Note: Descriptions are shown in the official language in which they were submitted.
21~7~
X-8266A -1-
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
X-8266A -2-
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
R3N
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 ~
X-8266A -5-
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
X-8266A -7-
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~
X-8266A -8-
/~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 ~ ~ ~
X-8266A -9-
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~
X-8266A -10-
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~
X-8266A -11-
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-
X-8266A -12-
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~
X-8266A -13-
Scheme 1
M HET
~ + I ~ ~NR1R2
Z-N Z-N
HET
~,NR~R2
R3 - N
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
X-8266A -15-
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~
X-8266A -16-
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~
X-8266A -17-
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
X-8266A -18-
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~
X-8266A -19-
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~
X-8266A -20-
Scheme 3
Rc R Rc
Rc ~ Ra R ~ Ra Ra Ra
ArcoRd~ NH2 o H30+,~ 0 N
-H20
Ar Ar 31
HO NH2
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~
X-8266A -21-
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~
X-8266A -23-
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
X-8266A -24-
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.
'
. . .. . .
.. : .
X-8266A -25-
Scheme 8
ArLi or ArMgBr H Ar
I ~o]
q~ O OH N~oH
Ra o~JI~ H2NOH N ~!_
Ar Ar
base or
AC20,
3--N
N~ R~
8-1
2~a~
X-8266A -26-
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~
X-8266A -27-
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~
X-8266A -28-
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
11-4
Cl
Et2ElCI
ArCN~ ArC=N-13Et2 o Ra
NH3~ RaJ~ RRa ~6~ Ra
HNq~NH2 Ra ~ N;~N
Ar
Ar
.
2~ ~7~39
X-8266A -29-
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
NH2
Oq~ NH
Ar
H2N
H2NNHCSNH2, PPA 3' = ~
ArCOOH ~ S~f N
Ar 12-4
2~ ~7~
X - 8 2 6 6A - 3 0 -
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
NH3 /
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~
X-8266A -31-
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
142
2~07~
X-8266A -32-
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
15-2
2~ ~7~
X - 8 2 6 6A - 3 3 -
Scheme 1 6
Raney Ni ~ Lawessen's S R PhlO Ra
~Ra H2N~R ~DH2N~ Phl(OAc)2 N~R
Ar Ar Ar Ar
16-1
Ra
N=~ O-N
analogous chemistry ior ~ R and R ~ Ra
Ar Ar
12
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
1 6-5
21~7~
X- 8 2 6 6A - 3 4 -
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
1 7-2
2 1 ~
X-8266A -35-
~ Z
S
Z cnO
o¦I T
;~
D ~ -S= ~ I
æ
æ
~1~7~i3~
X- 8 2 6 6A - 3 6 -
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
19-2
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
194
where R is hydrogen, Cl-C3 alkyl or phenyl
Scheme 20 illustrates a preparation of a starting
material for reaction Scheme 1.
...
.
., .
2~ ~73`~
X-8266A -37-
Scheme 2 0
X O ~ ~OH
Z 14 16 Z - N 1a
X X R10
~NHz ~NHR~ $~N
~4 ~2 Z
1 ~ .
X M
~,NRlR2 ~ ,NR1R2
Z N~.2~ Z - N~CH 2
2~ 0703~
X - 8 2 6 6A - 3 8 -
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~
X-8266A -39-
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
X-8266A -40-
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~
X-8266A -41-
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
X-8266A -42-
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~
X-8266A -43-
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~
X-8266A -44-
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~
X-8266A -45-
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 ~
X-8266A -46-
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~
X-8266A -47-
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
X-8266A -48-
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 ~
X-8266A -49-
Scheme 21
NR1R2 CN NR1R2 R12~C,p NRlR2
DM~ ~ Rl2MgBr D
32 34
Pd(PPh3)4
Rl2- C a Sn(CH3)3
~ ~ .
R12
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
X-8266A -50-
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.
X-8266A -51-
Scheme 22
C C
¢o~NR1R2 ~ NR1R2 ¢~NRlR2
~`H Pd(PPh~ ~`H ~H
Z - N R3SnRI2 Z- N HN
34 40
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~
X-8266A -52-
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~
X-8266A -54-
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~
X-8266A -55-
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~
X-8266A -56-
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~
X-8266A -59-
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~
X-8266A -60-
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
X-8266A -63-
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~
X-8266A -64-
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~
X-8266A -65-
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~
X-8266A -67-
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~
X-8266A -68-
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~
X-8266A -69-
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
X-8266A -70-
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 ~
X-8266A -72-
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
X-8266A -73-
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~
X-8266A -74-
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
X-8266A -75-
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~
X-8266A -76-
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~
X-8266A -77-
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~
X-8266A -78-
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
X-8266A -79-
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.~
X-8266A -80-
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
X-8266A -81-
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~
X-8266A -82-
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~
X-8266A -83-
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
X-8266A -84-
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~
X-8266A -85-
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.
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X-8266A -86-
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
X-8266A -87-
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~
X-8266A -88-
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~
X-8266A -89-
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.
