Note: Descriptions are shown in the official language in which they were submitted.
CA 02508477 1994-06-03
X-9078 -1-
METHOD OF PREVENTING EMESIS
S AND TREATING SEXUAL DYSFUNCTION USING
TETRAHYDROBENZ(CD1INDOLE-6-CARBOXAMIDES
The present invention relates to a method of
preventing emesis and treating sexual dysfunction in
mammals as well as pharmaceutical formulations suitable
theref or .
Extensive research has been conducted for a
number of years directed toward the development of
compounds capable of preventing emesis and treating sexual
dysfunction in mammals. For example, buspirone, 8-hydroxy-
dipropylamino tetralin, yohimbine, scopolamine and various
serotonin-3 antagonists have all been evaluated for
prevention of emesis. However, to date, such compounds
have proven unsatisfactory as anti-emetics for a variety of
reasons including lack of user safety, insufficient
efficacy, presence of undesirable side-effects and lack of
broad spectrum anti-emetic activity. Similarly,
bromocriptine, yohimbine, bupropion, naltrexone,
methysergide, buspirone and gonadotropin releasing hormone
have all been evaluated for treating sexual dysfunction.
Again, to date, such compounds have proven unsatisfactory
in treating sexual dysfunction for many of the same reasons
described above.
CA 02508477 1994-06-03
X-9078 -2-
It is an object of this invention to provide a
new method for preventing emesis and treating sexual
dysfunction in mammals, which method comprises
administering a compound selected from among certain
tetrahydrobenz[cd]indoles of the general formula
O
NR~ R2
The tetrahydrobenz[cd]indoles utilized in the instantly
claimed method are believed to provide a safe, broad
spectrum, way of preventing emesis and treating sexual
dysfunction with a minimum of side effects. As such, the
instantly claimed method is believed to obviate many of the
defects observed with compounds previously tested for
treating sexual dysfunction and preventing emesis.
Since the present invention provides a new
method for preventing emesis and treating sexual
dysfunction in mammals, pharmaceutical formulations
suitable for such new method will be required.
Accordingly, a further object of this invention is to
provide pharmaceutical formulations suitable for use in the
instantly claimed method.
CA 02508477 1994-06-03
X-9078 -3-
The objects of the present invention employ
certain tetrahydrobenz[cd]indoles of the general formula
O
R~R2
.,
Such compounds are known in the art, as described below,
and have been found to possess various utilities.
Flaugh, U.S. Patent No. 4,576,959, discloses
that the primary amino carboxamide compounds employed in
the present invention (i.e., those compounds wherein R3 and
R4 are both hydrogen) are central serotonin agonists. As
such, the compounds are taught to be useful in treating
depression, obesity, alcoholism, smoking and senile
dementia. In fact, one of the compounds disclosed in the
Flaugh patent; namely, (t)-4-dipropylamino-1,3,4,5-
tetrahydrobenz[cd]indole-6-carboxamide, is presently
undergoing clinical trials for use in treating depression
in humans.
Leander, U.S. Patent No. 4,745,126, discloses
that the primary amino carboxamide compounds disclosed in
the above-mentioned Flaugh patent are also useful for
treating anxiety. In fact, one of the compounds disclosed
in the Leander patent; namely, the 6-carboxamide compound
described above, is also presently undergoing clinical
trials for use in treating anxiety in humans.
Finally, European Patent Application 392,768
discloses that the substituted amino carboxamide compounds
employed in the present invention (i.e., those compounds
CA 02508477 1994-06-03
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wherein either R3 and/or R4 are other than hydrogen) are
useful in treating conditions requiring enhancement of
serotonin function in the body. Such conditions are
denoted as including depression, anxiety, alcoholism,
obesity, smoking, sexual dysfunction and senile dementia.
The primary amino carboxamide compounds employed
in the method of the present invention have not heretofore
been disclosed as being useful for preventing emesis or
treating sexual dysfunction in mammals. Further, the
substituted amino carboxamide compounds employed in the
method of the present invention have not heretofore been
disclosed as being useful for preventing emesis. The known
activities of such compounds, as described above, do not
suggest the method of the present invention. Accordingly,
an object of the present invention is to provide new
pharmacological uses, and formations suitable therefore,
for certain known tetrahydrobenz[cd]indoles.
