Note: Descriptions are shown in the official language in which they were submitted.
CA 02350089 2001-06-08
64680-892D
-1-
INDOLE DERIVATIVES
This is a divisional application of Canadian Patent
Application Serial No. 2,178,161 filed June 4, 1996.
The subject matter claimed in the parent application
was restricted to those compounds of the formula I described
hereinunder and their use. The subject matter claimed in this
divisional application is restricted to those compounds of the
formula V described hereinunder and their production processes.
However, it should be understood that the expression "the
present invention" or the like encompasses the subject matters
of both the parent and divisional applications.
The present invention relates to indole derivatives,
to processes and intermediates for their preparation, to
pharmaceutical compositions containing them and to their
medicinal use. The active compounds of the present invention
are useful in treating migraine and other disorders.
United States Patents 4,839,377 and 4,855,314 and
European Patent Application Publication Number 313397 refer to
5-substituted 3-aminoalkyl indoles. The compounds are said to
be useful for the treatment of migraine.
European Patent Application Publication Number 303506
refers to 3-poly:hydro-pyridyl-5-substituted-1H-indoles. The
compounds are said to have 5HT1-receptor agonist and
vasoconstrictor activity and to be useful in treating migraine.
European Patent Application Publication Number 354777
refers to N-piperidinyl:indolyl:ethyl-alkane sulfonamide
derivatives. The compounds are said to have 5HT1-receptor
agonist and vasoconstrictor activity and to be useful in
treating cephalic pain.
CA 02350089 2001-11-29
64680-892D
-la-
The present invention relates to compounds of the
formula:
N- Rs
H
n
R2 ~ ~ (I)
'N
i
X R~
CA 02350089 2001-06-08
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wherein n is O, 1, or 2; X is chlorine, bromine, or iodine;
Ri is hydrogen; R2 is selected from hydrogen, halogen (e. g.,
fluorine, chlorine, bromine or iodine), cyano, -OR4,
- ( CHz ) ",- ( C=O ) NRsRe ~ - ( CH2 ) m-SO2NRSR6, - ( CH2) m-NR~ ( C=O ) Rg,
- ( CHz ) n,-NR~SOZRg , - ( CH2 ) m-S ( O ) xRs ~ - ( CHz ) m-NR~ ( C=O )
NRSR6 ~
- ( CHz ) m-NR~ ( C=O ) ORg, and -CH=CH ( CH2) yRlo; R3 is selected from
hydrogen and C, to C6 linear and branched alkyl; R4 is
selected from hydrogen, CI to C6 alkyl, and aryl; RS and R6
are independently selected from hydrogen, C1 to C6 alkyl,
aryl, and C, to C3 alkyl-aryl or RS and R6 taken together to
form a 4, 5, or 6 membered ring; R~ and Rg are independently
selected from hydrogen, C1 to Cb alkyl, aryl, and C1 to C3
alkyl-aryl; R9 is selected from hydrogen, C1 to C6 alkyl,
aryl, and C~ to C3 alkyl-aryl; Rla is selected from -(C=O)NRSR6
and -SO2NR5R6, wherein RS and R6 are defined as above, and
-NR~ ( C=O ) Rg , -NR~SOzRB , -NR~ ( C=O ) NRSR6 , -S ( O ) xR$ and -NR~ ( C=O
) ORg,
wherein R~, Rg, and R9 are as defined above; m is 0, 1, 2, or
3; y is 0, 1, or 2; x is 1 or 2; and the above aryl groups
and the aryl moieties of the above alkylaryl groups are
independently selected from phenyl and substituted phenyl,
wherein said substituted phenyl may be substituted with one
to three groups selected from C1 to C4 alkyl, halogen (e. g.,
fluorine, chlorine, bromine or iodine), hydroxy, cyano,
carboxamido, nitro and C1 to C4 alkoxy, with the proviso that
when R, is hydrogen or -O~ and R4 is hydrogen, n is 0 or 1,
and the pharmaceutically acceptable salts thereof. These
compounds are useful in treating migraine and other
disorders. Compounds of the formula I wherein R2 is
-CH=CH ( CHz ) yR,o and compounds of f ormula I where X is
chlorine, bromine, or iodine are also useful as
intermediates for preparing other compounds of the formula
I.
The compounds of the invention include all optical
isomers of formula I (e. g., R and S enantiomers) and their
. r~
CA 02350089 2001-06-08
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racemic mixtures. The R enantiomers at the designated
chiral site in formula I are preferred.
Unless otherwise indicated, the alkyl groups referred
to herein, as well as the alkyl moieties of other groups
referred to herein (e. g. alkoxy), may be linear or branched,
and they may also be cyclic (e. g., cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl) or be linear or branched and
contain cyclic moieties.
Preferred compounds of the invention are compounds of
the formula I wherein R~ is hydrogen; Rz is -(CHz)m-SOzNHRS.
- ( CH., ) m-NHSOZRg , - ( CHz ) m-SOZRg, - ( CHz) m- ( C=0 ) NHRS, Or
- ( CH, ) m-NH ( C=0 ) Rg; R3 is hydrogen or methyl; and m, RS and R8
are as defined above and the pharmaceutically acceptable
salts thereof. Of the foregoing preferred compounds, the R
enantiomers at the designated chiral site in formula I are
more preferred.
The following compounds are preferred:
(R)-7-Bromo-5-(t-butylaminosulphonylmethyl)-3-(N-
methylpyrrolidin-2-ylmethyl)-1H-indole; and
(R)-7-Bromo-5-(methylaminosulfonylmethyl)-3-(N-
methylpyrrolidin-2-ylmethyl)-1H-indole.
The present invention also relates to a pharmaceutical
composition for treating a condition selected from
hypertension, depression, anxiety, eating disorders,
obesity, drug abuse, cluster headache, migraine, pain, and
chronic paroxysmal hemicrania and headache associated with
vascular disorders comprising an amount of a compound of the
formula I or a pharmaceutically acceptable salt thereof
effective in treating such condition and a pharmaceutically
acceptable carrier.
The present invention also relates to a pharmaceutical
composition for treating disorders arising from deficient
serotonergic neurotransmission (e. g., depression, anxiety,
eating disorders, obesity, drug abuse, cluster headache,
migraine, pain, and chronic paroxysmal hemicrania and
headache 'associated with vascular disorders) compri,ø~.ng an
~T
r CA 02350089 2001-06-08
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amount of a compound of the formula I or a pharmaceutically
acceptable salt thereof effective in treating such condition
and a pharmaceutically acceptable carrier.
The present invention also relates to a method for
treating a condition selected from hypertension, depression,
anxiety, eating disorders, obesity, drug abuse, cluster
headache, migraine, pain and chronic paroxysmal hemicrania
and headache associated with vascular disorders comprising
administering to a mammal (e. g., a human) requiring such
treatment an amount of a compound of the formula I or a
pharmaceutically acceptable salt thereof effective in
treating such condition.
The present invention also relates to a method for
treating disorders arising from deficient serotonergic
neurotransmission (e. g., depression, anxiety, eating
disorders, obesity, drug abuse, cluster headache, migraine,
pain and chronic paroxysmal hemicrania and headache
associated with vascular disorders) comprising administering
to a mammal (e.g., a human) requiring such treatment an
amount of a compound of the formula I or a pharmaceutically
acceptable salt thereof effective in treating such
condition.
The present invention also relates to a compound of the
formula
N~
~'~a
R2
N
R1
wherein X is bromine, chlorine, or iodine; W is -C02R11 or
R3; Q is CHz or C=0; n, Rl, Rz and R3 are as defined for
formula I; and R,~ is selected from C, to C6 alkyl, ben~:yl and
CA 02350089 2001-11-29
64680-892D
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aryl, wherein aryl is as defined above, with the proviso
that when W is R~, Q is C=0.. The compounds of formula V
are useful as intermediates in preparing compounds of the
formula I.
