ ~ N~

Oxazoles Isothiazoles 1 =\N S~ ~3 Triazoles Thiophenes N~N

Furans Pyrlmldlnes r~ N--S S~ r~ r S~N N ~ N~N N~S S~

Thiadiazoles N~ N~

Pyrazoles Pyridazines 7 ~ ~ ~

While all of the compounds described herein are believed useful for the method of treating emesis and motion sickness provided herein, certain of such compounds are preferred for such use. PreEerably R1 and R2 are both C1-C4 alkyl, particularly n-propyl, R3 is hydrogen, and HET is one of the following isoxazole, oxazole, pyrazole, pyridine, thiazole, furan, thiophene or oxadiazole. Other preferred aspects of the present invention are noted hereinafter.

I ~ d~ N~ Nf~3 F\ I Q F\ l ~ I =\ ~ FN~o q~ S~N N~N o~N

The compounds of the instant invention, and the compounds employed in the method of the present invention, have at least two chiral centers and therefore at least four stereoisomers can exist for each. Chiral centers exist at positions 2a and 4 of Formula 1. If a substitutent group contains a chiral center, then additional stereoisomers can exist.
Racemic mixtures as well as the substantially pure stereoisomers of Formula 1 are contemplated as within the scope of the present invention. sy the term "substantially pure~, it is meant that at least about 21~7~

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. Particularly preferred stereoisomers of Formula 1 are those in which the configuration of the chiral center at position 2a is S
and at position 4 is R, i.e., 2aS, 4R, or the configuration of the chiral center at position 2a is R
and at position 4 is S, i.e., 2aR,4S.
The terms "Rl' 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 Illeft~ refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (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 stereochemistry is contained in the book: The Vocabularv of Oraanic Chemistrv, orchin, et al., John Wiley and Sons Inc., publishers, page 126, which is incorporated herein by reference.
As set forth above, this invention includes the pharmaceutically acceptable salts of the compounds of Formula 1- Since the compounds of Formula 1 are amines, they are basic in nature and accordingly react 2~07~

with any number of inorganic and organic acids to form pharmaceutically acceptable salts using acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and others, as well as salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, amino 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, 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, ~-hydroxybutyrate, glycolate, malate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mesylate.
Particularly preferred compounds of Formula 1 for use ln the method of treating emesis and motion sickness disclosed herein include the compounds in which R3 is hydrogen, R1 and R2 are both either n-propyl or methyl and HET is 3-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 5-oxazolyl, 3-isothiazolyl, 5-isothiazolyl, 2-imidazolyl or 4-imidazolyl. These compounds include the racemic mixtures of possible stereoisomers as well as the substantially pure stereoisomers with different configurations at positions 2a and 4, i.e., 2aR, 4R or 2aR, 4S or 2aS, 4R or 2aS, 4S.
As depicted in Scheme I, the compounds used in the method of the present invention, as well as the compounds of the present invention, can be prepared by reacting a 4-amino-6-metallo-substituted hexahydrobenz[cd]indole as represented by structure 2 with a heterocyclic compound represented by structure 4. In structure 2, M represents a metallo moiety such as lithium, magnesium, zinc, tin, mercury, boronic acid (-BO2H2) and the like while Z is an amino-blocking group. When the metallo moiety is multivalent, it is normally associated with other moieties such as, for example, halo for magnesium (Grignard reagent) and alkyl groups for tin (trialkyltin). The heterocycle represented by structure 4 contains a leaving group "L", such as a chloro, bromo, or trifluoromethylsulfonoxy group, which can be displaced by the metallo-indole. The heterocycle can be substituted as set forth hereinabove.

2~7~

Scheme 1 M HET
~ + I ~ ~NR1R2 Z-N Z-N

HET
~,NR~R2 The reaction of the metallo-indoline 2 and heterocycle 4 is accomplished in the presence of a palladium or nickel catalyst such as Pd[P(C6Hs)3]4, PdC12, Pd[P(C6H5)3]2C12~ Ni(acac)2~ NiC12[P(C6H5)3]2 and the like, wherein ~acac" represents acetylacetonate and "C6Hs" represents a phenyl group. The organometallic reagent 2 is prepared by methods commonly used in the art for such preparations, for example, the lithium or magnesium reagents can be prepared by contacting the appropriate 6-chloro-, 6-bromo- or 6-iodo-substituted hexahydrobenzindole with an organolithium reagent or magnesium metal in a 2~07~
X-8266~ -14-solvent such as ether or tetrahydrofuran. Other organometallic derivatives can be used such as zinc, tin, mercury or boronic acid (-so2H2)- The zinc, tin and mercury reagents can be prepared by reaction of the lithiated benzindole with a zinc, tin or mercury derivative such as zinc chloride, chlorotrialkylstannane, or mercuric chloride. The boronic acid derivative can be prepared by reacting the lithium reagent with trimethylborate followed by hydrolysis of the resulting boronate ester. Mercuric acetate can be contacted directly with the hexahydrobenzindole to provide the mercurated derivative.
The l-nitrogen of the hexahydro benzindole is preferably protected with a group such as triphenylmethyl (trityl), benzyl, or benzoyl. These protecting groups are represented by z in structures 2.
The protecting group can be removed after the coupling reaction is accomplished to provide the 1-hydrobenzindole compound.
An alternative method of preparing the compounds of Formula 1 involves contacting an organometallic reagent prepared from a heterocyclic compound with a 6-bromo or 6-iodo-4-aminobenzindole. The reaction is accomplished in the presence of a catalyst such as that used in reaction Scheme I. The metal in the organometallic derivative of the heterocycle can be lithium, magnesium (Grignard reagent), zinc, tin, mercury, or a boronic acid (-BO2H2). These organometallic compounds can be prepared by standard methods, as described above for the benzindoles. Alternatively, the lithiated heterocycles can be prepared by treating a heterocycle 2~7~9 with a strong base such as an alkyllithium or a lithium dialkylamide.
Unless otherwise indicated, in the following preparation procedures, Ra and Ral may independently be hydrogen, Cl-C3 alkyl, halogen, OH, O(Cl-C3 alkyl), S(Cl-C3 alkyl), NH2, CN, or phenyl. Rb may be hydrogen, Cl-C3 alkyl, phenyl, or (Cl-C3 alkyl)phenyl. Rc may be hydrogen or Cl-C3 alkyl. Rd may be OH, o(Cl-C3 alkyl), O(phenyl), O(Cl-C3 alkylphenyl), halo, S(Cl-C3 alkyl), S(phenyl), S(Cl-C3 alkylphenyl), NH2, NH(Cl-C3 alkyl), N(Cl-C3 alkyl)2, OCO(Cl-C3 alkyl), OCO(phenyl), OCO(Cl-C3 alkylphenyl) or the like.
In an alternative preparation procedure, compounds of Formula 1 having a 5-membered heterocyclic ring in the 6-position can be prepared by the cycloaddition of a compound of the type represented in structure 8 wherein Rl and R2 are as defined above and B is an amino-protecting group or hydrogen, Ra lll ~ ~NR1R2 ` B-N

21 070~

with a 1,3-dipole of the type +T=U-V- in which T, U, and V can be selected from the following list of (a) through (i) .

T_ U V
(a) CRa N CHRa (b) CRa N NRb (c) CRa N O
(d) N N o (e) CRa CRa' NRb (f) CRa CRa~ O
(g) N CRa l CHRa (h) N CRa NRb (i) N CRa' O

In this list Ra and Ra~ are not OH or NH2, N represents nitrogen and O represents oxygen. ThiS cycloaddition provides products of the structure lQ, wherein R1 and R2 are as defined above and s is an amino protecting group or hydrogen.
U=T
V~Ra ~NRl R2 B-N
lQ

, 21~7~

The 1-nitrogen of structures 8 and 10 can be protected using standard protecting groups preferably (C2Hs)2NC(O)-, triisopropylsilyl, benzoyl, or benzenesulfonyl.
Alternatively, the 6-alkyne-substituted indole of structure 8 can be reacted with a dipole of the type +T-U=V- in which T, U, and V are selected from the following list for (j) and (k):

T U _ V
(j) CHRa N N
(k) NRb N N

In this list Ra is not OH or NH2 and N is nitrogen.
This reaction provides products of structure 12, U-T
V~Ra ~J~NR1R2 B-N

wherein R1, R2, Ra and B are as defined above.
Alternative procedures for preparing certain of the compounds useful in the method of the present invention are set forth hereinbelow in Schemes 2 through 19. Scheme 19, in particular, discloses processes for preparing the novel tetrazolyl and substituted tetrazolyl compounds of the present invention. As used in these reaction Schemes, "Ar~' refers to the 1,2,2a,3,4,5-hexahydrobenz[cd]indole, with the indicated substituent in the 6-position. In these Schemes, IlMe" is methyl, "Et" is ethyl, "Nss"
represents n-bromosuccinimide, Ra~ Rb, Rc and Rd are defined above, "MsCl" represents methanesulfonyl chloride, ~ represents heat, ~0~ and "Ph" each represent phenyl, ~DME~ represents dimethylformamide, "DMS" represents dimethyl sulfide, ~TMS" represents trimethylsilyl, "[O]" represents an oxidant, Lawesson's reagent is p-methoxyphenylthionophosphine sulfide dimer, "Ac" represents acetyl, "NCS" represents N-chlorosuccinimide, "DCC" representsdicyclohexylcarbodiimide, "Im" represents 1-imidazolyl, and "[H]" represents a reductant. As set forth hereinabove, the 1-nitrogen of the benz[cd]indole is normally protected with an amino blocking group, preferably triisopropylsilyl.

2~7~

Scheme 2 Ra Ra ~Ra Br2 H+ O~R NH4+RaC OD ~--Ra ~ N~S~Ra PhCH2N(CH3)3- Ar Ar2-1 Ar 2-2 1. NaN3 \~ [H], acid N,OH \~ NH3+
BUONO OqJ~Ra 2, Y ~ qJ~Ra base Ar acid Ar ~ ¦ RaCOX
1. HCOORO qJ~ /catalyst ~

2. PhN2+ Ar Ra Ar l H20 Ra ~=N
d~Ra Ar ~ ;~

2~7~

Scheme 3 Rc R Rc Rc ~ Ra R ~ Ra Ra Ra ArcoRd~ NH2 o H30+,~ 0 N

Ar Ar 31 O~N
Ar 3-2 * When Rd is OH the ArCORd substrat:e is preferably a~tivated by prior contact with DCC or diimidazolyl-carbonyl.