Other objects, features and advantages of the
present invention will become apparent from the subsequent
description and the appended claims.
As noted above, the present invention provides a
method of preventing emesis and treating sexual dysfunction
in mammals comprising administering to a mammal susceptible
to or suffering from emesis or sexual dysfunction an
effective amount of a compound of the formula I
O
NR~RZ
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X-9078 -5-
wherein:
R1 is hydrogen, C1-C4 alkyl or allyl;
R2 is hydrogen, C1-C4 alkyl or allyl; or
a pharmaceutically acceptable acid addition salt
thereof.
The present invention also provides a method of
preventing emesis is mammals comprising administering to a
mammal susceptible to or suffering from emesis an effective
amount of a compound of the formula II
O
CNR3R4
NR~R2
wherein:
R1 is hydrogen, C1-C4 alkyl or allyl;
R2 is hydrogen, C1-C4 alkyl or allyl;
R3 and R4 are each independently hydrogen, C1-C4
alkyl, C1-C4 alkyl substituted with a phenyl group, phenyl,
or R3 and R4, taken together with the nitrogen atom to
which they are attached, form a C3-C5 heterocyclic ring,
with the proviso that only one of R3 and R4 can be hydrogen
while the other of R3 and R4 must be other than hydrogen;
or
a pharmaceutically acceptable acid addition salt
thereof.
Finally, since the present invention provides
new methods for preventing emesis and treating sexual
dysfunction in mammals, pharmaceutical formulations
suitable for such methods will be required. Accordingly,
CA 02508477 1994-06-03
' _6_
the present invention also provides pharmaceutical
formulations useful for preventing emesis and treating
sexual dysfunction comprising a compound of formulae I or
II, or a pharmaceutically acceptable acid addition salt
thereof, in combination with one or more pharmaceutically
acceptable carriers, diluents or excipients thereof.
As used herein, the term "C1-C4 alkyl" represents
a straight or branched chain alkyl group having from one to
four carbon atoms. Typical C1-C4 alkyl groups include
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and
the like.
The term C3-C5 heterocyclic ring" includes
pyrrolidine, piperidine, morpholine and the like.
While all of the compounds of formulae I and II
are believed useful for the methods of treating emesis and
sexual dysfunction presented herein, certain of the
compounds of formulae I and II are preferred for such uses.
Preferably R1 and R2 in formulae I and II are both C1-C4
alkyl (especially n-propyl) and R3 and R4 in formula II are
either both methyl or R3 is methyl while R4 is hydrogen.
Other preferred aspects of the present invention are noted
hereinafter.
The pharmaceutically acceptable acid addition
salts of the compounds of formulae I and II are also useful
in the instantly disclosed methods of preventing emesis and
treating sexual dysfunction. Accordingly, such salts are
included within the scope of the methods of this invention.
The term 'pharmaceutically acceptable acid
addition salts", as used herein, refers to the acid
addition salts of the compounds of formulae I and II which
are substantially non-toxic to living organisms. Typical
pharmaceutically acceptable acid addition salts include
those salts prepared by reaction of the free base form of
the compound of formulae I or II with a pharmaceutically
CA 02508477 1994-06-03
_7 _
acceptable mineral or organic acid. Pharmaceutically
acceptable mineral or organic acids commonly employed to
form such salts include inorganic acids such as
hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and
phosphoric acid, as well as organic acids such as para-
toluenesulfonic, methane-sulfonic, hippuric, oxalic, para-
bromophenylsulfonic, carbonic, succinic, citric, benzoic,
acetic, and related inorganic and organic acids. Such
pharmaceutically acceptable salts thus include sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydro-genphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, hydrochloride, hydrobromide, hydroiodide,
acetate, nitrate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caprate, heptanoate,
propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-
dioate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
phthalate, terephathalate, sulfonate, xylenesulfonate,
phenylacetate, phenylpropionate, phenylbutyrate, citrate,
lactate, ~3-hydroxybutyrate, glycollate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-2-
sulfonate, p-tolutenesulfonate, mandelate, hippurate, and
like salts. A preferred pharmaceutically acceptable acid
addition salt for use in the methods of the present
invention is the hippurate salt. Such salt form, and
processes for preparing same, is disclosed in European
Patent Application 444,852.