Compounds of formula I are prepared by catalytic
reduction of a compound of the formula
~N-R-,
to
R
(XV>
"1
wherein R3 is as defined above or is a substituent of the
formula -COz-Rg, Ra is benzyl or substituted benzyl, and where
R', RZ, and n are as defined above and X is chlorine, bromine
or iodine (preferably bromine or iodine) under an atmosphere
of hydrogen, preferably at a pressure of about 1 to 4
atmospheres, or using a hydrogen source such as ammonium
formate or formic acid in an inert solvent. Suitable
catalysts include 20% palladium (II) hydroxide on carbon,
palladium on carbon, Raney'nickel, platinum oxide, rhodium
and ruthenium. The preferred catalyst is 20% palladium (II)
hydroxide on carbon. Suitable solvents include C1 to C6
alcohols, N, N-dimethylformamide, ethyl acetate and
acetonitrile. The preferred solvent is ethanol. The
reaction is generally conducted at a temperature of about
0°C to about 60°C, most preferably.at about 25°C.
Compounds of formula XV are prepared by hydride
reduction of a compound of the formula
= Trade-park
CA 02350089 2001-06-08
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~N-R
R (XVI)
to
X
wherein R2 and n are as def fined above and A is a suitable
nitrogen protecting group and X is chlorine, bromine or
iodine (preferably bromine or iodine) with a hydride
reducing agent in an inert solvent. Suitable hydride
reducing agents include lithium aluminum hydride, diborane,
lithium borohydride, and sodium amide. The preferred
reagent is lithium aluminum hydride. Suitable solvents
include ethers, such as diethyl ether, tetrahydrofuran, 1,4-
dioxane and 1,2-dimethoxyethane. The preferred solvent is
tetrahydrofuran. The reduction is conducted at a
temperature of about 30°C to about 100°C, preferably about
65°C to about 70°C. Examples of A include t-
butoxycarbonyl(BOC) and benzyloxycarbonyl(CBZ), preferably
CBZ (See T. W. Green, Protecting' Groups in Organic
Synthesis, John Wiley & Sons (1981) pp 218-287). A side
product of this reaction can be a compound of formula I
where X is hydrogen and R3 is methyl.
Compounds of formula XVI can be prepared by the
transition metal catalyzed cyclization of a compound of the
formula
CA 02350089 2001-06-08
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/N ( ) n
A
,,'~., H
R
(XVII>
X V
wherein Rz, n, A, and V are as defined above, and X is
chlorine, bromine or iodine (preferably bromine or iodine)
in a suitable inert solvent with a phase transfer catalyst,
a base and a suitable transition metal catalyst. Suitable
transition metal catalysts include palladium salts such as
palladium (II) acetate or palladium (II) chloride
(preferably palladium acetate) and rhodium salts, such as
tris(triphenyl)rhodium (I) chloride. Suitable solvents
include N,N-dimethylformamide, N,N-dimethylformamide with
dimethoxyethane, acetonitrile, and N-methylpyrrolidine. The
preferred solvents are N,N-dimethylformamide and N,N-
dimethylformamide with dimethoxyethane. Suitable phase
transfer catalysts include tetraalkylammonium halides,
preferably tetra-n_-butylammonium chloride. Suitable bases
include tertiary amines, sodium hydrogen carbonate, and
sodium carbonate. The preferred base is triethylamine. The
reaction is conducted at a temperature of about 80°C to
about 180°C, preferably about 150°C to 160°C. Examples of
V include t-butoxycarbonyl-(BOC), benzyloxycarbonyl(CBZ),
and trifluoroacetyl, preferably trifluoromethylacetyl (See
T. W. Green, Protecting Groups in Organic Synthesis, John
Wiley & Sons (1981) pp 218-287).
Compounds of formula XVII can be prepared by the
Mitsunobu coupling reaction of compounds of formulae
64680-892
CA 02350089 2001-06-08
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R
)n
H
(XVIII>
(XIX)
wherein R,i, V, A and X are as defined above using a phosphine
and an azodicarboxylate in a suitable solvent. Suitable
phosphines include trialkylphosphines and triarylphosphines,
preferably triphenylphosphine. Suitable azodicarboxylates
include dialkyl azodicarboxylates, preferably diethyl
azodicarboxylate. Suitable solvents include methylene
chloride, ethers, including tetrahydrofuran, diethyl ether,
and 1,4-dioxane, N-N-dimethylformamide and acetonitrile.
The preferred solvent is tetrahydrofuran. The reaction is
conducted at a temperature of about 0°C to about 65°C, most
preferably at about 25°C.
Compounds of formula XVIII, if not available
commercially, can be prepared by reacting a compound of
f ormu 1 a
R2
H2
X
(XX>
wherein RZ and X are as defined above with the acid chloride
or the symmetrical carboxylic anhydride of the formula
V-O-V, where V is as defined above, in a suitable solvent
with a suitable base. The preferred acid chloride or
anhydride is trifluoroacetic anhydride. Suitable solvents
64680-892
CA 02350089 2001-06-08
_9_
include ethers, including tetrahydrofuran, diethyl ether and
1,4-dioxane, methylene chloride, and chloroform. The
preferred solvent is methylene chloride. Suitable bases
include triethylamine, pyridine, and sodium hydrogen
carbonate. The preferred base is pyridine. The reaction is
conducted at a temperature of about 0°C to about 65°C,
preferably at about 25°C.
Compounds of formula XX, if not available commercially,
can be prepared by reacting a compound of formula
to Rz
CXXI> -
NH2
wherein RZ is as defined above with either chlorine, bromine
or iodine in a suitable solvent with a suitable base using
two equivalents of halogen. Reaction with bromine is
preferred. Suitable solvents include C1-C6 alcohols,
methylene chloride, methanol with methylene chloride,
chloroform, or carbon tetrachloride. The preferred solvents
are methanol and methanol with methylene chloride. Suitable
bases include triethylamine, pyridine, sodium carbonate, and
sodium hydrogen carbonate. The preferred base is sodium
hydrogen carbonate. The reaction is conducted at a
temperature of about 0°C to about 65°C, preferably at about
25°C.
Unless indicated otherwise, the pressure of each of the
above reactions is not critical. Generally, the reactions
will be conducted at a pressure of about one to about three
atmospheres, preferably at ambient pressure (about one
atmosphere).
The compounds of the formula I which are basic in
nature are capable of forming a wi-de variety of different
salts with various inorganic and organic acids. Although
such salts must be pharmaceutically acceptable for
administration to animals, it is often desirable in practice
CA 02350089 2001-06-08
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to initially isolate a compound of the formula I from the
reaction mixture as a pharmaceutically unacceptable salt and
then simply convert the latter back to the free base
compound by treatment with an alkaline reagent, and
subsequently convert the free base to a pharmaceutically
acceptable acid addition salt. The acid addition salts of
the base compounds of this invention are readily prepared by
treating the base compound with a substantially equivalent
amount of the chosen mineral or organic acid in an aqueous
solvent medium or in a suitable organic solvent such as
methanol or ethanol. If necessary, upon careful evaporation
of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the
pharmaceutically acceptable acid addition salts of the base
compounds of this invention are those which form non-toxic
acid addition salts, i.e., salts containing
pharmacologically acceptable anions, such as hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate or bisulfate,
phosphate or acid phosphate, acetate, lactate, citrate or
acid citrate, tartrate or bitartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate
and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-
naphthoate)] salts.
Those compounds of the formula I which are also acidic
in nature, e.g., where R2 contains a carboxylate, are capable
of forming base salts with various pharmacologically
acceptable cations. Examples of such salts include the
alkali metal or alkaline-earth metal salts and particularly,
the sodium and potassium salts. These salts are all
prepared by conventional techniques. The chemical bases
which are used as reagents to prepare the pharmaceutically
acceptable base salts of this invention are those which form
non-toxic base salts with the herein described acidic
compounds of formula I. These non-toxic base salts include
those derived from such pharmacologically acceptable cations
as sodium, potassium calcium and magnesium, etc. ir~hese
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salts can easily be prepared by treating the corresponding
acidic compounds with an aqueous solution containing the
desired pharmacologically acceptable cations, and then
evaporating the resulting solution to dryness, preferably
under reduced pressure. Alternatively, they may also be
prepared by mixing lower alkanolic solutions of the acidic
compounds and the desired alkali metal alkoxide together,
and then evaporating the resulting solution to dryness in
the same manner as before. In either case, stoichiometric
quantities of reagents are preferably employed in order to
ensure completeness of reaction of maximum product of yields
of the desired final product.