.~
, 2~ ~7~

Scheme 4 ~Ra N=~Ra Oq ~ 1 baseqJ~ Ra H2NOH ~ Ra Ar 2. RaCOORc Ar 4-1 NMe2 N

q~¢ ~ Ra Ar Ar 4-2 2 cass2e MeS SMe ~<SMe q~ Ra 1' ~ Ra Ar Ar ~, 3 OH 0~
H2NOH N~ 1. base ~ Ra 2. RaCOORc Ar (orRaCONMe2) 4 4 3. H30+

SMe SMe O-N
03P=CHSMe~ DMF ~ OHC ~,~ NH20H
ArCHO - ~ r ~, ~
Ar POCI3 Ar Ar 4-5 ~1~7~:9 X-8266A -22~

Scheme 5 NH
Br RaJ~ N H2 )r Oq~R Br2, H ~ qJ~Ra ~Ra Ar PhCH2N(CH3)3+ Ar \ Ar \ 1. NaN3 5-1 \ 2. [H], acid ,OH
BuONO 0~ ~--R
~ `I
base Ar H2, catalys~

N_NHPh NH~
1. HCOORc. Il H2, catalyst o~l base~ ~P~a acid 3~ Ar 2. PhN2~ / ¦ RaCOX
1. KSCN
RCS ~ 2. RCX~ base ~NH NH
N~R~ qJ~Ra Ar 5-2 Ra / Ar ,~N H ~ NH3, -H20 Ar 53 ~1~70~

Scheme 6 Et2BCI ~ ~H2NRb R J'' Ra Ra HNq~NHRb a Br N~"N_F~b Ar Ar 6-1 NHRb~HX 0~ NH3,-H20 ~
ArCOOH ~ ~ N ~~ ~I~N_ Rb base v~,, ~ Rb + coupling agent~ Ar Ar ~2 N=N
q~Ra 1- base, RbN3 Rb--N~`Ra Ar2. MsCI, pyridine Ar ~

NH2 OJ`NH
ArCN-~., HNq~l~H HNq~NH
Ar Ar N H Ra Ra Ra~NHNH2 O~NH NH3,-H20 ~N,H
ArCOOH - 3~ Oq~NH ~ D~ N~,f~N
Ar Ar 64 * For example, DCC or Im2CO.

2~7~9 Scheme 7 OH
HNq,~NH N=( ArCORd --Ra _ ~ O~f~N
Ar 7-1 Im2CO

~ ~ Ra Ar-C-N~q H2NOH DOq~NH N ~N
Ar Ar 7-2 la J~ 0~ N H Ra ~N
Il ~ Ra NHNH2 o N H-H20 ~ O~N

Ar-C-N Ar Ar \9N ~

\NH2NH2 ~ - (Cl-C4 alkyl)O~t / P~aCOORc Ra NH2 (Cl-C4 alkyl 0)--~N
Oq~NH Ra(OC1-C4 alkyl)3 Oq~NH
Ar Ar * When Rd is OH a coupling agent, for example DCC or IM2CO, is preferably also employed.

' . . .. . .
.. : .

Scheme 8 ArLi or ArMgBr H Ar I ~o]

q~ O OH N~oH
Ra o~JI~ H2NOH N ~!_ Ar Ar base or AC20, N~ R~

2~a~

Scheme 9 Br Oq--~R Br2; H ~ qJ~R
Ar PhCH2N(GH3)3+ Ar 1. NaN3 \~[H], acid N,OH \~ NH3+
BuONO o~ H2, catalyst qJ~Ra base Ar acid Ar 1. HCOORC. I /~catalyst O
base ~ qJ~ Ra / acld RaJ~
+ Ar NH2 2. PhN ~ Ra []

Ra ~!~N

N~ a ~-1 s : :, 2~07~

Scheme 1 0 ~/Ra Ra O~R 1 Basb ~o~R \~ A~Ra \HC(NMe2)3 H2NNHRbi~
~(R, RN~N~ Fla Ar Ar 1 MeS /sMe SMe SMe ~ H2NNHRb r~ Rb~ ~
~a ~ RbN~ ~
Ar Ar ~ Q3 Ar 10-4 SMe SMe ArC~O 03P=CHSM~ ~ DMF OHC~ H2NNHRb Ar Ar Ar - 21~7~

Scheme 11 q~Ra Ra~NH Pia~yN Ra q~ a qJ~ a ~ a Ar æ RaCOORc Ar Ar ~ NMe2 Ra ~pNH Ra ~ N
D~ OqJl NH2 ~ Nq3 Ar Ar 11-~

2 CaSs2e MeS ~Me Ra~NH Ra~N SMe q~Ra ~ ~'' q3 ~R~, Ar Ar 11-3 Ra SMe SMe Ra~NH N~N
03P=CHSMe ~,~ DMF % NH
ArCHO ~ ,, OHC~ ~ ~, Ar POCI3lr Ar Cl Et2ElCI
ArCN~ ArC=N-13Et2 o Ra NH3~ RaJ~ RRa ~6~ Ra HNq~NH2 Ra ~ N;~N
Ar Ar .

2~ ~7~39 Scheme 1 2 1. CS2 2. RCX
ArMgBr --D ArCSSRc IR CH base Ra N N_ N
ArCOORc Lawesson~s S~ORc c~ 3D S~ Ra Reagent Ar Ar 12:1 RCOOC~

~q~ Ra H2NNHcOORc N ~ Ra soc12 ~ Ra Ar Ar Ar 1~2 ArCr~OH ~ ArC-N~d 2 o ~H P2ss S~--~N
A.r Ar ~2 I RaCOORc Oq~ NH
Ar H2NNHCSNH2, PPA 3' = ~
ArCOOH ~ S~f N
Ar 12-4 2~ ~7~

Scheme 13 ArCN

¦Et2BCI

SH SRc ArC-N-BEt2 H2NOH ~ HN NH CS2 N ~ RcX N--S
Ar Ar Ar ~:1.
\ \NHg \~ S_SNH2 S \ H2N~f~NH (CNS)2 N~,,N
~U~ \ Ar Ar 1~2 R ~ NH~\~

HN NH [ ] - D~ N N
q~ e.g. 12 or S2CI2 or SO2CI2 or Ar (PhSeO2)20 or PhlO or Ar 13-3 Phl(OAC)2 S -N
1) (iC4Hg)2AlH H2N~",CN [O]t ~N \~
ArCN ._ ~ -- Ir ~ Cl 2) HCN / Ar \ lr J
S-N l]' O O IOI S-N
Nq~clH2N~NH2 H2N~NH2 ~CI
Ar Ar Ar Ar 13-S

[O] *, e . g., SOC12 or SC12 or S2C12 or S02C12 2~ ~7~3~

Scheme 14 Br Ra Oq--R Me35lCI Me3s~o>=~Ra NBZ Oq~Ra RaCSNH2D ~ a O H~dd Ar 141 N NH3+
BuONO Oq~ ~t 0~ R
base Ar acid Ar I RaCOX
NHPh /~ ~

basaC'OqJ~ /, catalys~ Ra 2. PhN2~ Ar ~Ra Ar ~ P2S5 )=N
S ~ Ra 2~07~

Scheme 15 RaJ~ Ra~ a 1) Et2BCIS~NH2 Ra S~N
ArCN ~-- lr Ar 15-1 03P=CHSMe DMF SMe Ra ~
ArCHO ~ ~ -- 1~ ~ ~ S ,~>" R
Ar POCI3 l Ra R C-NH2 Ar a 2~ ~7~

Scheme 1 6 Raney Ni ~ Lawessen's S R PhlO Ra ~Ra H2N~R ~DH2N~ Phl(OAc)2 N~R
Ar Ar Ar Ar Ra N=~ O-N
analogous chemistry ior ~ R and R ~ Ra Ar Ar L~ H 1 KNSHCNorNaHSSO
ArCOORc I _ 0~ ~ _ r ,_ CuBr~DMS ~ 1. H2NSSO3K
Ar 2. base Ar 1. TMSC=CH
Cul, Pd(P03)2Ci2 NEt 2. F~) Ar 1. base 2. HCOORc or DMF
1. KSCN or NaHSSO3 N
~ ~CHO 2. NH3 ,~
Ar 1. H2NSSO3K
2. base Ar 21~7~

Scheme 17 COORc Im2CO il /~N O~J
ArCOOH - ~ ArC-N l ~ 1 W Ar l NH3 ArCN H2N~ CSC12 Et2BCI ,~ Ar Ar ~ ~ /~RCCC~2 17-1 Arc=NBEt2 / 2) H20 Cl ArMgBr 1. CS2 2. R,~
CN

Ar~ f :s~ Ra NCS ~ Ra Ar Ar 2 1 ~

~ Z

S
Z cnO
o¦I T

;~

D ~ -S= ~ I

æ

æ

~1~7~i3~

Scheme 1 9 1. (C1-C6 alkyl)3N3 H--I ~
Ar-CN ~N~,~N
2. H30+ lr 1~1 1. Al(N3)3 ~ ~
Ar-CN 3~ N~ N
2. H30+
Ar DEAD, Ph3P, TMS-N3 or H--0~ NH2CC4, Ph3P, NaN3 or Nl ~1 N~N
ArPOCI3, TEA, CH3CN, NaN3 Ir ~N--N
H~ I H--N--N
N=N l li Ar-l - -- -- ~ N~ N
catalyst 1~
Ar where R is hydrogen, Cl-C3 alkyl or phenyl Scheme 20 illustrates a preparation of a starting material for reaction Scheme 1.

...

.
., .

2~ ~73`~

Scheme 2 0 X O ~ ~OH

Z 14 16 Z - N 1a ~NHz ~NHR~ $~N

~4 ~2 Z
1 ~ .