The compounds employed in the methods of the
present invention have an asymmetric center at the carbon
atom at the 4-position of the tetrahydrobenz[cd]indole
ring. As such, the compounds can exist as either the
racemic mixture, or as individual stereoisomers. All such
types of compounds are contemplated for use in the methods
of the present invention.
CA 02508477 1994-06-03
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The following list illustrates representative
compounds suitable for use in the present invention.
(~)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide oxalate
(+)-4-amino, 1,3,4,5-tetrahydrobenz[cd]-indole-6-
carboxamide maleate
(-)-4-(methylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide formate
(-)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(+)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide oxalate
(+)-4-(ethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide phosphate
(~)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
hydrochloride
(~)-4-(n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide oxalate
(~)-4-(methylamino]-1,3,4,5-tetrahydrobenz[cd)indole-6-
carboxamide toluenesulfonate
(-)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
(+)-4-(methylethylamino)-1,3,4,5-tetrahydrobenz[cd]indole
6-carboxamide sulfate
(-)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(-)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
propionate
(+)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(~)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide hydroiodide
(~)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
(~)-4-(ethyl-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]-
indole-6-carboxamide
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X-9078 -9-
(~)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide succinate
(-)-4-(methyl-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]-
indole-6-carboxamide
(+)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
' carboxamide sulfate
(-)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
maleate
(+)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(t)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide hippurate
(+)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(-)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide acetate
(~)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
succinate
(t)-4-(dimethylamino)-1,3,4,5-tetrahydrobenz(cd]indole-6-
carboxamide citrate
(~)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide hydrobromide
(-)-4-(ethyl-n-propylamino)-1,3,4,5-tetrahydrobenz-
[cd]indole-6-carboxamide benzoate
(+)-4-(methyl-n-propylamino)-1,3,4,5-tetrahydrobenz
[cd]indole-6-carboxamide phthalate
(+)-4-(methylethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide
(+)-4-(methylallylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide mesylate
(-)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide maleate
(+)-4-(diallylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide succinate
(-)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
fumarate
CA 02508477 1994-06-03
' " -10-
(+)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide
(+)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide acetate
(t)-4-(ethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(-)-4-amino-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide
(+)-4-(methylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(+)-4-(n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide hydrobromide
(+)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide
(t)-4-(methylethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide hydroiodide
(+)-4-(allylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide malonate
(t)-4-(diethylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-
carboxamide
(~)-N,N-dimethyl-4-(di-n-propylamino)-1,3,4,5-tetrahydro-
benz[cd]indole-6-carboxamide
(t)-N-methyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz-
[cd]indole-6-carboxamide
(f)-N,N-diethyl-4-(di-n-propylamino)-1,3,4,5-
tetrahydrobenz[cd]indole-6-carboxamide
As noted hereinbefore, the compounds employed in
the methods of the present invention are known. For
example, methods of preparing the compounds of formula I
are taught in U.S. Patent Nos. 4,576,959 and 4,745,126,
while methods of preparing the compounds of formula II are
taught in U.S. Patent No. 5,204,340. A preferred method
for preparing the compounds of formulae I and II, and, in
particular, the stereoisomers of such compounds, is taught
in U.S. Patent No. 5,212,319 and its European patent
application cognate EP 444.851.
CA 02508477 1994-06-03
-11-
The present invention provides methods of
preventing emesis and treating sexual dysfunction in
mammals. Such activities were demonstrated in the
following test systems.
