Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
Fl
6/DAM2
1 337427
17940
TITLE OF THE INVENTION
(QUINOLIN-2-YLMETHOXY)INDOLES AS INHIBITORS OF THE
BIOSYNTHESIS OF LEUKOTRIENES.
BACKGROUND OF THE INVENTION
European PatentApplications 166,591 (published
January 2, 1986) and 275,667 (published December 15,
1987) disclose a series of indole-based compounds with
activity as prostaglandin antagonists and inhibitors of
leukotriene biosynthesis respectively. In EP 181,568
(published October 30, 1985) and EP 200,101 (published
April 16, 1986) are disclosed a series of compounds,
containing two aromatic nuclei, which are described as
possessing activity as lipoxygenase inhibitors. In EP
279,263 (published February 2, 1988) is disclosed a
series of indoles, benzofurans and benzothiophenes which
are described as possessing activity as lipoxygenase
inhibitors. U.S. Patent 4,629,733 describes novel
indolinones which are antithrombotic and inhibit both
"~''''~
~ 337427
Fl
6/DAM2 - 2 - 17940
phosphodiesterase and tumor metastasis. The chemical
preparation of quinolylindoles is referred to by
Sheinkman, et al., Chem. Ab., Vol. 67, 54017 (1967),
without mentioning any utility for such compounds. A
number of N-acyl derivatives of indole-3-acetic acid
are described as potential anti-inflammatory agents
by Biniecki, et al., Chem. Ab., Vol. 98, 197936
(1983), by Pakula, et al., Chem. Ab., Vol. 105,
190835 (1986), and in British Pat. Spec. 1,228,848.
SUMMARY OF THE INV~;N110N
The present invention relates to compounds
having activity as leukotriene biosynthesis
inhibitors, to methods for their preparation, and to
methods and pharmaceutical formulations for using
these compounds in mammals (especially humans).
- Because of their activity as leukotriene
biosynthesis inhibitors, the compounds of the present
invention are useful as anti-asthmatic,
anti-allergic, and anti-inflammatory agents and are
useful in treating allergic rhinitis and chronic
bronchitis and for amelioration of skin diseases like
psoriasis and atopic eczema. These compounds are
also useful to inhibit the pathologic actions of
leukotrienes on the cardiovascular and vascular
systems for example, actions such as result in angina
or endotoxin shock. The compounds of the present
invention are useful in the treatment of inflammatory
and allergic diseases of the eye, including allergic
conjunctivitis. The compounds are also useful as
cytoprotective agents and for the treatment of
migraine headache.
El 7 3 3 7 4 2 7
6/DAM2 - 3 - 17940
Thus, the compounds of the present invention
may also be used to treat or prevent mammalian
(especially, human) disease ~tateæ such as erosive
gastritis; erosive esophagitis; inflammatory bowel
disease; ethanol-induced hemorrhagic erosions;
hepatic ischemia; noxious agent-induced damage or
necrosis of hepatic, pancreatic, renal, or myocardial
tissue; liver parenchymal damage caused by hepatoxic
agents such as CC14 and D-galactosamine; ischemic
renal failure; disease-induced hepatic damage; bile
salt induced pancreatic or gastric damage; trauma- or
stress-induced cell damage; and glycerol-induced
renal failure.
The compounds of this invention are
inhibitors of the biosynthesis of 5-lipoxygenase
metabolites of arachidonic acid, such as 5-HPETE,
5-HETE and the leukotrienes. Leukotrienes B4, C4, D4
and E4 are known to contribute to various disease
conditions such as asthma, psoriasis, pain, ulcers
and systemic anaphylaxis. Thus inhibition of the
synthesis of such compounds will alleviate these and
other leukotriene-related disease states.