X M
~,NRlR2 ~ ,NR1R2 Z N~.2~ Z - N~CH 2 2~ 0703~

In Scheme 20, epoxides of Formula 16 are known to the art or can be prepared from compounds known to the art using common reagents and techniques. For example, Flaugh, ~_~1~, J~ Med. Chem., 31, 1746 (1988); Nichols et al., Orq. 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 structures 16. Those skilled in the art of organic chemistry will recognize that there are four stereoisomers of structure 16:

~ 16b Z 16c Z

Structures 1~ and 16b are herein referred to collectively as the exo-isomers, similarly, structures 16c and 16d are the endo-isomers. Leanna e~
su~ra, teach the preparation of epoxides of structures 16 which are substantially exo or substantially endo, as desired. The preferred starting material is the compound of structure 16 wherein Z is benzoyl and X is hydrogen; the most preferred starting material is the mixture of substantially the exo-isomers thereof.
Amino alcohols of structure 18 are formed by reacting an epoxide of structure 16 with an amine of formula Rl0NH2~ 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 21~7~

stereoisomers of structure 18a-d are formed from, respectively, stereoisomers of structure 16a-d, X NHRl X NHRl X NHRl oH X NHRl ~JH ~ ~H

z/ ~I z 1 8b 1 8c 1 A stereoselective synthesis of the amino alcohol of structure 1~, and hence of all the subsequent intermediates and products of Scheme 20, can be effected by using a substantially pure enantiomer of an amine of the formula R1ONH2 wherein R10 contains at least one chiral center. 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, n-butanol, and mixtures of hexane and ethyl acetate. An alternative method of achieving a stereospecific synthesis is depicted in Scheme 20 and comprises conversion of all the diastereomers of structure 18 to corresponding diastereomers of structure 20, followed by the separation of said diastereomers of structure 2Q; that alternative method is discussed below. If a stereoselective synthesis is not desired, then separation of the stereoisomers of the amino alcohol of structure 18 is not required and the amine R1ONH2 need not be optically active.
A particularly efficient stereoselective process for a highly preferred compound of structure 18, 1-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,2a,3,4,5-21~7Q~9 hexahydrobenz[cd]indole, comprises the reaction of a mixture of substantially the exo-isomers of the corresponding epoxide of structure 16, or a mixture of substantially the endo-isomers of the corresponding epoxide of structure 16, with a substantially pure enantiomer of l-phenethylamine in the solvent n-butanol and the subsequent selective crystallization of one of the two isomers of the amino alcohol. The temperature of the reaction can be from about 50 to about 150C, preferably about 80 to about 100C.
After the reaction is complete, as determined for example by thin layer chromatography or liquid chromatography, the desired amino alcohol is crystallized at about -20 to about 40C; the preferred temperature for the crystallization is about 0 to about 15C. 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 l-phenylethylamine, R or S, one can determine which of the stereoisomers of the compound of structure 18 precipitate from the reaction mixture.
A number of methods of forming aziridines such as those of structure 20 from amino alcohols such as those of Formula 18 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 triphenyl-phosphine (J. P. Freemer and P. J. Mondron, Synthesis,December, 1974, page 894). A particularly efficient alternative to the above methods involves treating a compound of structure 18 with a tertiary amine in an inert solvent followed by 210700~

the addition of methanesulfonyl chloride. The following stereoisomers of the aziridine of structure 20, 20a-d, arise respectively from the stereoisomers of structure 18a-d, with retention of configuration at any chiral center in the substituents z, Rl or X:

~/ X ~/

Z ~ Z 20b Z 20c 20d Suitable tertiary amines are those of the formula (Rll)3N, where the Rll groups are independently Cl-C4 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 about -35 to about 45C. In the preferred embodiment, the amino alcohol is treated with triethylamine in methylene chloride at about -20 to about 0C, then the reaction mixture is warmed to about 15 to about 35C for the completion of the reaction.
If desired, the product, an aziridine of structure 20, can be crystallized from an appropriate solvent such as acetonitrile or isopropanol after an aqueous workup.
In the event that Z contains at least one chiral center in substantially a single stereoconfiguration and that the aziridine of structure 20 is prepared as a mixture of stereoisomers, said stereoisomers can be separated by methods such as chromatography and crystallization, 21~7~9 thereby providing a stereospecific synthesis of the aziridine of structure 20 and subsequent products.
The aziridine ring can be opened to form an intermediate secondary amine of structure 22. 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 structure 22 be substantially regiospecific; 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. The preferred solvent for preparing the compound of structure 22, wherein Z
is benzoyl, X is hydrogen, and R10 is l-phenylethyl, is a mixture of tetrahydrofuran and phosphoric acid or acetic acid. The source of hydrogen can be an atmosphere of elemental 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, hydrazine, or cyclohexene. The preferred hydrogen source is an atmosphere of hydrogen gas supplied at about 1 to about 10 atmospheres pressure. The 21 07~

temperature of the reaction may be from about -20 to about 80C; the preferred temperature for the hydrogenolysis of the aziridine wherein Z is benzoyl, X is hydrogen, and Rl is l-phenylethyl is about -20 to about 0C.
The conversion of compounds of structure 20 to compounds of structure 22 proceeds without disturbing the stereochemical configuration of the chiral centers at the 2a- or 4-positions oE the structure 22 or of the chiral centers that may be present in any of the substituents.
If desired, the compound of structure 22 can be isolated by the usual methods such as crystallization.
The secondary amine of structure 22 can be converted to a primary amine of structure 24 by a number of methods known to the art of organic chemistry, or alternatively the secondary amine itself can be isolated.
However, the preferred method is to convert the secondary amine of structure 22 to the primary amine of structure 24 without isolating the secondary amine, but rather by simply continuing without interruption the hydrogenolysis reaction that produced the compound of structure 22. Therefore, the preferred solvent and catalyst are the same as those for the preparation of the secondary amine of structure 22. It may be deslrable to conduct the hydrogenolysis of the secondary amine of structure 22 at a different temperature or a different pressure or different temperature and pressure than the hydrogenolysis of the aziridine of structure 20. For the hydrogenolysis of the preferred compound of structure 22 wherein Z is benzoyl, X is hydrogen, and Rl is l-phenylethyl, the preferred temperature and pressure are about 50 to about 60C and about 1 to about 20 atmospheres. Under 7~

these conditions the hydrogenolysis of compounds of structure 22 to compounds of structure 24 proceeds without disturbing the stereochemical configuration of the chiral center at the 4-postion.
The isolation of the compound of structure 24 can be accomplished by the usual methods such as crystallization. If desired, the compound of structure 24 can be further purified, for example by recrystallization.
Of course, as those skilled in the art will recognize, variations of Scheme 20 will be desirable or necessary for certain embodiments of the invention.
For example, it may be undesirable to subject a compound in which X is halo to the catalytic hydrogenolysis steps of Scheme 20 because the undesired displacement of the halogen may compete with the desired hydrogenolysis of the carbon-nitrogen bonds.
One alternative strategy is to postpone the halogenation until after the hydrogenolysis. Another alternative strategy is to use a milder means of reduction that would leave the halogen in place. A
third alternati~e, useful in the instance when the halogen is to serve as a leaving group, is to perform the desired displacement of halogen before the hydrogenolysis step.
Compounds of Formula 1 can be prepared from the compound of structure 24, 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. Preferably Z is an amino blocking group such as benzoyl. A preferred method of introducing the bromo substituent at the 6-position is by reaction with 2~ ~7~

bromine in glacial acetic acid, buffered with sodium acetate. Amino blocking groups can be added, if desired, to the 4-amino substituent using such methods as those disclosed by Greene, su~ra, and Barton, su~ra.
Alkyl groups can be added, if desired, to the 4-amino substituent using such common methods as ammonolysis of the appropriate halide as discussed by Morrison and Boyd, Chapter 22, Orqanic Chemistrv, Third Edition, Allyn and sacon, Boston, 1973, to provide a compound of structure 26 wherein Rl and R2 are defined hereinabove.
If desired, the benzoyl group can be removed from the l-position using known methods and optionally replaced with other amino-protecting groups. Preferably the benzoyl group represented by Z is replaced with a triphenylmethyl group prior to the metallating step to form structure 2. The amino-protecting groups and alkyl groups can be added either before or after the bromination, as desired.
The 4-amino-6-bromohexahydrobenz[cd]indole starting materials used to prepare the compounds of Formula 1 can be readily prepared by other processes such as depicted in Reaction Scheme 2 disclosed in United States Patent No. 4,576,959 of Flaugh, incorporated herein by reference in its entirety.
The procedure of Scheme 20 using the 4,5-epoxide provides a convenient way to prepare the optically active isomers of the compounds of Formula 1. Such isomers can also be isolated by resolving racemic mixtures. This resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization. Particularly useful resolving agents are d- and l-tartaric acids, d- and 1-ditoluoyltartaric acids, and the like.

2 ~

The methods of preparation described in Schemes 2-19 provide compounds in which the heteroaromatic ring may or may not be substituted. The general reactions provided below set forth methodology for incorporating, interconverting, and removing substituents on the heteroaromatic ring. Additional methods for performing these transformations are cited in Com~rehensive Orqanic Transformations by Richard C. Larock, VCH
Publishers, Inc., New York (1989) which is incorporated herein by reference. ~HET" refers to the heteroaromatic attached to the hexahydrobenz[cd]indole at position C-6.
1. Halogen substituent (X):
HET-OH ---~~ HET-X POX3, PX3, SOX2, PPh3-X2, or p(OR)3-X2 HET-NH2 -- ~ HET-X 1. HONO; 2. CuX, or KI, or HBF~, 2. O(C1 - C3 alkyl), i.e., [OR]
HET-X ---~~ HET-OR RO-, CuI, (DMF, or DMAc, or NMP), ~
HET-OH - ~ HET-OR Base, RX; or CH2N2 3. Hydroxy substituent:
HET-NH2 ~ HET-OH 1. HONO; 2. H30+, HET-OMe ~ HET-OH 48% HBr, ~; or BBr3 2~ ~7~

4. Cyano substituent:
HET-NH2 ' HET-CN 1. HONO; 2. CuCN

HET-X - D HET-CN CuCN, (DMF, or DMAc, or NMP), ~;
or CN-, 5. S(Cl - C3 alkyl), i.e, [SR]
HET-NH2 ~- HET-SR 1. HONO; 2. RSH, base HET-X ---~~ HET-SR RS-, CuI, (DMF, or DMAc, or NMP), 6. Amino substituent:
HET-NO2 ~ HET-NH2 H2, catalyst (i.e., Pt or Pd) 7. Hydrogen substituent:
HET-X ---~~ HET-H H2, catalyst; or R3SnH, 2,2l-azobis(2-methyl)-propionitrile), ~
HET-OH D HET-H 1. 5-chloro-1-phenyltetrazole, 2. H2, catalyst HET-NH2 - ~~ HET-H 1. HONO, 2. H3P2 HET-CH2Ph - ~ HET-H H2, catalyst (i.e., Pd) (This applies if the benzyl 2~ Q7~9 group is attached to a nitrogen in the heterocyclic ring.) HET-SR ---~~ HET-H Raney Ni 6-acyl-substituted-hexahydrobenz[cd]indoles are preferred intermediates in the preparation of certain of the compounds of Formula 1, particularly 6-isoxazole-indoles and 6-pyrazole-indoles. The 6-acyl substituted indolines can be prepared by several routes using the 6-iodo-substituted indolines of structure 30 as depicted in Scheme 21 where Rl, R2 and Z are as defined hereinabo~e.

2 ~

Scheme 21 NR1R2 CN NR1R2 R12~C,p NRlR2 DM~ ~ Rl2MgBr D

Pd(PPh3)4 Rl2- C a Sn(CH3)3 ~ ~ .