881
Adult female cats of mixed strains were obtained
and housed such that they had free access to food and water
except during the time of testing. Cats were selected for
these studies based upon a minimum of 2 emetic episodes in
5 tests in response to a 30 minute rotation (0.28 Hz, 17
rpm) on a motion device such as that described in Crampton,
et al., Aviat. SnaSe Environ. Me_d.,~, pp. 462-465 (1985).
Single emetic response tests were conducted at intervals of
at least two weeks to prevent habituation to the motion
stimulus. Baseline responses (occurrence of retching and
vomiting) to motion following saline pretreatment were
determined before and after the evaluation of a test
compound. Subjects received subcutaneous injections of a
test compound in sterile saline to an injection volume of
0.1 mg/kg or vehicle 30 minutes before motion testing. The
order of the testing was saline, 0.02, 0.005, 0.01, 0.0075,
0.0025 mg/kg test compound and saline. The binomial data
for retch/vomits were analyzed using Cochrane~s Q test and
McNewmar~s test for repeated measures. The results of such
testing are reported in Table I below.
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Table I
Suv~ression of Motion Sickness in Cats
Treatment* Dose of Test # vomiting Change in Test
Compound # tasted Subject's
(mQ/ky) behavior
observed
Saline - 7/13 No
Test Com ound 0.0025 6/13 No
Test Com ound 0.005 5/13 No
Test Com ound 0.0075 1113 + No
Test Com ound 0.010 0/11 + No
Test Com ound 0.020 0/11 + No
Saline ~ - 13/13 No
* Test compound employed was (-)-4-dipropylamino-1,3,4,5-
tetrahydrobenz[cd]indole-6-carboxamide
+ Significant difference (p < .05) from control group
A group of 16 male White Carneaux pigeons,
weighing approximately 460 to 650 g (85-90~ of their free-
feeding body weights) were also tested. Animals were given
free access to water and oyster shell grit except during
the test sessions and were fed approximately 20 g of grain-
based feed (Purina Pigeon Checkers) once per day. The
colony room was illuminated from 6 a.m. to 6 p.m. daily.
All testing was conducted during the illuminated phase.
The pigeons were first fed 20 grams of Purina
Pigeon Checkers in their home cages. Five minutes later,
the birds were weighed and injected intravenously with
either 10 or 13 mg/kg of cisplatin (cis-platinum II
diammine dichloride; Signma Chemical Co., ST. Louis, MO)
and then placed in a plexiglas observation cage. After 45
CA 02508477 1994-06-03
X-9078 -13-
minutes, either vehicle, 0.08, or 0.32 mg/kg of test
compound were administered by intramuscular injection. The
test compound was dissolved in distilled water with the aid
of a few drops of lactic acid. The animals were then
observed for the next 4.5 hours for the number of both
retches and vomits. A vomit was considered to be the
active expulsion of fluid or solid matter, whereas retches
were considered to be vomiting movements without expulsion
of matter. Each pigeon was used only once, and they were
terminated immediately after the 4.5 hour observation
period. The results of such testing are shown in the Table
II below.
Table II
Sufluressioa of Cisvlatia Induced
Bmesis in Piaeoas
Dose of Dose of
Treatment * Cisplatin Test # of # of # of
(mg/kg) Compound Pigeons Retches Vomits
(m /k )
Vehicle 10 - 4 2.010.73 4.81.59
Test Com ound 10 0.08 4 3.2511.65 3.01.22
Test Com ound 10 0.32 4 0 0
Vehicle 13 - 2 1.5 6
Test Com ound 13 0.32 2 0 0
* Test compound employed was (-)-4-dipropylamino-1,3,4,5-
tetrahydrobenz[cd]indole-6-carboxamide.
CA 02508477 1994-06-03
X-9078 -14-
Another group of 20 male White Carneaux pigeons,
weighing approximately 460 to 650 g (85-90~ of their free-
feeding body weights) were also tested using
ditolylguanidine (DTG) in place of cisplatin to induce
emesis. Animals were given free access to water and oyster
shell grit except during the test sessions and were fed
approximately 20 g of grain-based feed (Purina Pigeon
Checkers) once per day. The colony room was illuminated
from 6 a.m. to 6 p.m. daily. All testing was conducted
during the illuminated phase.