DETAILED DESCRIPTION OF THE INv~NLlON
The present invention provides novel
compounds of the formula I:
R~?~CH~O ~ ~cRllRll)n-ym-(cRllRll)p-Q
(o) v R3 R~
I
1 337427
Fl
6/DAM2 - 4 - 17940
wherein:
Rl, R2, R3, R4 and R10 are independently hydrogen,
halogen, lower alkyl, lower alkenyl, lower alkynyl,
-CF3, -CN, -N02, -N3, -C(OH)RllRll, -C02R12, -SR14
S(o)Rl4 S(0)2R14 -s(o)2NR15R15, _oR15, _NR15R15,
-C(O)R16 or -(CH2)tR21;
R5 is hydrogen, -CH3, CF3, -C(O)H, Xl-R6 or X2-R7;
R6 and R9 are independently alkyl, -(CH2)UPh(Rl0)2 or
-(CH~)UTh(Rl0)2;
R7 is -CF3 or R6;
R8 is hydrogen or X3-R9;
each Rll is independently hydrogen or lower alkyl, or
two Rll's on same carbon atom are joined to form a
cycloalkyl ring of 3 to 6 carbon atoms;
R12 is hydrogen, lower alkyl or -CH2R21;
R13 is lower alkyl or -(CH2)rR21;
R14 is -CF3 or R13;
R15 is hydrogen, -C(O)R16, R13, or two R15 's on the
same nitrogen may be joined to form a monocyclic
heterocyclic ring of 4 to 6 atoms containing up to 2
heteroatoms chosen from 0, S or N;
R16 is hydrogen, -CF3, lower alkyl, lower alkenyl,
- 1 337427
Fl
6/DAM2 - 5 - 17940
lower alkynyl or -(CH2)rR21;
R17 is -(CH2)S-C(Rl8Rl8)-(CH2)s-Rl9 or
-CH2C(o)NR15R15;
R18 is hydrogen or lower alkyl;
R19 is a) a monocyclic or bicyclic heterocyclic ring
containing from 3 to 9 nuclear carbon atoms and 1 or
2 nuclear hetero-atoms selected from N, S or 0 and
with each ring in the heterocyclic radical being
formed of 5 or 6 atoms, or b) the radical W-R20;
R20 is alkyl or -C(o)R23;
R21 is phenyl substituted with 1 or 2 R22 groups;
R22 is hydrogen, halogen, lower alkyl, lower alkoxy,
lower alkylthio, lower alkylsulfonyl, lower
alkylcarbonyl, -CF3, -CN, -N02 or -N3;
R23 is alkyl, cycloalkyl, or monocyclic
monoheterocyclic ring;
R24 is the residual structure of a standard amino
acid, or R18 and R24 attached to the same N can
cyclize to form a proline residue;
m is 0 to 1;
n is 0 to 3;
p is 1 to 3 when m is 1;
1 337427
Fl
6/DAM2 - 6 - 17940
p is 0 to 3 when m is 0;
r is 0 to 2;
s is 0 to 3;
t is 0 to 2;
u is 0 to 3;
v is 0 or 1;
W is O, S or NR15;
xl is 0, or NR15;
x2 is C(0), CRllRll, S, S(0) or S(0)2;
X3 is C(0), CRllRll, 5()2 or a bond;
Y is Xl or X2;
Q is -C02R12, -C(o)NES(0)2R14, -NHS(0)2R14,
-S(0)2NHR15 -C(o)NR15R15, -C02R17, -C(o)NR18R24,
-CH2OH, or lH- or 2H-tetrazol-5-yl;
and the pharmaceutically acceptable salts thereof.
A preferred embodiment of Formula I is that in which:
Rl, R2, R3 and R4 are hydrogen;
R5 is X2-R7 or -oR6;
R7 is R6;
R8 is R9;
Rl is hydrogen or halogen;
m is 0;
n is 1 to 3;
u is 0 in R6 and 1 in R9;
x2 is cRllRll or S;
Q is -C02R12; and the remaining substituents are as
defined for Formula I;
and the pharmaceutically acceptable salts thereof.