C, R12 - CH2 "0 ~504 ~
Z-N Z-N
36 3~

In a preferred method of preparation as depicted in Scheme 21, the nitrile 32 is contacted with an organometallic reagent such as a Grignard reagent under standard conditions to provide the 6-acyl derivative 34. For this reaction Z is preferably benzoyl or trityl. Alternatively, a 6-alkyne intermediate of structure 36 can be prepared and then hydrolyzed to provide the acyl derivative 38. This method provides a methylene group adjacent to the carbonyl group. In this method Z can be an amino protecting group such as benzoyl although the unprotected l-nitrogen is preferred, i.e., Z is hydrogen. Compounds of structure 30 can be contacted with a palladium catalyst Pd(PPh3)~
[where Ph is phenyl] and the tin alkyne compound R12-C-C-Sn(CH3)3 wherein R12 is a Cl-C7 alkyl, substituted Cl-C7 alkyl, aryl (Cl-C3 alkyl), substituted aryl (Cl-C3 alkyl), or C3-C7 cycloalkyl.
This reaction is normally conducted in a solvent such as toluene at an elevated temperature, for example at about 100C. Typically an excess of the tin alkyne is used along with about 0.25 equivalents of the palladium compound based on compound 30. The 6-alkyne 36 is then contacted with HgSO4 in water to provide the ketone 38.
In another preparation method depicted in Scheme 22, the 6-iodo derivative 30 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(PPh3)4 [where Ph is phenyl] as described in the literature for arylhalides.
[A. Schoenberg and R. F. Heck, J. Qra. Chem., 39, p.
3327 (1974); and A. Schoenberg, I. sartoletti, and R.
F. Heck, J. Or~. 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, or the blocking group can be removed to provide compounds of structure 40 where Rl, ~5 R2 and R12 are as defined above.

Scheme 22 C C
¢o~NR1R2 ~ NR1R2 ¢~NRlR2 ~`H Pd(PPh~ ~`H ~H
Z - N R3SnRI2 Z- N HN

The following examples further illustrate the preparation of compounds used in the method of this invention. The examples are provided for purposes of illustration only and are not to be construed as limiting the scope of the instant invention in any way.
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" means milliliter; "M" refers to molar; "min" refers to minutes; llhr" refers to hours; "N~R" refers to nuclear magnetic resonance; and ~MS~ refers to mass spçctrometry.
Exam~le A. Pre~aration of (+)-l-Bçnzovl-6-cvano-4-(di-n-ro~vlamino)-1.2.2a.3.4,S-hçxahvdrobenz~c.dl indole To a solution of (+)-l-benzoyl-6-bromo-4- (di-n-propylamino)hexahydrobenz[cd]indole (5.5 g, 12.5 mmol) in DMF (100 mL) under a N2 atmosphere was added 3.4g (37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The 2~7~

reaction mixture was then stirred at 140C. for 6 hr.
The reaction mixture was poured onto ice, diluted with water, CH2C12 added and stirred for 30 minutes. The mixture was filtered through a Celite pad and the filtrate was extracted twice with CH2Cl2. The organic solution was washed twice with saturated NaCl solution.
The CH2C12 solution was dried over MgSO4 and then evaporated to provide 4 g of a solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2C12 as eluent gave 3 g (62~) of product.
mp = 122-124C.

s. Preparation of (-)(2aS.4R)-l-senzovl-6-cvano-4-(di-n-proovlamino)-1.2,2a,3,4,5-hexahydrobenz-~cdlindole To a solution of (-)-(2aS,4R)-6-bromo compound (30.0 g; 0.068 mol) in 500 ml of DMF was added CuCN
(18.3 g; 0.2 mol) and CuI (38.0 g; 0.2 mol). The reaction mixture was then stirred at 140C for 6 hr.
The reaction mixture was poured into 4L, of water. The precipitate was collected and washed several times with water. The precipitate was suspended in dilute NH40H
and slurried with ethyl acetate. The whole mixture was filtered through a celite pad. The ethyl acetate solution was separated and washed with brine solution.
The ethyl acetate solution was dried (MgSO4) and concentrated to dryness to provide 21.3 g of the (-)-6-nitrile.

C. Preparation of the (+)(2aR,4S)-6-cyano counter-part of Exam~le ls.
In a similar manner as in Example lB above, the (-~)-(2aR,4S)-6-bromo compound (17.1 g, 0.039 mol) was contacted with CuCN (10.75 g; O.I2 mol) and CuI (22.8 X-8266A -53- 2~70~

g; 0.12 mol) in 300 ml DME to give 11.6 g of (+)-6-cyano compound.

Exam~le 2 Pre~aration of (+)-6-cyano-4-(di-n-~ropvlamino)-1,2.2a,3,4.5-hexahydrobenzlcdlindole.
To a stirred solution of 4.8 g (0.0124 mol) of (+)-1-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 200 mL of THF
cooled to -78C under a N2 atmosphere were added 16 m~
(0.025 mol) of a 1.6 M solution of n-butyl lithium in hexane. The reaction mixture was stirred at -78C for 30 minutes and then allowed to warm to -20C. To the reaction mixture was added 100 mL of lN HCl. The mixture was extracted once with ethyl ether. The acidic solution was made alkaline with the addition of cold 5N NaOH. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed with a saturated NaCl solution. The CH2Cl2 solution was dried over MgSO4 and evaporatecl to give 4 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 3 g ~5%) of product as an oil which upon standing solidified.

Example 3 Pre~aration of (+)(2aS.4R)-1-tritvl-6-cvano-4-(di-n-pro~lamino)-1,2,2a,3,4,5-hexahvdrobenz~cdlindole.
To a solution of (~)(2aS,4R)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (12.8 g, 0.045 mol) and triethylamine (4.5 g, 0.045 mol) in 400 mL of methylene chloride was added a solution of triphenylmethyl chloride (trityl chloride) (12.6 g, 0.045 mol) in 100 mL of methylene chloride dropwise at room temperature. The reaction mixture was stirred for 2~ ~7~

16 hr at room temperature. The reaction mixture was extracted with water and cold lN HCl. The organic solution was washed with a saturated NaHCO3 solution and with a saturated brine solution. The organic layer was dried (MgSO4) and concentrated to dryness in vacuo to give a residue. The residue was slurried with warm hexanes, cooled and filtered to remove insolubles. The filtrate was concentrated to an oil. The oil was chromatographed (silica gel, 20% ethyl acetate in hexanes) to provide 20.6 g of the (+)-trityl nitrile.

Exam~le 4 Preparation of (+)(2aS,4R)-6-acetyl-4-(di-n-pro~vlamino)-1.2,2a,3 4,5-hexahvdrobenz~cdlindole.
A solution of 2.4 g (4.6 mmol) of (+)-(2aS,4R)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 mL of THF was treated with 25 m~ of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16 hr.
The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of a saturated NH4Cl solution. The reaction mixture was extracted with ethyl acetate. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL
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 concentrated NH40H
solution. The basic mixture was extracted twice with ethyl acetate. The combined organic solution was washed once with a saturated NaCl solution and dried over MgSO4. The ethyl acetate solution was evaporated to yield 1.4 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 1.2 g (87%) of product. Recrystallization from hexanes 21 ~70~

yielded 840 mg of the product (+) ketone.
mp = 121-122~C
[ a] D + 67.40(MeOH).

Exam~le 5 Preparation of (+)-6-acetyl-4-(di-n-propylamino)-1.2,2a,3,4,5-hexahvdrobenz~cdlindole.
A solution of 0.5 g (1.8 mmol) of (+)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 75 mL of benzene was treated with 5 mL of 2.0M
methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 2 days. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of a saturated NH4Cl solution. The benzene layer was separated and washed once with a saturated NaCl solution. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL
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 concentrated NH40H
solution. The basic mixture was extracted twice with CH2C12. The combined organic solution was washed once with a saturated NaCl solution and dried over MgS04.
The CH2C12 solution was evaporated to yield 0.5 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 0.4 g (75%) of product as an oil which upon standing solidified.
mp = 76-77C

2~070tCJ~

Exam~le 6 Preparation of (+)(2aS,4R)-6-(3-pyrazolyl)-4-(di-n-propylamino)-1,2.2a.3,4,5-hexahydrobenz~cdlindole-2HCL.
A solution of (-~)-(2aS,4R)-l-triphenylmethyl-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.67 g, 3 mmol) and 3 mL of tris(dimethylamino)methane in 50 mL of toluene was refluxed for 5 hr. The reaction was concentrated ln vacuo and the residue was dissolved in 100 mL of CH30H.
To the CH30H solution was added 2 mL of 85% hydrazine and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 50 ml of lN HCl and stirred for an additional 1 hr. The solution was concentrated in vacuo to remove CH30H and the acidic solution was extracted with ethyl acetate. The acidic solution was separated and made alkaline with addition of excess concentrated NH40H.
The basic mixture was extracted with ethyl acetate.
The ethyl acetate solution was washed with a brine solution, dried (MgS04) and concentrated n vacuo to provide 900 mg of an oil. The crude product was chromatographed through silica gel (flash column, ethyl acetate) to yield 700 mg of pyrazole compound. The oil was dissolved in 50 mL of CH30H and 2 equivalents of 0.1 N HCL was added to the solution. The solution was concentrated ln vacuo and the residue was crystallized from ethanol/diethyl ether.
Yield - 400 mg mp = 260 d MS m/e 324(FD) [a] D +19 . 84(MeOH).

X-8266A -57- 210 7 0 ~ 9 Analysis calculated for C2oH28N4~2Hcl Theory: C, 60.45; H, 7.61; N, 14.10;
Found: C, 60.21; H, 7.60; N, 14.26.

Example 7 Pre~aration of (+)-6-(5-isoxazolvl)-4-(di-n-~ro~ylamino)-1,2,2a,3,4.5-hexahvdrobenz~cdlindole-2HCl.
To a solution of (+)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (2.3 g, 7.7 mrnol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH2Cl2 under N2 was added dropwise a solution of 2,2,2-trichloroethyl chloroformate. The reaction mixture was stirred at room temperature for 1 hr. The CH2Cl2 solution was extracted with water and lN HCl.
The organic solution was washed with a saturated NaHCO3 solution and with a brine solution. The CH2C12 solution was dried (MgSO4) and concentrated 1B vacuo to give 3.3 g of the l-carbamylindoline.
A solution of this l-carbamylindoline (3.3 g, 7.7 mmol) and tris(dimethylamino)methane (5 mL) in 70 mL of toluene was stirred at reflux for 16 hr. The reaction mixture was concentrated to dryness n vacuo. The residue was dissolved in 50 mL of acetic acid and hydroxylamine hydrochloride (2.5 g, 36 mmol) was added.
The reaction mixture was stirred at room temperature for 16 hr and then concentrated n vacuo to dryness.
The residue was suspended in water and excess concentrated NH40H was added to the mixture. The basic mixture was extracted with CH2C12. The organic solution was washed with a brine solution, dried (MgSO4) and concentrated n vacuo to give 3.1 g of an oil. The crude product was chromatographed (flash column, silica gel, 20~ hexanes in ethyl acetate) to yield 2.0 g of (+)~1-carbamyl-6-isoxazolylindoline.