The pigeons were first fed 20 grams of
Purina Pigeon Checkers in their home cages. Five minutes
later, the birds were weighed, injected with various doses
of test compound and returned to their home cages. The
test compound was dissolved in distilled water with the aid
of a few drops of lactic acid. All injections were given
into the breast muscle in a volume of 1 ml/kg. After 15
minutes, a 5.6 mg/kg dose of DTG was administered and the
pigeons were placed into Plexiglas observation chambers.
One hour later, the birds were removed from the observation
chambers and returned to their home cages and the floor of
the observation cage was examined for the presence of
expelled food. The dependent variable in the instant study
was the percent of birds at each dose that exhibited
evidence of expelled food. The results of such study are
presented in Table III below.
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X-9078 -15-
Table III
Suppression of Ditolylaruanidine
Induced Emesis in Pigeons
Dose of Test Compound * Percent of Pigeons
(mg/kg) Vomiting
0.01 100
0.02 75
0.04 50
0.08 25
0.16 0
* Test compound employed was (-)-4-dipropylamino-1,3,4,5-
tetrahydrobenz[cd]indole-6-carboxamide
The data in Tables I, II and III establish that
compounds of formulae I and II can be used to prevent
emesis. The term "emesis", as used for purposes of the
present invention, means vomiting (the actual expulsion of
stomach contents), retching (vomiting movements without
expulsion of matter) and the concomitant nausea associated
with such conditions. Accordingly, the compounds of
formulae I and II can be used to suppress emetic responses
to provocative 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.
CA 02508477 1994-06-03
X-9078 -16-
Sexual Dvsfuactfon
Male Sprague-Dawley rats and ovariectomized,
Long-Evans rats purchased from Charles River Laboratories
(Portage, MI) were used in this study. All of the rats
were housed in a temperature controlled room in which the
lights were off from 10:00 to 20:00. The ovariectomized
rats used as sexual partners for the test males were made
sexually receptive by administering 400 ~g of estrone in
propylene glycol subcutaneously 48 hours prior to testing
and 2.5 mg of progesterone in propylene glycol
subcutaneously 4 hours prior to testing. The male rats
were individually housed beginning 4 weeks prior to testing
and were tested at 2 week intervals beginning at 6 months
of age and ending at 12 months of age using the procedure
previously published in Foreman, g~ ~., J. Neural. Trans.,
~$,, pp. 153-170 (1987). Mating tests were conducted
between 12:00 and 17:00 during the dark phase of the
lighting cycle. Each behavioral test was initiated with
the introduction of a receptive female rat into the arena
and was terminated either 30 minutes later or immediately
following the first postejaculatory mount. Prior to
treatment with a drug solution, each male rate was required
to have at least two consecutive vehicle tests with similar
sexual performance. Following each drug testing,
additional vehicle tests were performed. In an effort to
eliminate behavioral responses with drug treatment that may
be due to spontaneous changes in baseline mating
performance, a criterion of reversibility of behavioral
response with subsequent vehicle treatment was used. Thus,
a valid behavioral response to a drug treatment was
arbitrarily set as a response that either did not change
from the prior control response or was reversed in the
subsequent control test with vehicle. Statistical
comparisons between the sexual responses to vehicle and
CA 02508477 1994-06-03
X-9078 -17-
drug treatments for each animal were made using the
Wilcoxon paired-sample test. The results of such testing
are reported in Table IV below.
In Table IV, Column 1, discloses the dose of
test compound administered to each test subject. Columns 2
and 3 disclose the percent change from control of
ejaculatory latency and total number of mounts required for
ejaculation, respectively, for each dose tested. Finally,
Columns 4 and 5 disclose the percent change from control of
copulatory efficiency and copulatory rate, respectively,
for each dose tested.
CA 02508477 1994-06-03
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CA 02508477 1994-06-03
X-9078 -19-
The data in Table IV establishes that compounds
of formula I can be used to treat sexual dysfunction. The
term °sexual dysfunction", as used herein, means any
disorder related to the erectile response in male mammals
and the sexual drive and sexual (both arousal and
orgamsmic) reflexes in male or female mammals.