1 337427
Fl
6/DAM2 - 7 - 17940
Definitions
The following abbreviations have the
indicated meanings:
Me = methyl
Bz = benzyl
Ph = phenyl
t-Bu = tert-butyl
i-Pr = isopropyl
c-C6Hll = cyclohexyl
c-Pr = cyclopropyl
c- = cyclo
Ac = acetyl
Tz = 5-tetrazolyl
Th = 2- or 3- thienyl
Alkyl, alkenyl, and alkynyl are intended to
include linear, branched, and cyclic structures and
combinations thereof.
As used herein, the term "alkyl" includes
"lower alkyl" and extends to cover carbon fragments
having up to 20 carbon atoms. Examples of alkyl
groups include octyl, nonyl, norbornyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl,
3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclododecyl,
adamantyl, and the like.
As used herein, the term "lower alkyl"
includes those alkyl groups of from 1 to 7 carbon
atoms. Examples of lower alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, sec- and
tert-butyl, pentyl, hexyl, heptyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
~ 337427
Fl
6/DAM2 - 8 - 17940
2-methylcyclopropyl, cyclopropylmethyl, and the like.
The term 'Icycloalkyl" refers to a
hydrocarbon ring having from 3 to 7 carbon atoms.
Examples of cycloalkyl groups are cyclopropyl,
cyclopentyl, cycloheptyl and the like.
"Lower alkenyl" groups include those alkenyl
groups of 2 to 7 carbon atoms. Examples of lower
alkenyl groups include vinyl, allyl, iæopropenyl,
pentenyl, hexenyl, heptenyl, cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl,
l-propenyl, 2-butenyl, 2-methyl-2-butenyl and the
like.
"Lower alkynyl" groups include those alkynyl
groups of 2 to 7 carbon atoms. Examples of lower
alkynyl groups include-ethynyl, propargyl,
3-methyl-1-pentynyls 2-heptynyl and the like.
As used herein, the term "lower alkoxy"
includes those alkoxy groups of from 1 to 7 carbon
atoms of a ætraight, branched, or cyclic
configuration. Examples of lower alkoxy groups
include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy, and the like.
The term "monocyclic monoheterocyclic ring"
which defines R23 includes those monocyclic groups of
5 to 7 members containing only 1 heteroatom selected
from N, S or 0 in the ring. Examples include
tetrahydrofuran, tetrahydrothiophene, pyrrolidine,
piperidine, tetrahydropyran, and the like.
The term "monocyclic or bicyclic
heterocyclic ring" which defines R19 may be
2,5-dioxo-1-pyrrolidinyl, (3-pyridinylcarbonyl)
amino, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl,
1,3-dihydro-2H-isoindol-2-yl,
1 ~37427
Fl
6/DAM2 - 9 - 17940
2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl,
2-imidazolyl, 2-oxo-1,3-dioxolen-4-yl,
piperidin-l-yl, morpholin-l-yl, piperazin-l-yl and
the like.
The point of attachment of any heterocyclic
ring may be at any free valence of the ring.
The term standard amino acid is employed to
include the following amino acids: alanine,
asparagine, aspartic acid, arginine, cysteine,
glutamic acid, glutamine, glycine, histidine,
isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine,
tryptophan, tyrosine and valine. (See F.H.C. Crick,
Symposium of the Society for Experimental Biology,
1958 (12) p. 140.)
It is understood that Rl and R2 may be
located at any of positions 3,4,5,6,7 or 8 of the
quinoline ring.
As used herein the term "lower alkylthio'l
includes those alkylthio groups of from 1 to 7 carbon
atoms of a straight, branched or cyclic
configuration. Examples of lower alkylthio groups
include methylthio, propylthio, isopropylthio,
cycloheptylthio, etc. By way of illustration, the
propylthio group signifies -SCH2CH2CH3.
The terms Ph(R10)2 and Th(R10)2 indicate a
phenyl or thienyl group substituted with two R10
substituents.
Halogen includes F, Cl, Br, and I.