X-8266A -58- 2 ~ ~ 7 ~ ~ ~

This isoxazole carbamate was dissolved in 20 mL of acetic acid and 1 g of zinc dust was added all at once.
The reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The residue was suspended in a saturated NaHCO3 solution and extracted with CH2Cl2. The organic solution was washed with a brine solution, dried (MgSO4) and concentrated to an oil. The crude material was chromatographed (flash column, silica gel, ethyl acetate) to give 500 mg of isoxazole indoline. The product was dissolved in 50 mL of CH30H and 2 equivalents of O.lN HCl were added. The solution was concentrated to dryness and the residue was crystallized from ethanol/diethyl ether to give 85 mg of isoxazole substituted product as the dihydrochloride.
mp = 226C d MS m/e 325(FD) Analysis calculated for C20H27N3O-2HCl Theory: C, 60.30; H, 7.34; N, 10.55;
Found: C, 58.83i H, 7.18; N, 10.01.

Exam~le 8 Preparation of (+)(2aS,4R)-6-(3-isoxazolyl)-4-~di-n-~ro~vlamino)-1.2, 2a 3,4,5-hexahvdrobenz~cdlindole-2 A solution of (+)-(2aS,4R)-1-triphenylmethyl-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (3.33 g, 6 mmol), 5 g hydroxylamine hydrochloride, 20 mL pyridine and 30 mL
of ethanol was refluxed for 16 hr. The reaction mixture was concentrated to dryness ln vacuo and the 2 1 ~7~

residue was dissolved in 5N HCl. The acidic mixture was extracted with ethyl acetate. The acidic solution was made alkaline with excess NH40H solution and extracted with ethyl acetate. The ethyl acetate solution was washed with a brine solution, dried (MgS04) and concentrated in vac_Q to give 1.5 g of crude product which was chromatographed (flash column, silica gel, ethyl acetate) to give 1.2 g of oxime.
mp = 129-130C.
To a solution of this oxime (1.2 g, 3.8 mmol) in 100 mL of THF cooled to -5C under a N2 atmosphere was added 7.5 mL n-butyllithium (1.6 M in hexanes) dropwise with stirring. The reaction mixture was stirred with continued cooling for 1 hr. To the reaction mixture was added 2 mL (26 mmol) of DMF all at once and then stirred for 1 hr at room temperature. The reaction mixcure was poured into 50 mL of lN H2S04 and the acidic solution was warmed on a steam bath for 1 hr.
The acidic solution was cooled, extracted with diethyl ether, and then made alkaline with excess 5N NaOH. The basic mixture was extracted with ethyl acetate. The organic was layer was washed with a brine solution, dried (MgS04) and concentrated n vacuo to give 1 g of an oil. The oil was chromatographed (flash column, silica gel, ethyl acetate) to yield 500 mg of product as an oil. The oil was dissolved in 50 mL of CH30H and 2 equivalents of O.lN HCL were added. The solution was concentrated to dryness in vacuQ and the residue was crystallized from ethanol/diethyl ether.
Crystallization gave 300 mg of the dihydrochloride of the 6-isoxazolyl product.
mp = 215C d MS m/e 325(FD) [a]D +26.4(MeOH).

2~7~

Example 9 Preparation of (+)-1-benzoyl-6-~4-(2-amino-thiazolyl)l-4-(di-n-pro~vlamino)-1,2,2a 3,4,~
hexahvdrobenzLcdlindole, To a solution of (+)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (205 mg, 0.7 mmol) and triethylamine (81 mg, 0.8 mmol) in 20 mL of CH2Cl2 was added a solution of benzoyl chloride (112 mg, 0.8 mmol) in 20 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was sucessively washed with water, a saturated NaHCO3 solution, a brine solution and dried (MgSO4). The organic layer was concentrated to dryness in vacuo to give 200 mg of the 1-benzoyl derivative.
A solution of this N-benzoyl compound (200 mg, 0.5 mmol) in 20 mL of acetic acid was saturated with Hsr(gas). To the solution was added dropwise a solution of bromine (0.2 mL) in 5 mL of acetic acid.
The reaction was stirred at room temperature for 30 min and then concentrated to dryness ~a vacuo. The residue was dissolved in 30 mL of ethanol then 500 mg of thiourea were added and the mixture refluxed for 16 hr.
The reaction was concentrated to dryness ia vacuo and the residue dissolved in water. The solution was made alkaline with the addition of concentrated NH40H. The basic mixture was extracted with CH2Cl2. The organic solution was washed with a brine solution, dried (MgSO4) and evaporated to dryness to give 200 mg of an oil. The oil was chromatographed (flash column, silica gel, ethyl acetate) to provide 140 mg of the above-named 6-aminothiazolyl compound.
MS m/e 460(FD) X-8266A -61- 2~ ~D~

Example 10 Preparation of (-~)(2aS 4R)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahvdrobenz~cdlindole-2 HCl To a solution of (+)t2aS,4R)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole ~1 7 g, 5.7 mmol) and triethylamine (0.8 ml, 6 mmol) in 90 ml CH2Cl2 was added dropwise a solution of 2,2,2-trichloroethyl chloroformate (1.3 g, 6 mmol) in 10 ml CH2Cl2. The reaction mixture was stirred at room temperature for one hour and then extracted with water and lN HCl. The organic solution was washed with a saturated NaHCO3 solution, a saturated brine solution, dried over MgSO4 and then concentrated to dryness ln vacuo to give 2.5 g of the l-carbamylindoline.
A solution of the l-carbamylindoline (2.5 g, 5.7 mmol) and tris(dimethylamino)methane (5 ml) in 100 ml of toluene was stirred at reflux for 16 hours. After 16 hours the reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in 50 ml of acetic acid and 1.5 g (22 mmol) of a hydroxylamine hydrochloride solution were added. The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated to dryness in vacuo. The resulting residue was suspended in water and an excess of a concentrated NH4OH solution was added to the mixture. The basic mixture was then extracted with CH2Cl2 and the resul~ing organic extract was washed with a saturated brine solution, dried over MgSO4 and then concentrated n vacuo to give 2.1 g of an oil. This oil was chromatographed (flash column, silica gel, EtOAc) to yield 1.9 g of ~+)(2aS,4R)-6-(5-isoxaæolyl)indoline. The isoxazolylindoline was dissolved in 30 ml of acetic acid and 1.5 g of zinc dust were added all at once. The resulting reaction mixture was stirred at room temperature ~O;~9 X~8266A -62-for four hours and then filtered through a celite pad.
The filtrate thus obtained was then concentrated to dryness ln va~uo. The resulting residue was suspended in a saturated NaHCO3 solution, which was then extracted with CH2Cl2. The organic extract was then washed with a saturated brine solution, dried over MgSO4 and concentrated in vacuo to an oil. This oil was chromatographed (flash column, silica gel, EtOAc) to give 400 mg of isoxazolylindoline. Such compound was dissolved in 50 ml of methanol and two equivalents of 0.lN HCl were added. The resulting solution was concentrated to dryness n vacuo and the resulting residue was then crystallized from ethanol/diethyl ether to give 170 mg of title compound.
mp = 235DC d MS m/e 325(FD) [a] D + 27.29 (MeOH) Analysis calculated for C20H27N3O-2HCl Theory: C, 60.30; H, 7~34~ N, 10.55;
Found: C, 60.53; H, 7.54; N, 10.26.

Exam~le 11 Preparation of (-)(2aR,4S)-6-(5-isoxazolyl)-4-(di-n-~ro~vlamino)-1,2.2a,3,4,5-hexahvdrobenz~cdlindole-2 HCl The title compound was prepared substantially in accordance with the method described in Example 10, above, utilizing 2.5 g (8.3 mmol) of (-)(2aR,4S)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (prepared substantially in accordance with the method described in Example 4) and 1.5 g (22 mmol) of a hydroxylamine hydrochloride solution. Such reaction sequence provided 500 mg of title compound.

2107~9 m.p. 235C d MS m/e 325(FD) [a]D -29.18(MeOH) Analysis calculated for C20H27N3O-2HCl Theory: C, 60.30; H, 7.34; N, 10.55;
Found: C, 60.11; H, 7.41; N, 10.43.

Exam~le 12 Pre~aration of (2aR,4S~-6-(3-~henvl-1,2 4-oxa-diazol-5-~1)-4-(di-n-~ro~vlamino)-1,2,2a,3 4 5-hexahvdro-benz~cdlindole A sodium ethoxide solution was prepared by dissolving 49 mg (2.1 mmol) of sodium in 35 ml of ethanol.
Phenylhydroxamidine (1.73 g, 12.71 mmol) and 6-ethoxycarbonyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (890 mg, 2.1 mmol) were added to the ethoxide solution and the resulting solution was heated to reflux and stirred at that temperature for 6.25 hours and then stirred overnight at room temperature. The next morning additional sodium ethoxide solution (50 mg of sodium in 10 ml of ethanol) was added and the reaction mixture was again stirred at reflux overnight. The next morning water was added to the reaction mixture and the resulting solution was then extracted with ethyl acetate.
The organic extract was washed sequentially with water and a saturated brine solution, dried over sodium sulfate and then concentrated n vacuo to provide 2.33 g of a brown oil. This oil was purified by flash chromatography (2-.5%
isopropanol in chloroform plus 0.5% ammonium hydroxide) to provide 260 mg of title product as a light yellow solid.
Such product was purified by recrystallization from hexane.

2~70~

Analysis calculated for C25H30N4O
Theory: C, 74.59; H, 7.51; N, 13.92;
Found: C, 74.59; H, 7.52; N, 13.90.