Accordingly, the compounds of formula I can be used to
treat erectile dysfunction, retarded ejaculation and
anorgasm. The compounds can, further, also be used to
increase sexual desire in mammals of both sexes.
As discussed above, the compounds of formulae I
and II are physiologically active thereby lending
themselves to the valuable therapeutic methods claimed
herein. These methods comprise administering to a mammal
(preferably a human) needing prevention of emesis or
treatment of sexual dysfunction an effective amount of one
or more compounds of formulae I (emesis and sexual
dysfunction) or II (emesis alone) sufficient to achieve the
therapeutic or prophylactic intervention desired. The
compounds can be administered by a variety of routes
including the oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular or intranasal routes. The oral
and transdermal routes of administration are preferred. No
matter what route of administration is chosen, such
administration is accomplished by means of pharmaceutical
compositions which are prepared by techniques well known in
the pharmaceutical sciences.
The methods of the present invention encompass
prevention of emesis and treatment of sexual dysfunction in
a prophylactic manner (i.e., using the compounds of
formulae I and II to prevent emesis or treat sexual
dysfunction 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
CA 02508477 1994-06-03
X-9078 -20-
trip which, normally, would result in the patient's
suffering a motion sickness attack; 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 patient is about
to undergo or is undergoing treatment with an anxiolytic,
such as a benzodiazepine, or an antidepressant, such as a
5-HT reuptake inhibitor or a tricyclic antidepressant,
which is known to cause sexual disorders; the patient has
experienced sexual dysfunction in the past, is about to
engage in sexual intercourse and wishes to prevent a re-
occurrence of the dysfunction; or the patient wishes to
increase his or her sexual drive.
As mentioned above, the methods of the present
invention utilize pharmaceutical compositions. In making
these compositions, one or more active ingredients will
usually be mixed with a carrier, or diluted by a carrier,
or enclosed within a carrier which may be in the form of a
capsule, sachet, paper or other container. When the
carrier serves as a diluent, it may be a solid, semi-solid
or liquid material which acts as a vehicle, excipient 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 carriers, excipients,
and diluents include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, saline solution, syrup, methylcellulose,
methyl- and propylhydroxybenzoates, talc, magnesium
CA 02508477 1994-06-03
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stearate and mineral oil. The formulations can
additionally include lubricating agents, wetting agents,
emulsifying and suspending agents, preserving agents,
sweetening agents or flavoring agents. The compositions may
be formulated so as to provide rapid, sustained or delayed
release of the active ingredient after administration to
the patient by employing procedures well known in the art.
The compositions are formulated, preferably in a
unit dosage form, such that each dosage contains from about
5 to about 500 mg, more usually about 25 to about 300 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 or
prophylactic effect, in association with one or more
suitable pharmaceutical diluents, excipients or carriers.
The compounds employed in the methods of the
present invention are effective over a wide dosage range
for preventing emesis and treating sexual dysfunction.
Thus, as used herein, the term "effective amount" refers to
a dosage range of from about 0.5 to about 500 mg/kg of body
weight per day. In the treatment of adult humans, the range
of about 1 to about 100 mg/kg, in single or divided doses,
is preferred. However, it will be understood that the
amount of compound actually administered will be determined
by a physician, in light of the relevant circumstances
including the condition to be treated, the choice of
compound to be administered, whether prophylactic or
therapeutic effect is desired, the chosen route of
administration, the age, weight, and response of the
individual patient, and the severity of the patient's
symptoms, and, therefore, the above dosage ranges are not
intended to limit the scope of the invention in any way.
CA 02508477 1994-06-03
10
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The following formulation examples may employ as
active ingredients any of the compounds of formulae I or
II. The examples are illustrative only and are not intended
to limit the scope of the invention in any way.
Example 1
Hard gelatin capsules suitable for preventing
emesis are prepared using the following ingredients:
Quantity (ma/capsule)
(~)-4-dipropylamino-1,3,4,5-
tetrahydrobenz[cd)indole-6-
carboxamide hippurate 250
Starch dried 200
Magnesium stearate 10
The above ingredients are mixed and filled into
hard gelatin capsules in 460 mg quantities.