It is intended that the definitions of any
substituent (e.g., Rl, R2, R15, Ph(R10)2, etc.) in a
particular molecule be independent of its definitions
elsewhere in the molecule. Thus, -NR15R15 represents
I 337427
Fl
6/DAM2 - 10 - 17940
-NHH, -NHCH3, -NHC6H5, etc.
The monocyclic heterocyclic rings formed
when two R15 groups join through N include
pyrrolidine, piperidine, morpholine, thiamorpholine,
piperazine, and N-methylpiperazine.
The prodrug esters of Q (i.e., when Q =
Co2R17) are intended to include the esteræ such as
are described by Saari et al., J. Med. Chem., 21, No.
8, 746-753 (1978), Sakamoto et al., Chem. Pharm.
Bull., 32, No. 6, 2241-2248 (1984) and Bundgaard et
al., J. Med. Chem., 30, No. 3, 451-454 (1987).
Some of the compounds described herein contain
one or more asymmetric centers and may thus give rise
to diastereomers and optical isomers. The present
invention is meant to comprehend such possible
diastereomers as well as their racemic and resolved,
enantiomerically pure forms and pharmaceutically
acceptable salts thereof.
The pharmaceutical compositions of the
present invention comprise a compound of Formula I as
an active ingredient or a pharmaceutically acceptable
salt, thereof, and may also contain a
pharmaceutically acceptable carrier and optionally
other therapeutic ingredients. The term
"pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic
bases including inorganic bases and organic bases.
Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic salts, manganous, potassium,
sodium, zinc and the like. Particularly preferred
are the ammonium, calcium, magnesium, potassium and
~ 337~27
Fl
6/DAM2 - 11 - 17940
sodium salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include æalts of
primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins,
such as arginine, betaine, caffeine, choline,
N,Nl-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine,
hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the
like.
When the compound of the present invention
is basic, salts may be prepared from pharmaceutically
acceptable non-toxic acids, including inorganic and
organic acidæ. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric,
ethanesulfonic, fumaric, gluconic, glutamic,
hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic,
nitric, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric, p-toluenesulfonic acid and the
like. Particularly preferred are citric,
hydrobromic, hydrochloric, maleic, pho~phoric,
sulfuric and tartaric acids.
It will be understood that in the discussion
of methods of treatment which follows, references to
the compounds of Formula I are meant to also include
the pharmaceutically acceptable salts.
1 331427
Fl
6/DAM2 - 12 - 17940
The ability of the compounds of Formula I to
inhibit biosynthesis of the leukotrienes makes them
useful for inhibiting the symptoms induced by the
leukotrienes in a human subject. This inhibition of
the mammalian biosynthesis of leukotrienes indicates
that the compounds and pharmaceutical compositions
thereof are useful to treat, prevent, or ameliorate
in mammals and especially in humans: 1) pulmonary
conditions including diseases such as asthma, 2)
lo allergies and allergic reactions such as allergic
rhinitis, contact dermatitis, allergic
conjunctivitis, and the like, 3) inflammation such as
arthritis or inflammatory bowel disease, 4) pain, 5)
skin conditions such as psoriasis and the like, 6)
cardiovascular conditions such as angina, endotoxin
shock, and the like and 7) renal insufficiency
arising from ischaemia induced by immunological or
chemical (cyclosporin) etiology, and that the
compounds are cytoprotective agents.
The cytoprotective activity of a compound
may be observed in both animals and man by noting the
increased resistance of the gastrointestinal mucosa
to the noxious effects of strong irritants, for
example, the ulcerogenic effects of aspirin or
indomethacin. In addition to lessening the effect of
non-steroidal anti-inflammatory drugs on the
gastrointestinal tract, animal studies show that
cytoprotective compounds will prevent gastric lesions
induced by oral administration of strong acids,
strong bases, ethanol, hypertonic saline solutions
and the like.
Fl 1 3 3 7 4 2 7
6/DAM2 - 13 - 17940
Two assays can be used to meaæure
cytoprotective ability. These assays are; (A) an
ethanol-induced lesion assay and (B) an
indomethacin-induced ulcer assay and are described in
EP 140,684.