Example 13 Preparation of (-)(2aR,4S)-6-(2-furyl)-4-(di-n-propylamino)-1,2,2a.3,4,5-hexahydrobenz~cdlindole To a sealable tube with threads containing 13 ml of dry tetrahydrofuran were added 1.2 g (2.46 mmol) of ~+)(2aR,4S)-l-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 968 mg (2.71 mmol) of 2-(tributylstannyl)furan and 200 mg of bis(triphenyl-phosphine)palladium(II) chloride. The resulting mixture - was then deaerated with argon for 15 minutes. After deaeration, the tube was sealed with a teflon cap and the contents thereof were heated to 100C for 24 hours. After 24 hours, the reaction mixture was cooled, filtered through a celite pad and the resulting filtrate was then concentrated n vacuo to provide a viscous orange oil.
Flash chromatography of this oll over silica gel with 60%
ethyl acetateJhexane plus 0.5% ammonium hydroxide as eluent gave the protected analog of the title compound in 61% yield.
The above-mentioned protected analog (635 mg, 1.4 mmol) was dissolved in 10 ml of dry tetrahydrofuran and the resulting solution was chilled to -78C. Once chilled, 1.5 ml (2.39 mmol) of a 1.7M solution of n-butyllithium in hexane was added dropwise via syringe.
Once n-butyllithium addition was complete the reaction mixture was warmed to room temperature. The reaction mixture was quenched with a saturated NaHCO3 solution and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with a saturated 21 ~70~

brine solution, dried over sodium sulfate and then concentrated ln vacuo to provide a viscous orange oil.
This oil was chromatographed over silica gel (elution with 20% ethyl acetate/hexane plus 0.5% ammonium hydroxide) to provide 161 mg of title compound as a pale yellow oil.
MS m/e 324(ED) [~] D -45.63(MeOH) Analysis calculated for C2lH28N2:
Theory: C, 77.74; H, 8.70; N, 8.63;
Eound: C, 78.74; H, 8.82; N, 8.27.

Exam~le 14 Pre~aration of (+)(2aS,4R)-6-(2-furyl~-4~(di-n-~ro~vlamino)-1,2,2a.3,4,5-hexahvdrobenz~cdlindole The title compound was prepared substantially in accordance with the method set forth in Example 13, above, utilizing 1.5 g (3.07 mmol) of (-)(2aS,4R)-1-benzoyl-6-lodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 250 mg of bis(triphenyl-phosphine)palladium(II) chloride and 1.21 g (3.38 mmol) of 2-(tributylstannyl)furan to provide 592 mg of title compound as a viscous brown oil.
MS m/e 325.22(FD) [~] D +42.0(MeOH) Analysis calculated for C21H28N2:
Theory: C, 77.74; H, 8.70; N, 8.63;
Eound: C, 77.59; H, 8.10; N, 8.83.

X-8266A -66- 210 7 ~ ~ 9 Example 15 Preparation of (+)(2aS,4R)-6-(3-furvl)-4-(di-n-propvlamino)-1 2.2a,3.4.5-hexahydrobenz~cdlindole The title compound was prepared substantlally in accordance with the method described in Example 13, above, utilizing 1.50 g (3.07 mmol) of (+)(2aS,4R)-l-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 1.21 g (3.38 mmol) of 3-(tributylstannyl)furan and 250 mg of bis(triphenylphosphine)palladium(II) chloride to provide 711 mg of title product as a pale yellow viscous oil.
MS m/e 324(FD) Analysis calculated for C2lH28N2:
Theory: C, 77.24; H, 8.70; N, 8.63;
Found: C, 77.49; H, 8.68; N, 8.45.

Exam~le 16 Preparation of (+)(2aS,4R)-6-(2-~hienvl)-4-(di-n-pro~vlamino)-1,2 2a,3,4,5-hexahyçlrobenz~cdlindole The title compound was prepared substantially in accordance with the method set forth in Example 13, above, utilizing 1.5 g (3.1 mmol) of (-)(2aS,4R)-l-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 150 mg of bis(triphenylphosphine)palladium(II) chloride and 1.27 g (3.41 mmol) of 2-(tributylstannyl)thiophene to provide 719 mg of title compound as a light brown viscous oil.
MS m/e 341(FD) Analysis calculated for C21H28N2S:
Theory: C, 74.07; H, 8.29; N, 18.60; S, 9.42;
Found: C, 74.24; H, 8.60; N, 17.52; S, 9.15.

2~7~

Exam~le 17 Preparation of (t)(2aS,4R)-6-(2-pyridYl)-4-(di-n-prQpylamino)-1,2,2a,3,4,5-hexahydrobenz r cdlindole The title compound was prepared substantially in accordance with the method set forth in Example 13, above, utilizing 1.50 g (3.07 mmol) of (-)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole, 250 mg of bis(triphenylphosphine)palladium(II) chloride and 1.24 g (3.38 mmol) of 2-(tributylstannyl)pyridine to produce 474 mg of title compound as a colorless foam. The hydrochloride salt of the title compound was prepared by dissolving the foam in diethyl ether and then treating the resulting solution with a saturated hydrochloric acid in methanol solution. A yellow foam comprised of such salt was afforded after concentration in vac~o.
MS m/e 336.24(FD) Analysis calculated for C22H29N3~HCl Theory: C, 71.04; H, 8.13; N, 11.30;
Found: C, 70.60; H, 8.46; N, 10.58.

Example 18 Preparation of (~)(2aS ~ 6-(3-pyridyl)-4-(di-n-pro~ylamino)-1,2,2a 3,4,5-hexah~drobenz r cdlindole The title compound was prepared substantially in accordance with the procedure set forth in Example 13, above, utilizing 1.50 g (3.07 mmol) of (-)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 250 mg of bis(triphenyl-phosphine)palladium(II) chloride and 1.24 g (3.38 mmol) of 3-(tributylstannyl)pyridine to produce 475 mg of title compound as a pale yellow oil. The dihydrochloride salt of the title compound was prepared by dissolving the oil in 21~7~

diethyl ether and then adding a saturated hydrochloric acid in methanol solution dropwise. Once an excess of hydrochloric acid had been added the mixture was concentrated ln vacuo to provide a pale yellow foam.
MS m/e 336.24(FD) Analysis calculated for C22H2gN3-2HCl:
Theory: C, 64.70; H, 7.65; N, 10.29;
Found: C, 65.34; H, 7.S5; N, 9.76.
xample 19 Pre~aration of (-)(2aR ~4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2 2a,3,4.5-hexahydrobenzrcdlindole A. 2-tributylstannyloxazole A solution of 1.00 g (14.5 mmol) of oxazole in 25 ml of THF at -78C was treated with 10.2 ml (14.6 mmol) of 1.43M butyllithium in hexane. After stirring for 30 minutes, an addition of 3.93 ml (14.5 mmol) of tributyltin chloride was made, and the solution was allowed to warm to room temperature. Stirring was continued for another hour after which most of the solvents were evaporated n vacuo. The resulting residue was taken up in 50 ml of hexane, and the resulting precipitate was separated by filtration through filtercel. Evaporation of the solvent from the filtrate provided 5.13 g of a colorless oil which was identified by NMR as the 2-stannyl derivative plus a small amount of tetrabutylstannane.

B. (2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-~-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-21070~

propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in lM HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2C12. Concentration of the extract ln vacuo gave about 4 g of a brown oil.
When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-l-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. mp 103-104C.

C. (-)(2aR,4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz~cd]indole A solution of 1.00 g (2.33 mmol) of the above 1-benzoyl compound in 25 ml of THF was stirred at -78C
as 3.0 ml (4.29 mmol) of 1.43M butyllithium in hexane was added. The resulting solution was allowed to warm to 0C, then poured into water and extracted with CH2Cl2. The CH2Cl2 extract was then, in turn, extracted with lM HCl. The resulting aqueous extract was made alkaline with lM NaOH, and, in turn, extracted with CH2Cl2. After drying over Na2SO4, the extract was 21070~9 concentrated ln vacuo to provide title compound as a viscous oil. m.p. 103-104C
MS m/e 326(ED) [a]D = -60(MeOH).
Analysis calculated for C20~27N3:
Theory: C, 73.81; H, 8.36; N, 12.91;
Found: C, 73.37; H, 8.26; N, 12.09.

Example 20 Pre~aration of (-)(2aR,45)-6-(5-isoxazolyl)-4~~di-(c~clopropylmethvl)aminol-1,2L2a,3,4,5-hexahydrobenz-~cdlindole To a solution of (-)(2aR,4S)-6-acetyl-4-[di-(cyclopropylmethyl)amino]-1,2,2a,3,4,5-hexahydrobenz-[cd]indole (2.5 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH2Cl2 was added dropwise a solution of 2,2,2-trichloroethylchloroformate (1.7 g, 8 mmol) in 10 ml C~2Cl2. The reaction mixture was stirred at room temperature for one hour and then extracted with water and lN HCl. The organic solution was washed with a saturated NaHCO3 solution and a saturated brine solution, dried over MgSO4 and then concentrated to dryness in vacuo to give 3.1 g of the 1-carbamylindoline.
A solution of the 1-carbamylindoline (3.1 g, 6.2 mmol) and tris(dimethylamino)methane (5 ml) in 100 ml of toluene was stirred at reflux for 16 hours. After 16 hours the reaction mixture was concentrated to dryness ~ vacuo. The resulting residue was dissolved in 50 ml of acetic acid and 2.0 g (29 mmol) of a hydroxylamine hydrochloride solution were added. The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated to 2107~9 X-8266A -7~-dryness in vacuo. The resulting residue was suspended in water and an excess of a concentrated NH40H solution was added to basify the mixture. The basic mixture was then extracted with CH2Cl2 and the resulting organic extract was washed with a saturated brine solution, dried over MgSO4 and then concentrated ln vacuo to give 2.1 g of an oil. This oil was chromatographed (flash column, silica gel, EtOAc) to yield 1.7 g of the protected (+) (2aR,4S)-6-(5-isoxazolyl)indoline.
The above compound (1.7 g, 3.2 mmol) was dissolved in 30 ml of acetic acid and 1.5 g of zinc dust were added all at once. The resulting reaction mixture was stirred at room temperature for four hours and then filtered through a celite pad. The filtrate thus obtained was then concentrated to dryness ln . The resulting residue was suspended in a saturated NaHCO3 solution, then extracted with CH2Cl2.
The organic extract was then washed with a saturated brine solution, dried over MgSO4 and concentrated ln vacuo to an oil. This oil was chromatographed (flash column, silica gel, EtOAc) to give 660 mg of title compound.

Exam~le 21 Preparation of (-)t2aR,4S)-6-(5-oxazol~1)-4-(di-n-~ropylamino)-1 2 2a 3,4,5-hexahydrobenz~cdlindole A. (-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole To a sitrred solution of 12.8 g (29 mmol) of (+)(2aR,4S)-l-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 200 ml of tetrahydrofuran cooled to -78C under a nitrogen atmosphere was added 20 ml (32 mmol) of a 1.6M solution 2 1 ~

of n-butyllithium in hexane. The reaction mixture was stirred at -78C for 30 minutes and then allowed to warm to -20C. To the reaction mixture was added 50 ml of a lN hydrochloric acid solution. The mixture was extracted once with diethyl ether. The acidic solution was made alkaline with the addition of cold 5N sodium hydroxide solution. The basic mixture was extracted twice with methylene chloride. The combined organic solution was washed with a saturated sodium chloride solution. The methylene chloride solution was dried over magnesium sulfate and evaporated to give 9.6 g of (-)(2aR,4S)-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
To a solution of the above product (9.6 g, 0.028 mol ) and triethylamine (3.03 g, 0.03 mol) in lQ0 ml of methylene chloride was added a solution of trityl chloride (7.8 g, 0.028 mol) in 100 ml of methylene chloride dropwise at room temperature. The reaction mixture was stirred for 16 hours at room temperature.
The reaction mixture was extracted with water and a cold lN hydrochloric acid solution. The organic solution was washed with a saturated sodium bicarbonate solution and with a saturated brine solution. The organic solution was dried over magnesium sulfate and concentrated to dryness in vacuo to give a residue.
The residue was slurried with warm hexane, cooled and filtered to remove insolubles. The filtrate was concentrated to an oil. The oil was chromatographed (silica gel, 20~ ethyl acetate in hexane) to provide 12.7 g of the above-titled compound.