Example 2
A tablet suitable for preventing emesis is
prepared using the ingredients below:
Ouantity (maltablet)
(~)-N-methyl-4-dipropylamino-
1,3,4,5-tetrahydrobenz[cd)indole
-6-carboxamide hydrochloride 250
Cellulose, microcrystalline 400
Silicon dioxide 10
Stearic acid 5
The components are blended and compressed to
form tablets each weighing 665 mg.
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Examflle 3
An aerosol solution suitable for treating sexual
dysfunction is prepared containing the following
components:
~eiaht
(+)-4-diethylamino-1,3,4,5-
tetrahydrobenz[cd]indole-6-
carboxamide 0.25
Ethanol 29.75
Propellant 22 70.00
(Chlorodifluoromethane)
The active compound is mixed with ethanol and
the mixture added to a portion of the propellant 22, cooled
to -30°C and transferred to a filling device. The required
amount is then fed to a stainless steel container and
diluted with the remainder of the propellant. Valve units
are then fitted to the container.
Tablets suitable for treating sexual
dysfunction, each containing 60 mg of active ingredient
are
made up as follows:
(+)-4-diethylamino-1,3,4,5-
tetrahydrobenz[cd]indole-6-
carboxamide 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone
(as 10~ solution in water) 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 ma
Total 150 mg
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The active ingredient, starch and cellulose are
passed through a No. 45 mesh U.S. sieve and mixed
thoroughly. The solution of polyvinylpyrrolidone is mixed
with the resultant powders which are then passed through a
No. 14 mesh U.S. sieve. The granules so produced are dried
at 50-60°C and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate and
talc, previously passed through a No. 60 mesh U.S. sieve,
are then added to the granules which, after mixing, are
compressed by a tablet machine to yield tablets each
weighing 150 mg.
Examflle 5
Capsules suitable for preventing emesis, each
containing 80 mg of medicament, are made as follows:
(t)-N-methyl-4-diethylamino-
1,3,4,5-tetrahydrobenz[cd]indole-
6-carboxamide hippurate 80 mg
Starch 59 mg
Microcrystalline cellulose 59 mg
Magnesium stearate 2 ma
Total 200 mg
The active ingredient, cellulose, starch and
magnesium stearate are blended, passed through a No. 45
mesh U.S. sieve, and filled into hard gelatin capsules in
200 mg quantities.
3 0 Examflle 6
Suppositories suitable for treating sexual
dysfunction, each containing 225 mg of active ingredient,
are made as follows:
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(~?-4-diallylamino-1,3,4,5-
tetrahydrobenz[cd]indole-
6-carboxamide 225 mg
Saturated tatty 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.
Exaamle 7
Suspensions suitable for preventing emesis, each
containing 50 mg of medicament per 5 ml dose, are made as
follows:
(-)-N,N-diethyl-4-dipropyl-
amino-1,3,4,5-tetrahydrobenz[cd]-
indole-6-carboxamide 50 mg
Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 ml
Benzoic acid solution 0.10 ml
Flavor q.v.
Color q.v.
Purified water to 5 ml
The medicament is passed through a No. 45 mesh
U.S. sieve and mixed with the sodium carboxymethyl
cellulose and syrup to form a smooth paste. The benzoic
acid solution, flavor and color are diluted with some of
the water and added, with stirring. Sufficient water is
then added to produce the required volume.
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Examflle 8
Capsules suitable for use in treating sexual
dysfunction, each containing 150 mg of medicament, are made
as follows:
(-)-4-dipropylamino-1,3,4,5-
tetrahydrobenz[cd]indole-
6-carboxamide hippurate 150 mg
Starch 164 mg
Microcrystalline cellulose 164 mg
Magnesium stearate 22 mg
Total 500 mg
The active ingredient, cellulose, starch and
magnesium stearate are blended, passed through a No. 45
mesh U.S. sieve, and filled into hard gelatin capsules in
500 mg quantities.