The magnitude of prophylactic or therapeutic
dose of a compound of Formula I will, of course, vary
with the nature of the severity of the condition to
be treated and with the particular compound of
Formula I and its route of administration. It will
also vary according to the age, weight and response
of the individual patient. In general, the daily
dose range for anti-asthmatic, anti-allergic or
anti-inflammatory use and generally, uses other than
cytoprotection, lie within the range of from about
0.001 mg to about 100 mg per kg body weight of a
mammal, preferably 0.01 mg to about 10 mg per kg, and
most preferably 0.1 to 1 mg per kg, in single or
divided doses. On the other hand, it may be
necessary to use dosages outsi-de these limits in some
cases.
For use where a composition for intravenous
administration is employed, a suitable dosage range
for anti-asthmatic, anti-inflammatory or
2s anti-allergic use is from about 0.001 mg to about 25
mg (preferably from 0.01 mg to about 1 mg) of a
compound of Formula I per kg of body weight per day
and for cytoprotective use from about 0.1 mg to about
100 mg (preferably from about 1 mg to about 100 mg
and more preferably from about 1 mg to about 10 mg)
of a compound of Formula I per kg of body weight per
day.
1 337427
Fl
6/DAM2 - 14 - 17940
In the case where an oral composition is
employed, a suitable dosage range for anti-asthmatic,
anti-inflammatory or anti-allergic use is, e.g. from
about 0.01 mg to about 100 mg of a compound of
Formula I per kg of body weight per day, preferably
from about 0.1 mg to about 10 mg per kg and for
cytoprotective use from 0.1 mg to about 100 mg
(preferably from about 1 mg to about 100 mg and more
preferably from about 10 mg to about 100 mg) of a
compound of Formula I per kg of body weight per day.
For the treatment of diseases of the eye,
ophthalmic preparations for ocular administration
comprising 0.001-1% by weight solutions or
suspensions of the compounds of Formula I in an
acceptable ophthalmic formulation may be used.
The exact amount of a compound of the
Formula I to be used as a cytoprotective agent will
depend on, inter alia, whether it is being
administered to heal damaged cells or to avoid future
d~amage, on the nature of the damaged cells (e.g.,
gastrointestinal ulcerations vs. nephrotic necrosis),
and on the nature of the causative agent. An example
of the use of a compound of the Formula I in avoiding
future damage would be co-administration of a
compound of the Formula I with a non-steroidal
anti-inflammatory drug (NSAID) that might otherwise
cause æuch damage ~for example, indomethacin). For
such use, the compound of Formula I is administered
from 30 minutes prior up to 30 minutes after
administration of the NSAID. Preferably it is
administered prior to or simultaneously with the
NSAID, (for example, in a combination dosage form).
1 337427
Fl
6/DAM2 - 15 - 17940
Any suitable route of administration may be
employed for providing a mammal, especially a human
with an effective dosage of a compound of the present
invention. For example, oral, rectal, topical,
parenteral, ocular, pulmonary, nasal, and the like
may be employed. Dosage forms include tablets,
troches, dispersions, suspensions, solutions,
capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the
present invention comprise a compound of Formula I as
an active ingredient or a pharmaceutically acceptable
salt thereof, and may also contain a pharmaceutically
acceptable carrier and optionally other therapeutic
ingredients. The term "pharmaceutically acceptable
lS saltsll refers to salts prepared from pharmaceutically
acceptable non-toxic bases or acids including
inorganic bases or acids and organic bases or acids.
The compositions include compositions
suitable for oral, rectal, topical, parenteral
(including subcutaneous, intramuscular, and
intravenous), ocular (ophthalmic), pulmonary (nasal
or buccal inhalation), or nasal administration,
although the most suitable route in any given case
will depend on the nature and severity of the
conditions being treated and on the nature of the
active ingredient. They may be conveniently
presented in unit dosage form and prepared by any of
the methods well-known in the art of pharmacy.