~7~9 s. (-)(2aR,4S)-6-formyl-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole To a solution of (-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (6.8 g, 12 mmol) in 100 ml of tetrahydrofuran cooled to -78C under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane. The reaction mixture waw stirred at -78C for 1 hour.
Dimethyltomamide (3 ml) was added to reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and then extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 5.6 g of the above-titled compound as an oil.

C. (-)(2aR,4S)-6-(5-oxazolyl)-4-(di-n-propylamino-1,2,2a,3,4,5-hexahydrobenz[cd]indole A reaction mixture of (-)(2aR,4S)-6-formyl-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.06 g, 2 mmol), tosylmethyl isocyanide (390 mg, 2 mmol) and potassium (304 mg, 2.2 mmol) in 100 ml of methanol was s~irred at reflux temperature under a nitrogen atomosphere for 16 hours.
The reaction mixture was concentrated to dryness and water was added to the residue. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to yield 1 g of an oil. The oil was dissolved in 20 ml of tetrahydrofuran and 50 ml of 5N
hydrochloric acid solution. The reaction mixture was stirred at room temperature for 30 minutes. The 2~7a~

reaction mixture was extracted twice with ethyl acetate and the acidic solution was then made alkaline by additio nof excess concentrated ammonium hydroxide solution. The basic mixture was extracted twice with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 0.5 g of an oil. The oil was purified by silica gel chromatography, with ethyl acetate as eluent, to give 0.3 g of title compound.
MS (ED) m/e/ 325 Example 22 Preparation of (2aR,4S)-6-(3-~vridyl)-4-(di-n-ropylamino)-1,2.2a.3,4,5-hexahydrobenzrcdlindole A. 3-pyridylboronic acid A solution of 4.0 ml (6.56 g, 42 mmol of 3-bromopyridine and 9 ml (8 mmol) of trimethylborate in 100 ml of diethyl ether was cooled to -70C the treated slowly with 33 ml (83.8 mmol) of a 2.54M tert-butyllithium in pentane solution. After allowing the resulting slurry to warm to room temperature, the solvents were evaporated under vacuum. The residual oil was treated carefully with 50 ml of a lM
hydrochloric acid solution. Several milliters of methylene chloride were added, and the mixture was stirred until the oil had dissolved. The aqueous layer was washed with fresh methylene chloride. The pH of the aqueous solution was raised to 12 with 5M sodium hydroxide solution, and the washing was repeated. The pH of the aqueous solution was then lowered to 6.t with a concentrated hydrochloric acid solution. After chilling, this solution was filtered, saturated with 21 070~9 sodium chloride, then extracted several times with a 2:1 mixture of diethyl ether and isopropanol.
Evaporation of these extracts produced a colorless solid. This material was further purified by dissolving in methanol, evaporating to a thick paste, adding a few ml of water, concentrating further under vacuum, then chilling and collecting the crystalline product. Additional product in the aqueous mother liquor was isolated by repeating this process.
Thorough drying of this hydrated product at 0.1 mm pressure afforded a fine powder weighing 2.2 g.
Elemental analysis and a mass spectrum indicated the product so isolated was primarily the anh~dride (tripyridylboroxane).
B. (2aR,4S)-l-benzoyl-7-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A solution of 4.00 g of (2aS,4R-l-benzoyl-6-iodo-4-(di-n-propylamine)-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 0.60 g (0.525 mmol) of tetrakis(triphenylphosphine)pallidium in 50 ml of toluene was combined with 10 ml of a 2M sodium bicarbonate solution. This mixture was treated with 1.1 g (9.0 mmol) of the above 3-pyridylboronic anhydriee, and it was stirred vigorously at 105C under - nitrogen for 24 hours. The half-complete reaction was charged with an additional 1.0 g of 3-oyridylboronic anhydride, and heating was continued another 24 hours.
The cooled mixture was filtered through filtercel. The organic layer was washed with a saturated sodium chjloride solution. The toluene was evaporated, and the residue was partitioned between lM hydrochloric acid solution and methylene chloride. The aqueous layer was basified with 5M sodium hydroxide solution, 2~ ~7~

and the product was extracted into methylene chloride.
After washing with a saturated sodium chloride solution and drying over sodium sulfate, the methylene chloride was evaporated leaving a viscous oil. This crude product was chromatographed over a silica gel column using 10% ethyl acetate in toluene, then 25% ethyl acetate in toluene, and finally 1:1 ethyl acetate toluene. The purified (2aR,4S)-l-benzoyl-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole was an oil weighing 2.99 g.

C. (2aR,4S)-6- (3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A solution of 2.75 g (6.26 mmol) of the above 1-benzoyl compound in 50 ml of tetrahydrofuran was stirred at -78C as 7.7 ml (11.3 mmol) of a 1.47M
butyllithium in hexane solution was added. This solution was allowed to warm to 0C, then poured into water and extracteed with methylene chloride. The methylene chloride was evaporated, and the residue was chromatographed over 50 g of florisil using ethyl acetate. The product from the column was a pale yellow oil weighing 2.0 g which assayed as title product.

Exam~le 23 Pre~aration of (-) (2aR,4S)-6-(3-isoxazolYl)-4- (di n-~roEylamlno)-1,2,2a,3,4 5-hexahydrobenz~cdl indole To a cool (-5C) solution of 2.6 g (3.6 mmol) of (-) (2aR,4S)-l-triphenylmethyl-6-(1-aximidoethane)-4-(di-n-propylamio)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (prepared substantially in accordance with the oxime prepared in Example 8) in 100 ml of tetrahydrofuran was added 6.9 ml of a 1.6M solution of n-butyllithium in hexane. The resulting solution was stirred at -5C for 2~ ~7i~

one hour and then 2 ml (26 mmol) of dimethylformamide was added all at once. The resulting solution was warmed to room temperature and then stirred for one more hour. After stirring at room temperature for one hour, the reaction solution was poured into 50 ml of a lN sulfuric acid solution. The acidic solution was warmed on a steam bath for one hour, cooled to room temperature and then extracted with diethyl ether to remove impurities. The acidic solution was then made alkaline with excess 5N sodium hydroxide solution and then extracted with ethyl acetate. The extract was washed with a saturated brine solution, dried over magnesium sulfate and then concentrated in vacuo to provide 1 g of an oil. This oil was purified by flash column chromatography (using ethyl acetate as eluent) to provide 400 mg of the title compound as an oil.

The compounds of Formula 1 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 1 are useful in treating disease states which require alteration of 5-HT receptor function, particularly 5-HTlA, and/or 5HTlD but without the side effects which may be associated with less selective compounds. This alteration may involve reproducing (an agonist) or inhibiting (an antagonist) the function of serotonin. These disease states include anxiety, depression, excessive gastric acid secretion, motion sickness, hypertension, nausea emesis, sexual dysfunction, cognition, senile dementia, migraine, consumptive disorders such as appetite disorders, alcoholism and smoking. The foregoing conditions are ~1~7~

treated with a pharmaceutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
- 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 (for example, motion sickness or emesis). The particular dose of compound administered according to this invention shall, 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 considerations. 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 about 0.01 mg/kg to about 50 mg/kg of the active compound of this invention when administered orally. Preferred oral doses will be about 0.01 to about 3.0 mg/kg, ideally about 0.01 to about 0.1 mg/kg. When a present 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 will be from about 10 ~g/kg to about 300 ~g/kg, preferably about 20 ~g/kg to about 50 ~g/kg.
The following experiments were conducted to demonstrate the ability of the compounds of Formula 1 to bind to 5-HT receptors. Such experiments demonstrate the utility of the compounds of Formula 1 in treating disease states (such as emesis and motion sickness) which require alteration of 5-HT receptor function.

21~70~9 The affinities of certain of the compounds of Formula 1 at the central 5-HTlA receptors were determined using a modification of the binding assay described by Taylor et al., J. Pharmacol. Ex~. 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. Membranes from the hippocampi were either prepared that day, or the hippocampi were stored frozen (-70C) until the day of preparation.
The membranes were prepared by homogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at 22C) using a Techmar Tissumizer (setting 65 for 15 sec), and the homogenate was centrifuged at 39800xg for 10 minutes. 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 minutes at 37C to facilitate the removal of endogenous ligands. The final pellet was resuspended in 67 mM
Tris-HCl, pH 7.4, to a concentration of 2 mg of tissue original wet weight/200 ~l. This homogenate was stored frozen (-70C) until the day of the binding assay. Each tube for the binding assay had a final volume of 800 ~1 and contained the following:
Tris-HCl (50 mM), pargyline, (10 ~M), CaC12 (3 mM), [3H]8-oH-DPAT (1.0 nM), appropriate dilutions of the drugs of interest, 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 minutes at 37C, and the contents were then 2~.~79.~

rapidly filtered through GF/s filters (pretreated with 0.5% polyethylenimine), followed by four 1 ml washes with ice-cold buffer. The radioactivity trapped by the filters was quantitated by liquid scintillation spectrometry, and specific [3H]8-OH-DPAT binding to the 5-HT1A sites was defined as the difference between [3H]8-OH-DPAT bound in the presence and absence of 10 ~M 5-HT.
The results of the evaluation of various compounds of Formula 1 in the test system described above are set forth in Table 1, below. In Table 1, the first column provides the Example Number of the compound evaluated while the second column provides the amount of test compound (expressed in nanomolar concentration) required to inhibit the binding of [3H]8-OH-DPAT by 50% (indicated as IC50)-Table 1 IN VITRO BINDING ACTIVITY AT THE 5-HTlA RECEPTOR

5-HTlA
in vitro binding Example No.(ICso, nM) 6 6.37 7 1.95 8 0.91 0.73 11 2.08 12 105.00 13 21.09 14 5.30 2.74 17 17.34 18 1.92 21~70~9 The affinities of certain of the compounds of Formula 1 at the central 5-HTlD binding sites were determined using a modification of the binding assay described by Heuring and Peroutka, J Neurosci., 7, 89 (1987). sovine brains were obtained and the caudate nuclei were dissected out and frozen at -70C 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 22C) with a Techmar Tissumizer (setting 65 for 15 sec), and the homogenate was centrifuged at 39,800xg for 10 minutes. 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 minutes at 37C to facilitate the removal of endogenous 5-HT. The final pellet was resuspended in the 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 ~1 and contained the following: Tris-HCl (50mM), pargyline (10 ~M), ascorbate (5.7 mM), CaC12 (3 mM), 8-OH-DPAT (100 nM to mask 5-HTlA receptors), mesulergine (100 nM to mask 5-HTlC receptors), [3H]5-HT (1.7-1.9 nM), appropriate dilutions of the drugs of interest, and membrane resuspension equivalent to 5 mg of original tissue wet weight, for a final pH of 7.4. The assay tubes were incubated for 10 minutes at 37C, and the contents were then rapidly filtered through GF/B
filters (pretreated with 0.5% polyethylenimine), followed by four 1 ml washes with ice-cold buffer. The radioactivity trapped by the filters was quantitated by 21 ~9~

liquid scintillation spectrometry, and specific [3H]5-HT binding to the 5-HT1D sites was defined as the difference between [3H]5-HT bound in the presence and absence of 10 ~M 5-HT.
The results of the evaluation of various compounds of Formula 1 in the test system described above are set forth in Table 2, below. In Table 2, the first column provides the Example Number of the compound evaluated while the second column provides the amount of test compound (expressed in nanomolar concentration) required to inhibit the binding of [3H]5-HT by 50% (indicated as ICso).