The compounds of the formula I and the pharmaceutically
acceptable salts thereof (hereinafter, also referred to as
the active compounds of the invention) are useful
psychotherapeutics and are potent serotonin (5-HT1) agonists
and may be used in the treatment of depression, anxiety,
eating disorders, obesity, drug abuse, cluster headache,
migraine, chronic paroxysmal hemicrania and headache
associated with vascular disorders, pain, and other
disorders arising from deficient serotonergic
neurotransmission. The compounds can also be used as
centrally acting antihypertensives and vasodilators.
The active compounds of the invention are evaluated as
anti-migraine agents by testing the extent to which they
mimic sumatriptan in contracting the dog isolated saphenous
vein strip (P.P.A. Humphrey et al., Br. J. Pharmacol., 94,
1128 (1988)). This effect can be blocked by methiothepin,
a known serotonin antagonist. Sumatriptan is known to be
useful in the treatment of migraine and produces a selective
increase in carotid vascular resistance in the anaesthetized
dog. It has been suggested (W. Fenwick et al., Br. J.
Pharmacol., 96, 83 (1989)) that this is the basis of its
efficacy.
CA 02350089 2001-06-08
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ECS~'s for the compounds of formula I tested for
contracting the dog isolated saphenous vein strip, using the
procedure referred to above, were less than 10'~ M.
The active compounds of the present invention are also
evaluated via the inhibition of plasma protein extravasation
response within the dura mater of guinea pigs following
unilateral electrical trigeminal ganglion stimulation. The
extent to which they mimic sumatriptan, in terms of both
potency and efficacy, is determined in this assay. The
procedure is performed on male Hartley guinea pigs (200-250
g, Charles River Laboratories, Wilmington, MA, U.S.A.) as
described in Markowitz et al., J. Neurosci., 7 (12), 4129-
4136 ( 1987 ) and also in Lee, et al. , Brain Research, 626,
303-305 (1993). The procedure briefly consists of placing
pentobarbitone-anesthetized animals in a stereotaxic frame.
'uI-BSA (bovine serum albumin) (50 ~CCi/kg 1) is first injected
into the femoral vein, followed 5 minutes later by drug or
vehicle. Bipolar electrodes are then lowered into the
trigeminal ganglia, and the right ganglion is stimulated for
5 minutes (1.2 mA, 5 Hz, 5 cosec). The animal is then
perfused with saline through the left cardiac ventricle and
sacrificed, and the dura mater is dissected, weighed, and
counted for radioactivity. Cpm/mg wet weight values are
determined for the right vs left dura mater, and a ratio for
the stimulated vs unstimulated sides is generated for each
animal. Unpaired student's t-test is used to statistically
compare these ratio values in respective groups treated with
vehicle or drug. The M.E.D. (minimally effective dose) for
a given compound is the lowest dose for which the mean value
of this ratio is significantly lower than that obtained for
the vehicle-treated group. The effect of the drugs in these
assays can be partially blocked by metergoline, a known
serotonin antagonist.
A similar procedure to the one described above can be
performed on rats, as described in Matsubara, et al., Br. J.
Pharmacol., 104, 3 (1991).
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The active compounds of the invention may also be
useful in the treatment of headache associated with
meningeal irritation, including bacterial, fungal, viral,
parasitic, and chemical meningitis, acquired immune
deficiency syndrome (AIDS) meningovascular inflammation, and
subarachnoid hemorrhage. [See W. S. Lee, et al., Evidence
Using Conformationally Restricted Sumatriptan Analogues, CP-
122,288 and CP-122,638, that 5-HT~p Receptors Do Not Mediate
Blockade of Neurogenic Inflammation, 23rd Annual Meeting of
the Society for Neuroscience, Washington, D.C., November 7-
12, 1993, Abstract #565.6; K. Nozaki, et al., CP-93,129,
Sumatriptan, Di-hydroergotamine Block c-fos Expression
Within Rat Trigeminal Nucleus Caudalis Caused by Chemical
Stimulation of The Meninges, Br. J. Pharmacol. (1992), 106,
409; and Lee, et al, Brain Research, 626, 303-305 (1993).]
The compositions of the present invention may be
formulated in a conventional manner using one or more
pharmaceutically acceptable carriers. Thus, the active
compounds of the invention may be formulated for oral,
buccal, intranasal, parenteral (e. g., intravenous,
intramuscular or subcutaneous) or rectal administration or
in a form suitable for administration by inhalation or
insufflation.
The compounds of the present invention may be useful in
the treatment of a considerable number of diseases. These
include dermatological disorders, including psoriasis;
eczema and atopic eczematous dermatitis; intractable itch
(pruritus), including itch associated with liver cirrhosis,
cancer and hemodialysis; burns and scalds; sunburn; insect
bites, urticaria and sweat gland abnormalities. Other
dermatological disorders include bullous penphgoid, photo
dermatoses, skin blisters, adult acne, chicken pox and
dermatitis herpetifunus.
Other diseases which may be treated with the compounds
of the present invention are peripheral neuropathies
including postherpetic neuralgia, diabetic neuropathy~s such
CA 02350089 2001-06-08
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as peripheral polyneuropathy and radiculopathy; causalgia
and reflex sympathetic dystrophy; post-mastectomy neuralgia;
post-surgical neuralgia and pain; vulvar vestibulitis;
phantom limb pain; thalamic syndrome (central post-stroke
pain); temporo mandibular joint syndrome; metarsalgia
(Morton's neuralgia); and neurogenic pain from nerve
compression caused, for example, by a prolapsed
intervertebral disc or carpal and tarsal tunnel syndromes.
The above-mentioned compounds may also be useful in
alleviating arthritis, including osteoarthritis, rheumatoid
arthritis, systemic lupus erythematosus, fibromyalgia,
ankylosing spondilitis and tendinitis. They are also
effective against gastrointestinal and urogenital diseases
including cystitis, gastroesophageal reflux, gastritis, urge
continence, inflammatory bowel disease and irritable bowel
syndrome; they are effective in regulatory gastrointestinal
tract motility.
The compounds may also be used in the treatment of
headache associated with substances or their withdrawal
(e. g. drug withdrawal), tension headache, pediatric migraine
and prophylaxis of migraine and post-traumatic dysautonomic
cephalgia.
They may also be used for treating orificial pain (for
example toothache and pain of dental origin, earache, TMJ
pain, sinus pain, myofacial pain, non-arthritic and non
musculoskeletal cervical pain), mouth ulcers, Meniere's
disease and atypical facial neuralgia, and also allergic and
chronic obstructive airways diseases such as rhinitis,
conjunctivitis, bronchial oedema, bronchial asthma,
neurological pulmonary oedema (adult respiratory disease
syndrome), anaphylaxis and angioedema. The compounds are
also efficacious in treating ocular pressure or glaucoma and
ocular inflammation.
It is believed that the compounds of formula I and
their salts are efficacious against emesis caused by several
factors not associated with migraine, including ~:mesis
CA 02350089 2001-06-08
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induced by anaesthesia, cancer chemotherapy and by motion
(seasickness, space and airsickness).
The activity of the compounds as anti-emetics may be
demonstrated by the method of Tatersall et al and Bountra et
al (European Journal of Pharmacoloay, 250 (1993) R5 and 249
(1993) R3-R4). In this method the extent to which they
reduce the latency or the number of retches and/or vomits
induced by emetogins in the conscious ferret compared to
vehicle - treated animals is measured. It is found that the
compounds are effective against emesis caused by a wide
range of emetogeny, extending from local irritants to anti-
cancer radiation treatment.
Compounds of formula I described above but for the fact
that one or more hydrogen, oxygen, or nitrogen atoms are
replaced by radioactive isotopes thereof. Such
radiolabelled compounds are useful as research or diagnostic
tools in metabolism pharmacokinetic studies and in binding
assays. Specific applications could include the discovery
of novel receptors involved in the pathogenesis of
neurogenic inflammation, leading to diseases such as
migraine. Isotopes included among the radiolabelled forms
of these compounds are the 3H and i4C isotopes thereof (e.g.
the 7 -ZH , 7 -3H , and N- ( 3H3 ) -methy 1 [ i . a . , having CT3 on the
pyrrolidinyl nitrogen]), for example, (R)-N-methyl-3-(1-
methyl-2-pyrrolidinylmethyl)-1H-[7-ZH]-indol-5-
yl]methanesulfonamide, (R)-N-methyl-[3-(1-methyl-2-
pyrrolidinylmethyl)-1H-[7-3H]-indol-5-yl]methanesulfonamide,
and (R)-N-methyl-[3-(1-(3H3)methyl-2-pyrrolidinylmethyl)-1H-
indol-5-yl]methanesulphonamide. The 7-ZH and 7-3H
derivatives of the invention can be prepared by the
deuteration or tritiation of the corresponding 7-bromo-
derivative, preferably in the presence of pre-reduced
Pearlman's catalyst in an organic solvent such as ethanol.