For administration by inhalation, the
compounds of the present invention are conveniently
delivered in the form of an aerosol spray
presentation from pressurized packs or nebulisers.
1 331427
Fl
6/DAM2 - 16 - 17940
The compounds may also be delivered as powders which
may be formulated and the powder composition may be
inhaled with the aid of an insufflation powder
inhaler device. The preferred delivery system for
inhalation is a metered dose inhalation (MDI)
aerosol, which may be formulated as a suspension or
æolution of Compound I in suitable propellants, such
as fluorocarbons or hydrocarbons.
Suitable topical formulations of Compound I
include transdermal devices, aerosols, creams,
ointments, lotions, dusting powders, and the like.
In practical use, the compounds of Formula I
can be combined as the active ingredient in intimate
admixture with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms
depending on the form of preparation desired for
administration, e.g., oral or parenteral (including
intravenous). In preparing the compositions for oral
dosage form, any of the usual pharmaceutical media
may be employed, such as, for example, water,
glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like in the
case of oral liquid preparations, æuch as, for
example, suspensions, elixirs and solutions; or
carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like in the
case of oral solid preparations such as, for example,
powders, capsules and tablets, with the solid oral
preparations being preferred over the liquid
preparations. Because of their ease of
I ~37427
Fl
6/DAM2 - 17 - 17940
administration, tablets and capsules represent the
most advantageous oral dosage unit form in which case
solid pharmaceutical carriers are obviously
employed. If desired, tablets may be coated by
standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set
out above, the compounds of Formula I may also be
administered by controlled release means and/or
delivery devices ~uch as those described in U.S.
Patent Nos. 3,845,770; 3,916,899; 3,536,809;
3,598,123; 3,630,200 and 4,008,719.
Pharmaceutical compositions of the present
invention suitable for oral administration may be
presented as discrete units such as capsules, cachets
- or tablets each cont-aining a predetermined amount of
the active ingredient, as a powder or granules or as
a solution or a suspension in an aqueous liquid, a
non-aqueous liquid, an oil-in-water emulsion or a
water-in-oil liquid emulsion. Such compositions may
be prepared by any of the methods of pharmacy but all
methods include the step of bringing into association
the active ingredient with the carrier which
constitutes one or more necessary ingredients. In
general, the compositions are prepared by uniformly
and intimately admixing the active ingredient with
liquid carriers or finely divided solid carriers or
both, and then, if necessary, shaping the product
into the desired pre~entation. For example, a tablet
may be prepared by compression or molding, optionally
with one or more accessory ingredients. Compressed
tablets may be prepared by compressing in a suitable
1 ;~37427
Fl
6/DAM2 - 18 - 17940
machine, the active ingredient in a free-flowing form
such as powder or granules, optionally mixed with a
binder, lubricant, inert diluent, surface active or
dispersing agent. Molded tablets may be made by
molding in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid
diluent. Desirably, each tablet contains from about
2.5 mg to about 500 mg of the active ingredient and
each cachet or capsule contains from about 2.5 to
about 500 mg of the active ingredient.
The following are examples of representative
pharmaceutical dosage forms for the compounds of
Formula I:
lS
Fl 1 3 3 7 4 2 7
6/DAM2 - 19 - 17940
Injectable Suspension (I.M.) ~/ml
Compound of Formula I 10
Methylcellulose 5.0
5 TweenT~80 0.5
Benzyl alcohol 9.0
Benzalkonium chloride 1.0
Water for injection to a total volume of 1 ml
lO Tablet mg/tablet
Compound of Formula I 25
Microcrystalline Cellulose 415
! Providone 14.0
Pregelatinized Starch 43.5
Magnesium Stearate
500
Capsule ~/capsule
Compound of Formula I 25
20 Lactose Powder 573 5
Magnesium Stearate 1.5
600
AeroRol Per canister
25 Compound of Formula I 24 mg
Lecithin, NF Liquid Concentrate 1.2 mg
Trichlorofluoromethane, NF 4.025 gm
Dichlorodifluoromethane, NF 12.15 gm
~ '
1 337427
Fl
6/DAM2 - 20 - 17940
In addition to the compounds of Formula I,
the pharmaceutical compositions of the present
invention can also contain other active ingredients,
such as cyclooxygenase inhibitors, non-steroidal
anti-inflammatory drugs (NSAIDs), peripheral
analgesic agents such as zomepirac diflunisal and the
like. The weight ratio of the compound of the
Formula I to the second active ingredient may be
varied and will depend upon the effective dose of
each ingredient. Generally, an effective dose of
each will be used. Thus, for example, when a
compound of the Formula I is combined with an NSAID
the weight ratio of the compound of the Formula I to
the NSAID will generally range from about 1000:1 to
about 1:1000, preferab~y about 200:1 to about 1:200.