Table 2 IN VITRO slNDING ACTIVITY AT THE 5-HTlD RECEPTOR
5-HTlD
in vitro binding Exam~le No.(:[Cso, nM) 6 30.00 7 23.58 8 9.12 11.24 11 1375.00 13 1887.62 14 43.14 19.40 17 163.02 18 40.29 The data in the Tables 1 and 2 establish that the compounds of Formula 1 can be used to treat emesis or motion sickness. The term ~emesis~, as used for purposes of the present invention, means 2~07~

vomiting (the actual expulsion of stomach contents) and retching (vomiting movements without expulsion of matter). Accordingly, the compounds of Formula 1 can be used to suppress emetic responses to provacative motion (motion sickness) and various chemical stimuli such as oncolytic agents (e.g., cisplatin) or other psychoactive agents (e.g., xylazine, analgesics, anesthetics and dopaminergic agents) and the like.
The method of the present invention encompasses treatment of emesis or motion sickness in a prophylactic manner (i.e., using the compounds of Formula 1 to prevent emesis or motion sickness in a mammal susceptible to such conditions before the conditions actually occur or re-occur). Such prophylactic method of administration may be especially appropriate in cases where the patient is susceptible to motion sickness and is about to go on a boat, car or plane trip which, normally, would result in the patient's suffering a motion sickness attack or the patient is about to undergo treatment with various chemical stimuli ~cancer chemo and radiation therapy, analgesic and anesthetic agents, etc.) known to cause emesis.
The compounds of the present invention, and the compounds used in the method 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 Formula 1, or a pharmaceuticlaly acceptable salt thereof, admixed with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.
The present pharmaceutical formulations are prepared by known procedures using well known and 2107~9 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 an excipient serving as 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.

21 ~7~

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 excipient.
The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
Formulation 1 Hard gelatin capsules suitable for use in treating motion sickness are prepared using the following ingredients:
Ouantitv (ma/ca~sule) (+)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexa-hydrobenz[cd]indole 25 Starch, dried 425 Magnesium stearate 10 _ Total ~60 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

21~70~9 Formulation 2 A tablet formula is prepared using the ingredients below:
Ouantity (m~/tablet) (+)-6-[3-(5-ethyltetrazolyl)]-4-(di-n-propylamino)-1,2,2a,3,4,5~
hexahydrobenz[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 15A dry powder inhaler formulation suitable for treating emsis is prepared containing the following components:
Weiaht %
~ 6-(5-isoxazolyl)-4-(di-n-20propylamino)-1,2,2a,3,4,5-hexa-hydrobenz[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 suitable for treating emesis each containing 60 mg of active ingredient are made up as follows:
(+)-6-(2-pyrazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexa-hydrobenz[cd]indole 60 mg Starch 45 mg Microcrystalline cellulose35 mg 211 070~9 Polyvinylpyrrolidone (as 10%
solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 ma 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 50-60C 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.

FQrmula~ion 5 Capsules suitable for treating rnotion sickness each containing 20 mg of medicament are made as follows:
(+)-6-(5-oxadiazolyl)-4-(di-methylamino)-1,2,2a,3,4,5-hexa-hydrobenz[cd]indole 20 mg Starch 169 mg Magnesium stearate 1 ma Total 190 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 190 mg auantities.

2~7~

Formulation 6 Suppositories suitable for treating motion sickness each containing 225 mg of active ingredient are made as follows:
(+)-6-(4-pyridyl)-4-(di-n-propyl-amino)-1,2,2a,3,4,5-hexahydrobenz-[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.

Formulation 7 Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows:
(+)-6-(2-tetrazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexa-hydrobenz[cd]indole 50 mg xanthan gum 4 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50 mg Sucrose 1.75 g Sodium benzoate 10 mg Flavor q.v.
Color q.v.
Purified water to 5 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and 2~ ~7~

then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

Formula~ion 8 Capsules suitable for treating emesis each 10 containing 50 mg of medicament are made as follows:
(+)-6-(5-isoxazolyl)-4-(dimethyl-amino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole 50 mg Starch 507 mg Magnesium stearate 3 mq Total 560 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules.

Claims (12)

1. The use of a compound, or a pharmaceutically acceptable salt thereof, of the formula wherein:
R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl (C1-C4 alkyl), -(CH2)nS(C1-C4 alkyl), -C(O)R4 or -(CH2)nC(O)NR5R6;
R2 is hydrogen, C1-C4 alkyl, cyclopropylmethyl or C3-C4 alkenyl;
R3 is hydrogen, C1-C4 alkyl or an amino blocking group;
n is 1-4;
R4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or phenyl;
R5 and R6 are independently hydrogen, C1-C4 alkyl, or C5-C8 cycloalkyl with the proviso that when one of R5 or R6 is a cycloalkyl the other is hydrogen;
HET is a tetrazolyl ring, a substituted tetrazolyl ring or an aromatic 5- or 6-membered heterocyclic ring, said ring having from one to three heteroatoms which are the same or different and which are selected from the group consisting of sulfur, oxygen, and nitrogen with the proviso that the 6-membered heterocyclic ring can only contain carbon and nitrogen and with the further proviso that the 5-membered ring contains no more than one oxygen or one sulfur but not both oxygen and sulfur; to prepare a medicament for treating emesis or motion sickness.

2. The use according to Claim 1 wherein the compound is one in which R1 and R2 are independently C1-C3 alkyl.

3. The use according to Claim 1 or Claim 2 wherein the compound is one in which R3 is hydrogen.

4. The use according to any one of Claims 1, 2 or 3 wherein the compound is one in which HET is an isoxazole, an oxazole, a pyrazole, or an oxadiazole.

5. The use according to Claim 1 wherein the compound is selected from the group consisting of 6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(3-pyrazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(4-pyrazolyl)-4-(dimethylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(4-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(2-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(2-thiazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(5-thiazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(2-oxadiazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(3-furyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole or a pharmaceutically acceptable salt thereof.

6. The use according to Claim 5 wherein the compound is 6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole or a pharmaceutically acceptable salt thereof.

7. The use according to Claim 5 wherein the compound is 6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical formulation adapted for the treatment of emesis or motion sickness comprising a compound as set forth in any one of Claims 1 through 7, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

9. A compound of the formula wherein:
R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl (C1-C4 alkyl), -(CH2)nS(C1-C4 alkyl), -C(O)R4 or -(CH2)nC(O)NR5R6;
R2 is hydrogen, C1-C4 alkyl, cyclopropylmethyl or C3-C4 alkenyl;
R3 is hydrogen, C1-C4 alkyl or an amino blocking group;
n is 1-4;

R4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or phenyl;
R5 and R6 are independently hydrogen, C1-C4 alkyl, or C5-C8 cycloalkyl with the proviso that when one of R5 or R6 is a cycloalkyl the other is hydrogen;
HET is a tetrazolyl ring or a substituted tetrazolyl ring; or pharmaceutically acceptable salts thereof.

10. A pharmaceutical formulation comprising a compound of Claim 9, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

11. A compound of Claim 9 for use in treating serotonin related disorders.

12. A process for preparing a compound of the formula I

(I) wherein:
R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl (C1-C4 alkyl), -(CH2)nS(C1-C4 alkyl), -C(O)R4 or -(CH2)nC(O)NR5R6;
R2 is hydrogen, C1-C4 alkyl, cyclopropylmethyl or C3-C4 alkenyl;
R3 is hydrogen, C1-C4 alkyl or an amino blocking group;
n is 1-4;

R4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or phenyl;
R5 and R6 are independently hydrogen, C1-C4 alkyl, or C5-C8 cycloalkyl with the proviso that when one of R5 or R6 is a cycloalkyl the other is hydrogen;
HET is a tetrazolyl ring or a substituted tetrazolyl ring; or a pharmaceutically acceptable salt thereof, which comprises a) reacting a 4-amino-6-metallo-substituted hexahydrobenz[cd]indole of the formula , wherein R1 and R2 are as set forth above; Z is an amino protecting group and M is a metallo moiety, with a heterocyclic compound of the formula HET-L, wherein HET is as defined above and L is a leaving group;
b) deprotecting a compound of the formula wherein HET, R1 and R2 are as defined above and R3 is an amino protecting group so as to provide a compound of the formula I wherein R3 is hydrogen;

c) reacting a 4-amino-6-halo-substituted hexahydrobenz[cd]indole of the formula wherein R1, R2 and R3 are as defined above and X is halo with an organometallic derivative of the formula M-HET
where HET is as defined above and M is lithium, magnesium, zinc, tin, mercury or boronic acid;
d) reacting a 4-amino-6-halo-substituted hexahydrobenz[cd]indole of the formula wherein R1, R2 and R3 are as defined above and X is halo with a compound of the formula H-HET
where HET is as defined above and H is hydrogen, in the presence of a catalyst;
e) reacting a nitrile of the formula wherein R1, R2 and R3 are as defined above, with an azide so as to provide a compound wherein HET is a tetrazolyl ring;

f) reacting a compound of the formula wherein R1, R2 and R3 are as defined above, with an azide so as to provide a compound wherein HET is a tetrazolyl ring; or g) reacting a compound of the formula wherein HET, R1, R2 and R3 are as defined above, with a pharmaceutically acceptable organlc or inorganic acid so as to form a pharmaceutically acceptable acid addition salt of such compound.