The 3H3 (i.e., tri-tritiated derivative) can be prepared by
the reaction of the corresponding compound having no
substitution on the pyrrolidinyl nitrogen, preferably as a
CA 02350089 2001-06-08
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salt such as the hydrobromide, with 3H3 methyl iodide,
preferably in the presence of a base such as potassium
\ carbonate.
For oral administration, the pharmaceutical
compositions may take the form of, for example, tablets or
capsules prepared by conventional means with
pharmaceutically acceptable excipients such as binding
agents (e. g. pregelatinized maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e. g. lactose, microcrystalline cellulose or calcium
phosphate); lubricants (e.g. magnesium stearate, talc or
silica); disintegrants (e. g. potato starch or sodium starch
glycollate); or wetting agents (e. g. sodium lauryl
sulphate). The tablets may be coated by methods well known
in the art. Liquid preparations for oral administration may
take the form of, for example, solutions, syrups or
suspensions, or they may be presented as a dry product for
constitution with water or other suitable vehicle before
use. Such liquid preparations may be prepared by
conventional means with pharmaceutically acceptable
additives such as suspending agents (e. g. sorbitol syrup,
methyl cellulose or hydrogenated edible fats); emulsifying
agents (e. g. lecithin or acacia); non-aqueous vehicles (e. g.
almond oil, oily esters or ethyl alcohol); and preservatives
(e. g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the
form of tablets or lozenges formulated in conventional
manner.
The active compounds of the invention may be formulated
for parenteral administration by injection, including using
conventional catheterization techniques or infusion.
Formulations for injection may be presented in unit dosage
form e.g. in ampules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous
vehicles, and may contain formulating agents such as
CA 02350089 2001-06-08
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suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form
for reconstitution with a suitable vehicle, e.g. sterile
pyrogen-free water, before use.
The active compounds of the invention may also be
formulated in rectal compositions such as suppositories or
retention enemas, e.g., containing conventional suppository
bases such as cocoa butter or other glycerides.
For intranasal administration or administration by
inhalation, the active compounds of the invention are
conveniently delivered in the form of a solution or
suspension from a pump spray container that is squeezed or
pumped by the patient or as an aerosol spray presentation
from a pressurized container or a nebulizer, with the use of
a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon
dioxide or other suitable gas. In the case of a pressurized
aerosol, the dosage unit may be determined by providing a
valve to deliver a metered amount. The pressurized
container or nebulizer may contain a solution or suspension
of the active compound. Capsules and cartridges (made, for
example, from gelatin) for use in an inhaler or insufflator
may be formulated containing a powder mix of a compound of
the invention and a suitable powder base such as lactose or
starch.
Aerosol formulations for treatment of the conditions
referred to above (e. g., migraine) in the average adult
human are preferably arranged so that each metered dose or
"puff" of aerosol contains 20 ~g to 1000 ug of the other
compounds of the invention. The overall daily dose with an
aerosol will be within the range 100 ~g to 10 mg.
Administration may be several times daily, for example 2, 3,
4 or 8 times, giving for example, 1.~ 2 or 3 doses each time.
The above-cited ranges will generally be those most
desirably employed in the administration of the active
compounds. Nevertheless, variations may still occur
CA 02350089 2001-06-08
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depending on the age, weight, the patient's individual
response to the compound being administered, as well as the
severity of the condition for which he, or, she, is being
treated and the type of pharmaceutical formulation chosen
and time period and interval at which such administration is
carried out. In some instances, dosage levels below the
lower limit of the aforesaid ranges may be more than
adequate, while in other cases still larger doses may be
employed without causing harmful side effects provided that
such higher dose levels are first divided into small doses
for administration throughout the day.
The following Examples illustrate the preparation of
the compounds of the present invention. Melting points are
uncorrected. NMR data are reported in parts per million (d)
and are referenced to the deuterium lock signal from the
sample solvent. Specific rotations were measured at room
temperature using the sodium D line (589 nm).
Commercial reagents were utilized without further
purification. Chromatography refers to column
chromatography performed using 32-63 um silica gel and
executed under nitrogen pressure or compressed air pressure
(flash chromatography) or gravity conditions. Room
temperature refers to 20 - 25°C.
EXAMPLE 1
General Procedure for the Reduction of Benzyloay-
carbonyl- Qyrrolidin-2 ylcarbonyl-1H-indole, N-Benzyloay-
carbonyl-azetidin-2 ~lcarbonyl-iH-indoles, or N-Benzylouy-
carbonvl-oiperidin-2-ylcarbonvl-18-indoles Forming 3-(N-
Methyl- pyrrolidin-2-ylmethyl)-iH-indoles. 3-(N-Methyl-
azetidin-2-Ylmethyl)-iH-indoles, or 3-(N-Methyhiperidin-2-
ylmethyl)-iH-indoles, respectively.
To a stirred solution of (R)- or (S)-(N-
benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole,
(R)-, (S), or (R,S)-(N-benzyloxycarbonylazetidin-2-
ylcarbonyl)-1H-indole, or (R)-, (S)-, or (R,S)-(N-
benzyloxycarbonylpiperidin-2-ylcarbonyl)-iH-indole, (5.00
CA 02350089 2001-06-08
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mmol) in anhydrous tetrahydrofuran (20mL) at room
temperature under nitrogen was carefully added lithium
aluminum hydride (0.57 g, 15.0 mmol, 3.0 eq) as a powder,
and the resulting mixture was stirred at room temperature
under nitrogen for 1 hour. The mixture was then heated at
reflux (66°C) under nitrogen for 12 hours. The reaction was
then quenched with successive additions of water (0.5 mL),
aqueous sodium hydroxide (20%, 0.5 mL), and then additional
water (1.0 mL), and the resulting mixture filtered through
diatomaceous earth (Celite (trademark)). The solids were
then washed with copious amounts of ethyl acetate (50 mL).
The combined filtrate was then washed with water (20 mL),
dried (MgSO4), and evaporated under reduced pressure. The
residue was then column chromatographed using silica gel (50
g) and elution with the appropriate solvent system to afford
the 3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, 3-(N-
methylazetidin-2-ylmethyl)-1H-indole, or 3-(N-
methylpiperidin-2-ylmethyl)-1H-indole. Following this
procedure the following compounds were prepared:
A. SS)-5-Methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-iH-
indole
(S)-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-
methoxy-1H-indole was used. The chromatographic eluent was
8% triethylamine in ethyl acetate to afford the title
compound (yields ranged from 22 to 57%) as an oil: IR
(CHC13) 3475, 1625, 1585, 1480, 1455 cm-i; 1H NMR (CDC13) 8
8.13 (br s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.4 Hz,
1H), 6.97 (d, J=2.2 Hz, 1H), 6.84 (dd, J=2.4 and 8.8 Hz,
1H) , 3.86 (s, 3H) , 3.17-3.10 (m, 2H) , 2.58 (dd, J=9.9 and
13.9 Hz, 1H), 2.50-2.40 (m, 1H), 2.47 (s, 3H), 2.26-2.17 (m,
1H), 1.89-1.72 (m, 2H), 1.70-1.52 (m, 2H); 13C NMR (CDC13) d
153.8, 131.4, 128.2, 122.7, 113.9, 111.8, 111.7, 101.1,
66.6, 57.5, 56.0, 40.8, 31.5, ,30.0, 21.9; LRMS, m/z
(relative intensity) 244 (M+, 7), 160 (20), 145 (16), 117
(21) , 84 (100) ; HRMS: calculated for CISH2oN2~: 244.1573;
found: 244.1575; [a]zsp = -96° (CHC13, c = 1.0) .