Combinations of a compound of the Formula I and other
active ingredients will generally also be within the
aforementioned range, but in each case, an effective
dose of each active ingredient should be used.
20 ~ NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;
(4) the biphenylcarboxylic acid derivatives;
and
(5) the oxicams
or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be
used comprise: alminoprofen, benoxaprofen, bucloxic
acid, carprofen, fenbufen, fenoprofen, fluprofen,
flurbiprofen, ibuprofen, indoprofen, ketoprofen,
1 337427
Fl
6/DAM2 - 21 - 17940
miroprofen, naproxen, oxaprozin, pirprofen,
prano-profen, suprofen, tiaprofenic acid, and
tioxaprofen. Structurally related propionic acid
derivatives having similar analgesic and
anti-inflammatory properties are also intended to be
included in this group.
Thus, ~'propionic acid derivatives" as
defined herein are non-narcotic
analgesics/non-steroidal anti-inflammatory drugs
lo having a free -CH(CH3)COOH or -CH2CH2COOH group
(which optionally can be in the form of a
pharmaceutically acceptable salt group, e.g.,
-CH(CH3)COO~Na+ or -CH2CH2COO~Na+),
typically attached directly or via a carbonyl
function to a ring system, preferably to an aromatic
ring system.
The acetic acid derivatives which may be
used comprise: indomethacin, which is a preferred
NSAID, acemetacin, alclofenac, clidanac, diclofenac,
fenclofenac, fenclozic acid, fentiazac, furofenac,
ibufenac, isoxepac, oxpinac, sulindac, tiopinac,
tolmetin, zidometacin and zomepirac. Structually
related acetic acid derivatives having similar
analgesic and anti-inflammatory properties are also
intended to be encompassed by this group.
Thus, "acetic acid derivatives" as defined
herein are non-narcotic analgesics/non-steroidal
anti-inflammatory drugs having a free -CH2COOH group
(which optionally can be in the form of a
pharmaceutically acceptable salt group, e.g.
-CH2COO~Na+), typically attached directly to a ring
system, preferably to an aromatic or heteroaromatic
ring system.
1 3374~7
Fl
6/DAM2 - 22 - 17940
The fenamic acid derivatives which may be
used comprise: flufenamic acid, meclofenamic acid,
mefenamic acid, niflumic acid and tolfenamic acid.
Structurally related fenamic acid derivatives having
similar analgesic and anti-inflammatory properties
are also intended to be encompassed by this group.
Thus, "fenamic acid derivatives" as defined
herein are non-narcotic analgesics/non-steroidal
anti-inflammatory drugs which contain the basic
structure:
~ H
CO2H
which can bear a variety of substituents and in which
the free -COOH group can be in the form of a
pharmaceutically acceptable salt group, e.g.,
-COO~Na+.
The biphenylcarboxylic acid derivatives
which can be used comprise: diflunisal and
flufenisal. Structurally related biphenylcarboxylic
acid derivatives having similar analgesic and
anti-inflammatory properties are also intended to be
encompassed by this group.