CA 02350089 2001-06-08
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B. (R)-5-MethoxY-3-(N-methylpyrrolidin-2-vlmethyl)-iH-
indole
(R)-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-
methoxy-1H-indole was used. The chromatographic eluent was
8% triethylamine in ethyl acetate to afford the title
compound (yields ranged from 13 to 61%) as an oil whose
spectral and physical properties were identical with the
spectral and physical properties of the title compound of
Example 1A with the exception of specific rotation of plane
polarized light: [a]ZSp - + 100° (CHC13, c - 1.0) . HRMS:
calculated for C,SHZON20: 244.1573; found: 244.1547.
C. (R)-5-Dibenzylamino-3-(N-methylpyrrolidin-2-
ylmethyl) -1H-indole
(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5
dibenzylamino-1H-indole was used. Column chromatography
using elution with methylene chloride/methanol/ammonium
hydroxide [9:1:0.1] afforded the title compound as a pale
green foam: ~H NMR (CDC13) 6 7.82 (br s, NH) , 7. 35-7. 19 (m,
10 H), 7.20 (d, J=8.6 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.85
(dd, J_=2.3 and 8.7 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 4.65 (s,
4H) , 3 . 25-3 . 02 (m, 2H) , 2. 52 (dd, J=9.5 and 13.9 Hz, 1H) ,
2.39-2.15 (m, 2 H), 2.30 (s, 3H), 1.85-1.40 (m, 4H); 13C NMR
(CDC13) 6 143.2, 139.7, 130.5, 128.5, 128.2, 127.3, 126.8,
122.9, 112.5, 112.2, 111.8, 103.4, 67.0, 57.4, 56.4, 40.6,
31. 4 , 29 . 7 , 21. 9 . HRMS: calculated for CZ8H31N3 409. 2520.
Found 409.2475.
D. (R)-5-Methoxy-3-(N-methylpioerid-2-vlmethyl)-iH-
indole
(R)-3-(N-Benzyloxycarbonylpiperid-2-ylcarbonyl)-5
methoxy-1H-indole was used. Column chromatography using
elution with 6% triethylamine in ethyl acetate afforded the
title compound as a white foam: '3C NMR (CDC13) 6 153.7,
131.4, 128.3, 123.3, 113.2, 111.7, 1.,1.6, 101.2, 64..4, 57.2,
55.9, 43.4, 31.0, 28.8, 25.9, 24.1; [a]ZSD - +67° (CDC13,
c=1.0); HRMS: calculated for Cl6HnN20: 258.1734. Found:
258.1710.
CA 02350089 2001-06-08
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E. (8)-5-Methoxy-3-(N-methylazetidin-2-ylmethyl)-iH-
indole
(S)-3-(N-Benzyloxycarbonylazetidinyl-2-ylcarbonyl)-5-
methoxy-1H-indole was used. The chromatographic eluent was
8% triethylamine in ethyl acetate to afford the title
compound as a white solid: mp, 118.0-120.0°C; 13C NMR (CDC13)
8 153.8, 131,.6, 128.0, 122.9, 112.3, 111.9, 111.8, 101.0,
68.5, 56.0, 53.1, 44.7, 32.4, 25.0; [a]~D - -44° (CHC13,
c=1.0) . Anal. calcd. for C14H1aN20: C, 73.01; H, 7.88, N,
12.16. Found: C, 72.65; H, 7.91; N, 12.06.
F. (R,S)-5-Methoxy-3-(N-methylazetidin-2-ylmethyl)-
1H-indole
(R,S)-3-(N-Benzyloxycarbonylazetidinyl-2-ylcarbonyl)-5
methoxy-1H-indole was used. The chromatographic eluent was
10% triethylamine in ethyl acetate to afford the title
compound as a white solid: mp, 116.0-119.0°C; Anal. calcd.
for C,4H,gN,O: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.61;
H, 7.99; N, 12.10.
EXAMPLE 2
1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxy~ropene
or 1-(N-Benz~loxycarbonylpiperid-2-yl)-3-hydroxypropene
To a stirred solution of either ethyl 3-(N-
benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate or ethyl-3-
(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate (R, or S, or
racemate, 10.00 mmol) in anhydrous tetrahydrofuran (75 mL)
at -78°C under nitrogen was added dropwise a solution of
diisobutylaluminium hydride (1.0 M in hexanes, 12.0 mL, 22.0
mmol, 2.2 eq). The resulting solution was stirred at -78°C
under nitrogen for 30 minutes. The reaction solution was
then allowed to warmed to room temperature over the course
of 2 hours. A saturated solution of sodium hydrogen
carbonate (50 mL) was added, and the aqueous mixture was
extracted with ethyl acetate (3 x 5Q mL). The extracts were
combined, dried (MgS04), and evaporated under reduced
pressure. Column chromatography of the residue with diethyl
ether/hexanes [1:~] afforded either 1-(N-benzyloxycazbonyl-
CA 02350089 2001-06-08
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pyrrolidin-2-yl)-3-hydroxypropene orl-(N-benzyloxycarbonyl-
piperid-2-yl)-3-hydroxypropene.
Following the procedure the following compounds were
prepared:
A. (R)-1-(N-Henzyloxycarbonylpyrrolidin-2-yl)-3-
hydroxypropene
(R)-Ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-pro-
penoate was used. Chromatography of the extraction residue
afforded the title compound as a clear, colorless oil: 1H
NMR (CDC13) S 7.40-7.25 (m, 5H), 5.75-5.53 (m, 2H), 5.20-5.00
(m, 2H), 4.38 (br m, 1H), 4.06 (br d, J=13.7 Hz, 2H), 3.45
(br t, J=7.0 Hz, 1H), 2.03-1.68 (m, 4H); [a]ZSD = +34° (MeOH,
c=1.0) ; HRMS: calculated for C~SH19N03 261. 1365, found
261.1356.
8. (R, s ) -1- (N-Henzy_loxycarbonylpiperid-2-yl) -3-
hvdroxvuropene
(R, S)-Ethyl 3-(N-benzyloxycarbonylpiperid-2-yl)-2-pro-
penoate was used. Chromatography of the extraction residue
afforded the title compound as a clear, colorless oil: LRMS
(m/z, relative intensity) 257 (3), 212 (12), 193 (8), 175
(65), 173 (100), 145 (27), 109 (24), 91 (87); 1H NMR (CDC13)
S 7.40-7.20 (m, 5H), 5.70-5.61 (m, 2H), 5.14 (d, J=17.6 Hz,
1H), 5.10 (d, J=17.5 Hz, 1H), 4.88 (br m, 1H), 4.14-4.00 (m,
3H), 2.91 (br t, J=12.7 Hz, 1H), 1.78-1.47 (m, 6H). Anal.
calcd. for C~6H2,N03~0.1 H20: C, 69.34; H, 7.71; N, 5.05.
Found: 69.38; H, 7.84; N, 5.16.
EXAMPLE 3
8ynthesis of Ethyl 3-(N-Henzyloxycarbonylpyrrolidin-2
yl)-2-propenoate or Ethyl 3-(N-Benzyloxycarbonylpiperid-2
3 0 y1 ) -2 =pr ~enoate
To a stirred solution of N-carbobenzyloxypyrrolidine-2-
carboxa'ldehyde or N-carbobenzyloxypiperidine-2-
carboxaldehyde (5.00 mmol) [S. K.iyooka, et al., J. Orcr.
Chem., 5409 (1989) and Y. Hamada, et al., Chem. Pharm.
Bull., 1921 (1982)] in anhydrous tetrahydrofuran at -78°C
was added (carbeth-oxymethylene)triphenylphosphorane (,2.09 g,
CA 02350089 2001-06-08
i .~ ..
-23-
6.00 mmol. 1.2 eq) as a solid portionwise. The resulting
reaction mixture was stirred at room temperature under
nitrogen for 2 hours, and then heated at reflux under
nitrogen for 1 hour. The reaction mixture was evaporated
under reduced pressure and the residue was column
chromatographed using silica gel (approximately 100 g) and
elution with 20% diethyl ether in hexanes afforded either
ethyl3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate or
ethyl 3-(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate.
20 A. (R)-Ethyl 3-(N-Benzyloxycarbonvlpvrrolidin-2-yl)-
2-propenoate
(R)-N-Carbobenzyloxypyrrolidine-2-carboxaldehyde was
used. Chromatography as described above afforded the title
compound as a clear, colorless oil: iH NMR (CDC13-db) s 7.34-
7.25 (m, 5H), 6.89-6.76 (m, 1H), 5.88-5.74 (m, 1H), 5.18-
5.05 (m, 2H), 4.60-4.43 (m, 1H), 4.17 (q, J=7.1 Hz, 2H),
3.55-3.40 (m, 2H), 2.11-2.00 (m, 1H), 1.90-1.75 (m, 3H),
1.28 (t, J=7. 1 Hz, 3H) ; ~3C NMR (CDC13) [Note: due to slow
nitrogen inversion two conformers of the products are seen
by NMR spectroscopy] 8 166.3, 154.7, 147.9, 147.4, 136.6,
128.4, 127.9, 120.9, 66.9, 65.8, 60.4, 58.1, 57.7, 46.8,
46.4, 31.6, 30.8, 23.6, 22.8, 22.6, 15.3, 14.2.
B. (R,8)-Ethyl 3-(N-Benzyloxycarbonylpiperid-2-yl)-2-
propenoate
(R,S)-N-Carbobenzyloxypiperidine-2-carboxaldehyde was
used. Chromatography as described above afforded the title
compound as a clear, colorless oil: 1H NMR (CDC13-db) 8 7.36-
7.27 (m, 5H), 6.85 (dd, J=4.4 and 16.3 Hz, 1H), 5.80 (dd, J-
2.4 and 16. 3 Hz, 1H) , 5. 11 (s, 2H) , 5.01 (br m, 1H) , 4.17
(q, J=6.7 Hz, 2H), 4.05 (br d, J=12.6 Hz, 1H), 2.87 (br t,
1H), 1.80-1.35 (m, 6H), 1.27 (t, J=6.6 Hz, 3H); FAB LRMS
(m/z, relative intensity) 318 ([MH+~, 100), 274 (86), 228
(14) , 210 (21) , 182 (43) , 138 (32)t
CA 02350089 2001-06-08
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EXAMPLE 4
General synthesis of Allylsulphonamides
A. lhllylsulphonamide
The title compound was prepared by the method of M. A.
Belous and I. Ya. Postouski, Zhur. Obschei. Khim., 1950, 20,
1701.
B. N-Methylallylsulphonamide
The title compound was prepared by an analogous
procedure to above by using methylamine instead of ammonia.
Anal. calcd. for CSHuNO2S: C, 40.25; H, 7.43; N, 9. 38. Found:
C,40.51; H,7.37; N,9.70.
EXAMPLE 5
Preparation of Ethy_lallylsulohone
The title compound was prepared by the method of R. J.
Palmer and C. J. M. Stirling., J. Amer. Chem. Soc.. 1980,
102, 7888.
EXAMPLE 6
General synthesis of yinyl sulphonamides
Where the required vinylsulphonamide was not
commercially available, they were prepared by the following
procedure based on the procedure described in Zhur. Obschei.
Khim., 1959, 29, 1494.
A. N,N-Dimethylvinylsulphonamide
To a stirred solution of chloroethylsulphonyl chloride
(25 g, 153 mmol) in dry diethyl ether (150 mL) at -10°C, was
added dropwise a solution of dimethylamine (30.5 mL, 460
mmol) in dry diethyl ether (100 mL) over 5 minutes. After
stirring for 90 minutes at -10°C the solution was filtered
and evaporated in vacuo. The residue was distilled to give
the title compound (9.5 g, 46%): b.p. 120-122°C (20 mm Hg).
Anal. calcd. for C,H9NOZS: C,35.54; H,6.71; N,10.36%. Found:
C,35.36; H,6.37; N,10.19.
B. The following examples were prepared by the
general procedure above, using the appropriate amine
starting material. Purification was by distillation or
column chromatography.
CA 02350089 2001-06-08
-25-
R2NS0z CH=CHZ
-R2N Isolated Form Analysis
(Theoretical in brackets)
C H N
MeNH- Oil b.p. 93-5°C Literature compound U.S. 3,761,473
(0.05 mm Hg)
Oil 47.97 7.41 7.81
(47.97 7.48 7.99)
N-
Oil 44.73 6.80 8.62
(44.70 6.88 8.69)
N-
nPr2N- Oil 50.37 8.79 7.68
(50.23 8.96 7.32)
nPrNH- Oil 40.22 7.35 9.1
(40.24 7.43 9.39)
Oil 40.51 5.85 9.35
(40.79 6.16 9.52)
~N-
iPrNH- Oil 40.42 7.33 9.30
(40.25 7.43 9.39)
EXAMPLE 7
General Synthesis of Vinyl Sulohones
Where the required vinyl sulphone was not commercially
available, they were prepared from the, corresponding thiols
using the procedure described by J. M. Gaillot, Y Gelas-
Mialhe -and R. Vessiere Can. J. Chem., 1979, 57, 1958. The
CA 02350089 2001-06-08
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following examples are representative.
RS-CHZCHz OH
Analysis
(Theoretical in brackets)
R Isolated Form C H
nPr Oil IA6 EtOAc 48.68 9.79
I/5 HZO (48.76 10.06)
nBu Oil T.Lc - Rf. 0.26
(SiOz, Ether/Hexane I:I)
RS-CHZCH2 CI
Analysis
(Theoretical in brackets)
R Isolated Form C H
nPr Oil I/5 H20 1/3041.63 7.60
CHZCI2 (41.65 7.69)
nBu Oil L0 Hz0 42.31 7.84
(42.21 8.27)
2 0 RSOZ-CHZCH2CI
Analysis
(Theoretical in brackets)
R Isolated Form C H
2 nPr Oil 34.75 6.68
5
(35.19 6.50)
nBu Oil 1/15 CHZCIZ 38.41 7.01
(38.27 6.95)
RSOi CH=CH2
30
Analysis
(Theoretical in brackets)
R Isolated Form C H
nBu Oil ~ 48.95 8.07
(48.62 8.16)
CA 02350089 2001-06-08
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EXAMPLE 8
4-(Nitrophenyl)methanesulphonyl chloride
To a stirred solution of sodium thiosulphate (72.0g,
0.291 mol) in water (75 mL) and methanol (50 mL) was added
at room temperature, over 5 minutes, 4-nitrobenzyl chloride
(50.0g, 0.291 mol). The resulting reaction mixture was
heated to reflux and stirred, at reflux, for a further 2.25
hours. The reaction mixture was then cooled down and
evaporated under reduced pressure, azeotropin with toluene
to give a white solid (150 g). The white solid was added to
a mixture of acetic acid (75 mL), water (100 mL) and ice,
the reaction mixture cooled to 0°C and chlorine gas passed
_ through the system for 1.25 hours, maintaining the reaction
temperature below 10°C throughout. The excess chlorine gas
was removed by purging the reaction mixture with nitrogen
gas for 1.25 hours. The resulting slurry was filtered,
drying the solid thus obtained in air. The title compound
thus obtained (60.5 g) was used as such in Example 37
without further purification or characterization.
EXAMPLE 9
4-t-Butylaminosulphonylmethylnitrobenzene
To a cooled (ice bath) solution of t-butylamine (48.45
mL, 461 mmol) in dichloromethane (500 ml) was added
dropwise, with stirring, a solution of the product of
Example 36 (54.33 g, 231 mmol) in dichloromethane (500 mL).
This addition was carried out over 15 minutes with the
temperature maintained below 10°C throughout. The reaction
was then allowed to warm to room temperature and stirred for
a further 12 hours. The reaction was then diluted with
water (200 mL), the organic layer separated, washed
sequentially with water and brine, dried (MgS04) and
evaporated under reduced pressure to give the product as a
brown solid. Recrystallization of the brown solid from
ethanol gave the title compound as a white solid (49.0 g):
mp, 156-158°C; TLC (dichloromethane/methanol 30:0.4): Rf =
0. 66. ~H NMR (CDC13) 6 8.25 (d, 2H) , 7. 6 (d, 2H) , 4,:4.0 (s,
CA 02350089 2001-06-08
. ...
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2H) , 4.10 (s, 1H) , 1.38 (s, 9H) . Anal. calcd. for C11H16Nz~as~
C, 48.55; H, 5.97; N, 10.30. Found: C, 48.53; H, 5.92; N,
10.29.
EXAMPLE 10
4-t-Butylaminosulphonylmethvlaniline
A solution of the product of Example 9 ( 1.17 g, 4 . 29
mmol) in absolute ethanol and 10% palladium on carbon (0.32
g) was stirred under a hydrogen atmosphere (60 psi) at 60°C
for 66 hours. The mixture was filtered through CELITE"
filter aid and the resulting solution evaporated under
reduced pressure to give the product as a solid.
Recrystallization from ethanol gave the title compound as a
white solid (0.95 g): mp, 137-138°C; TLC (dichloromethane/
methanol 30:0.4): Rf = 0.43. 1H NMR (CDC13) d 7.20 (d, 2H),
6.65 (d, 2H), 4.15 (s, 2H), 3.95 (br s, 1H), 3.75 (br s,
2H) , 1.32 (s, 9H) . Anal. calcd. for C11H1aNz~2S: C, 54.51; H,
7.49; N, 11.56. Found: C, 54.76; H, 7.60; N, 11.43.
EXAMPLE 11
4-(t-Butylaminosulphonylmethyll-2,6-dibromoaniline
To a stirred solution of the product of Example 10
(0.77 g, 3.17 mmol) in dichloromethane (15 mL) and methanol
(15 mL) was added sodium bicarbonate (0.80 g, 9.53 mmol)
with stirring, at 20°C. Bromine (0.315 mL, 6.11 mmol) was
then added dropwise, to the resultant slurry. The resulting
mixture was then stirred for 18 hours concentrated in vacuo
and taken up in ethyl acetate/water (1:1). The aqueous
layer was separated and extracted with ethyl acetate. The
combined organic layers were then washed with water, dried
(MgS04) and evaporated under reduced pressure to give the
product as a white solid. Recrystallization from
hexane/ethyl acetate gave the title compound as a white
solid (1.15 g). Mp 140-142°C; TLC (dichloromethane/methanol
30:0.4): Rf = 0.60. 1H NMR (CDC13) 8 7.45 (s, 2H), 4.65 (br
s, 2H), 4.05 (s, 2H), 4.00 (s, 1H), 1.40 (s, 9H). Anal.
calcd. for C,~H16Nz02SBrz: C, 33.02; H, 4.03; N, 7.00. Found:
C, 33.52; H, 4.0~; N, 6.92.
* Trade-mark
CA 02350089 2001-06-08
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EXAMPLE 12
4-t-Butylaminosulphonylmethvl-2.6-dibromo-N-
tritluoroacetylaniline
To a stirred solution of the product of Example 1l
(1.01 g, 2.52 mmol) and pyridine (0.26 mL, 3.28 mmol, 1.30
eq) in anhydrous methylene chloride (15 mL) at 0°C under a
nitrogen atmosphere was added dropwise trifluoroacetic
anhydride (0.38 ml, 2.68 mmol, 1.1 eq). The resultant
reaction mixture was stirred at 0°C, under a nitrogen
atmosphere, for 1 hour. The reaction mixture was then
diluted with dichloromethane (150 mL), washed with water (2
x 50 mL) and dried (MgS04). Evaporation under reduced
pressure gave a white solid which was recrystallized from
hexane/diethyl ether to give the title compound as a white
solid (1.10 g). Mp 166-167°C; TLC (dichloromethane/methanol
30: 0.4) : Rf = 0.21. 1H NMR (CDC13) a 7.75 (br s, 1H) , 7.70
(s, 2H), 4.20 (s, 2H), 4.10 (s, 1H), 1.45 (S, 9H). Anal.
calcd. for C13H15N2~3SBr2F3~ C, 31.48; H, 3.05; N, 5.65.
Found: C, 31.41; H, 3.11, N, 5.55.
EXAMPLE 13
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(4-t-
butylaminosul~honylmethyl-2.6-dibromo~henvl)-N-
tr if luoroacetylamino ] propene
To a stirred solution of the product of Example 12
(28.0 g, 56.0 mmol) and triphenylphosphine (15.0 g, 86.0
mmol, 1.53 eq) in anhydrous tetrahydrofuran (70 mL), under
a nitrogen atmosphere, at 10°C, was added dropwise a
solution of diethylazodicarboxylate (8.9 mL, 56 mmol) in
anhydrous tetrahydrofuran (15 mL). The reaction solution
was then warmed to 25°C and stirred for a further 25 minutes
whereupon a solution of the product of Example 2A (14.79 g,
57.0 mmol) in anhydrous tetrahydrofuran (45 mL) was added
dropwise, over 10 minutes. The reaction solution was then
stirred at 25°C, under a nitrogen atmosphere for 18 hours.
The resulting reaction solution was evaporated under reduced
pressure, triturated with diethyl ether, filtered and the
CA 02350089 2001-06-08
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filtrate evaporated under reduced pressure and the residue
was column chromatographed using silica gel (approximately
850 g), eluting with an ethyl acetate gradient in hexanes to
afford the title compound as a white foam. TLC
(hexane/ethyl acetate 1:1): Rf - 0.65. 1H NMR (CDC13)
[Note: due to slow nitrogen inversion two conformers of the
products are seen by NMR spectroscopy] d 7.50-7.80 (m, 2H),
7.25 - 7.42 (m, 5H), 5.42-5.65 (m, 2H), 5.30 (s, 0.14H),
5.00-5.20 (m, 2H), 4.02-4.55 (m, 6H), 3.28-3.45 (m, 2H),
1.25-1.90 (m, 13H) . Anal. calcd. for CZ8H3zN3O5SBr2F3. 7/100
CHZC12: C, 45.23; H, 4.34; N, 5.64. Found: C, 45.06; H,
4.44; N, 5.87.
EXAMPLE 14
(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethvl)-7-
bromo-5-(t-butvlaminosulphonylmethyl)-iH-iadole
To a stirred solution of the product of Example 13
(29.90 g, 40.44 mmol) in 1,2-dimethoxyethane (160 mL) under
a nitrogen atmosphere, at 20°C was added palladium (II)
acetate (0.97 g, 4.32 mmol) followed by tetrabutylammonium
chloride hydrate (11.25 g, 40.48 mmol) and triethylamine
(22.3 mL, 160 mmol). The reaction solution was stirred for
a further hour at 20°C and then heated at reflux for 18
hours. The reaction solution was then allowed to cool to
20°C, evaporated under reduced pressure, taken up in ethyl
acetate (800 mL) and washed with water. The organic layer
was separated, dried (MgS04) and evaporated under reduced
pressure to give a dark brown foam. Column chromatography
using elution with 10% acetone in dichloromethane failed to
provide a more pure title compound. The resulting crude
product (21.3 g of an off-white foam) was used as such in
the preparation of Example 43.
EXAMPLE 15
(R)-7-Bromo-5-(t-butylaminosulphonylmethvl)-3-(N-
methylpyrrolidin-2-ylmethyl)-iH-indole
To a stirred suspension of lithium aluminum hydride
(7.07 g, 186 mmol~ in anhydrous tetrahydrofuran (100 mL), at
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0°C, under a nitrogen atmosphere, was added dropwise, over
30 minutes, a solution of the resulting product of Example
14 (21.3 g) in anhydrous tetrahydrofuran (100 mL). The
resulting mixture was allowed to warm to room temperature
and then stirred for a further 56 hours. The reaction was
then cooled to 0°C and cautiously treated with water (7.0
mL), followed by 15% aqueous sodium hydroxide solution (7.0
mL), and then with more water (21.0 mL). The resulting
black precipitate was removed by filtration, washing with
ethyl acetate. The filtrate was then washed with water,
dried (MgS04) and evaporated under reduced pressure to give
the crude products as a gum. This was column
chromatographed using silica gel (50 g) and elution with
dichloromethane/methanol (100:5) followed by
dichloromethane/methanol/ammonium hydroxide (90:10:1) to
afford the title compound (9.9g) as a white foam. TLC
(dichloromethane/methanol/ammonium hydroxide 90:10:1):
Rf = 0. 33. 1H NMR (CDC13) S 8.35 (br s, 1H) , 7.52 (s, 1H) ,
7.40 (s, 1H), 7.12 (s, 1H), 4.30 (s, 2H), 4.00 (s, 1H),
3.12-3.25 (m, 2H), 2.60-2.72 (m, 1H), 2.50-2.10 (m, 1H),
2.49 (s, 3H), 2.22-2.38 (m, 1H), 1.55-1.78 (m, 4H), 1.39 (s,
9H). [a]uD - + 47° (CH30H, c=0.1). Anal. calcd. for
ClgFi28N302SBr: C,~ 51.59; H, 6.38; N, 9.50. Found: C, 51.84;
H,6.52; N, 9.52.
EXAMPLE 16
2,6-Dibromo-4-methylaminosulfonylmethylaniline
To a stirred solution of 4-methylaminosulfonyl-
methylaniline (l0 g) in a mixture of methylene chloride (100
mL) and methanol (200 mL) was added sodium bicarbonate (12.6
g) followed by bromine (16 g) in methylene chloride (80 mL).
Then the reaction mixture was evaporated in vacuo and the
residue partitioned between ethyl acetate (200 mL) and water
(100 mL). The ethyl acetate phase was washed with water and
brine then dried and evaporated to give the title compound
as a brown solid (17.1 g). Mp 155-157°C. 1H NMR (CDCL3) 8
7.4 (s, 2H), 4.6 ;(bs, 2H), 4.1 (m, 3H), 2.75 (d, 3H).
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EXAMPLE 17
2,6-Dibromo-4-methylaminosulfon~ilmethyl-N-trif luoro-
acetylaniline
2,6-Dibromo-4-methylaminosulfonylmethylaniline (410 g)
was stirred in methylene chloride (8 L) containing pyridine
(118 g) and treated with trifluoroacetic anhydride (307.5 g)
in methylene chloride (300 mL). Upon complete consumption
of the aniline the reaction mixture was diluted with
methylene chloride (2 L) and with water (5 L) resulting in
precipitation of the title compound (281.9 g) which was
removed by filtration. mp 179-180°C. TLC (EtOAc/hexane
1: 1) : Rf = 0.3. Anal. calcd. for Ct~Br2F3Nz03S . C 26.45; H,
2.00; N, 6.17. Found C 26.46; H, 1.79; N, 6.12.
Further title compound (165 g) was recovered by
crystallization from the (water-washed) combined filtrate
and washes upon concentration.
EXAMPLE 18
(R)-1-(N-HenzyloxycarbonylDVrrolidin-2-yl)-3-
hydroxypropene
To a stirred solution of (R)-ethyl 3-(N-
benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (574 g) in
tetrahydrofuran (5.7 L) at about -78°C was added boron
trifluoride etherate (295.4 g) and then diisobutylaluminum
hydride (1.5 M in toluene, 3.91 L, 3.1 eq) added (over two
hours) maintaining the temperature below -62°C. The
resulting solution was stirred (between -78 and -62°C) for
three hours and then quenched into aqueous citric acid
solution (2 kg citric acid in 5 L water plus 4 L ice) over
about 40 minutes. The phases were separated and the aqueous
phase extracted with ethyl acetate (2 x 2.1 L). The
combined organic solution was dried (over magnesium
sulphate) and evaporated, then the residual oil purified by
chromatography through silica gel,~eluting with mixed ethyl
acetate/hexane (9:1 to 4:1) to give the title compound as an
oil (260 g), as produced in Example 12A (as an alternative,
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the residual oil can be purified by chromatography through
silica gel eluting with ethyl acetate: hexane (1:1)).
EXAMPLE 19
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-[N-(4-
methylaminosulfonylmethyl-2,6-dibromophenyl)-N-
trifluoroacetylamino]propane
Triphenylphosphine (5.71 g) was dissolved in anhydrous
tetrahydrofuran (30 mL) and, in an ice bath, diethylazodi-
carboxylate (3.71 g in 20 mL anhydrous THF) was added
dropwise. Having removed the ice-bath, the reaction mixture
was diluted with a further 20 mL anhydrous THF, followed by
2,6-dibromo-4-methylamino-sulfonylmethyl-trifluoroacetyl-
aniline (6.45 g in 50 mL anhydrous THF), and (R)-1-(N-
Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene (5.51 g
in 30 mL anhydrous THF) added dropwise. When conversion was
judged complete the reaction mixture was evaporated in vacuo
(onto silica gel - 20 g) and purified by column
chromatography (Si02 - 1.6 kg) eluted with 5% acetone in
methylene chloride to give the title compound as a colorless
foam (9.13 g). TLC (methylene chloride/acetone 9:1) Rf -
0.60; Anal. calcd. for CuHZ6BrZF3N305S C 43.1; H, 3.7; N, 6Ø
Found C, 43.93; H, 3.99; N, 6.00.
Similarly, the reaction may be conducted in 1,2
dimethoxyethane solvent and processed without purification
to direstly yield the compound of Example 52 under standard
Heck coupling conditions (in mixed 1,2-dimethoxyethane with
N,N-dimethylformamide).
EXAMPLE 20
(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-
bromo-5-(methylaminosulfonvlmethyl)-1H-indole
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-[N-(4-
methylaminosulfonylmethyl-2,6-dibromophenyl)-N-trifluoro-
acetylamino]propane (9.00 g) in, triethylamine (70 mL)
containing N,N-dimethylformamide (20 mL), tetra-n-butyl-
ammonium chloride (3.61 g) and palladium acetate (1.01 g)
was heated at 80°C until conversion was complete. Tha cooled
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reaction mixture was filtered through CELITE*and washed with
methylene chloride. The combined filtrate and washings were
then evaporated in vacuo onto silica gel -(15 g) then
purified by column chromatography (Si02 - 1.6 kg) eluted
with 4% acetone in chloroform. The product-rich fractions
were combined and evaporated then re-purified by
crystallization from a mixture of diethyl ether (50 mL) and
methylene chloride (10 mL). The title compound was
recovered by filtration (washing with hexanes) as a
colorless solid (2.40 g). TLC (methylene chloride/acetone
10:1) Rf - 0.35; Anal. calcd. for C~HZ6BrN304S: C, 53.1; H,
5.0; N, 8.1. Found C, 53.13; H, 5.0; N, 7.8.
Further title compound (2.03 g) was recovered from the
crystallization liquor upon evaporation and purification by
silica chromatography (300 g Si02 eluted with diethyl
ether).
EXAMPLE 21
(R)-7-Bromo-5-(methylaminosulfonylmethyl)-3-(N-methyl-
g~rrolidin-2-~lmethyl)-18-indole
To a chilled suspension of lithium aluminum hydride
(47.89 g) in tetrahydrofuran (938 mL), (R)-3-(N-
benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-
(methylaminosulfonylmethyl)-1H-indole (262.7 g) in
tetrahydrofuran (1250 mL total) was added slowly dropwise.
The reaction mixture was stirred at ambient temperature and
then warmed to 40°C until conversion was complete. Then,
the mixture was cooled and quenched by slow addition of
industrial methylated spirit (160 mL), followed by 4M
aqueous sodium hydroxide solution (45 mL), then water (142
x
mL). The mixture was then filtered (through Arbacel). The
filtered solids were reslurried in hot industrial methylated
spirit (1600 mL) then refiltered. The filtered solids were
then washed with a further portion of industrial methylated
spirit (200 mL) and then again reslurried from hot
industrial methylated spirit (1600 mL). The resultant
slurry was again re-filtered. The combined filtrates and
* Trade-mark
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washings were evaporated in vacuo to give a crude oil which
was stirred in mixed water (1000 mL) / ethyl acetate (1000
mL). The aqueous phase was separated and washed with ethyl
acetate (500 mL)(then the aqueous discarded) and then the
ethyl acetate extracts combined and diluted with water (1000
mL) and the whole acidified (by addition of concentrated
hydrochloric acid). The aqueous phase was separated and the
organic phase washed with water (500 mL). These two aqueous
phases were combined and made basic (by addition of 40%
aqueous sodium hydroxide solution) and the product re-
extracted with ethyl acetate (2x1000 mL), then again at pH9
with further ethyl acetate (500 mL). The combined ethyl
acetate extracts were evaporated to an oil then re-
evaporated from acetone (250 mL) to give the title compound
(200.7 g) as a semi-solid mass. TLC (diethyl ether/ethyl
acetate/methanol/diethyl amine 50:50:5:5): Rf = 0.26. 1H NMR
(d6 DMSO) d 11.05 (s, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 7.2 (s,
1H), 6.85 (q, 1H), 4.35 (s, 2H), 2.95 (m, 2H), 2.55 (d, 3H),
2.5 (m, 1H), 2.35-2.3 (m, 1H and s, 3H), 2.1 (m, 1H), 1.75
1.4 (m, 4H).