Thus, ~biphenylcarboxylic acid derivatives"
as defined herein are non-narcotic
analgesics/non-steroidal anti-inflammatory drugs
which contain the basic structure:
1 ~37427
Fl
6/DAM2 - 23 - 17940
~'i
C2 H
which can bear a variety of substituents and in which
the free -COOH group can be in the form of a
pharmaceutically acceptable salt group, e.g.,
-COO-Na+.
The oxicams which can be used in the present
invention comprise: isoxicam, piroxicam, sudoxicam
and tenoxican. Structurally related oxicams having
similar analgesic and anti-inflammatory properties
are also intended to be encompassed by this group.
Thus, "oxicams" as defined herein are non_
narcotic analgesics/non-steroidal anti-inflammatory
drugs which have the general formula:
OH
C( O) NHR
/j~\ 3
O O
wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used:
amfenac sodium, aminoprofen, anitrazafen,
antrafenine, auranofin, bendazac lysinate,
benzydanin~, beprozin, broperamole, bufezolac,
cinmetacin, ciproquazone, cloximate, dazidamine,
1 337427
Fl
6/DAM2 - 24 - 17940
deboxamet, delmetacin, detomidine, dexindoprofen,
diacerein, di-fisalamine, difenpyramide, emorfazone,
enfenamic acid, enolicam, epirizole, etersalate,
etodolac, etofenamate, fanetizole mesylate,
fenclorac, fendosal, fenflumizole, feprazone,
floctafenine, flunixin, flunoxaprofen, fluproquazone,
fopirtoline, fosfosal, furcloprofen, glucametacin,
guaimesal, ibuproxam, isofezolac, isonixim,
isoprofen, isoxicam, lefetamine HCl, leflunomide,
lofemizole, lonazolac calcium, lotifazole,
loxoprofen, lysin clonixinate, meclofenamate sodium,
meseclazone, nabumetone, nictindole, nimesulide,
orpanoxin, oxametacin, oxapadol, perisoxal citrate,
pimeprofen, pimetacin, piproxen, pirazolac,
pirfenidone, proglumetacin maleate, proquazone,
pyridoxiprofen, sudoxicam, talmetacin, talniflumate,
tenoxicam, thiazolinobutazone, thielavin B, tiaramide
HCl, tiflamizole, timegadine, tolpadol, tryptamid and
ufenamate.
The following NSAIDs, designated by company
code number (see e.g., Pharmaprojects), may also be
used:
480156S, M861, AD1590, AFP802, AFP860, AI77B, AP504,
AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382,
EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4,
LA2851, MR714, MR897, MY309, ONO3144, PR823, PV102,
PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510,
SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-
indancarboxylic acid), TVX2706, U60257, UR2301, and
WY41770.
Finally, NSAIDs which may also be used include
the salicylates, specifically acetyl salicylic acid
Fl ~ 3 3 7 ~ 2 1
6/DAM2 - 25 - 17940
and the phenylbutazones, and pharmaceutically
acceptable salts thereof.
In addition to indomethacin, other preferred
NSAIDS are acetyl salicylic acid, diclofenac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen,
~etoprofen, naproxen, phenylbutazone, piroxicam,
sulindac and tolmetin.
Pharmaceutical compositions comprising the
Formula I compounds may also contain inhibitors of
the biosynthesis of the leukotrienes such as are
disclosed in EP 138,481 (April 24,1985), EP 115,394
(August 8, 1984), EP 136,893 (April 10, 1985), and EP
140,709 (May 8, 1985).
The compounds of the Formula I may also be
used in combination with leukotriene antagonists such as
those disclosed in EP 106,565 (April 25, 1984) and EP
104,885 (April 4, 1984), and others known in the art such
as those disclosed in EP Application Nos. 56,172 (July
21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent
Specification No. 2,058,785 (April 15, 1981).
2s Pharmaceutical compositions comprising the
Formula I compounds may also contain as the second
active ingredient, prostaglandin antagonists such as
those disclosed in EP 11,067 (May 28, 1980) or
thromboxane antagonists such as those disclosed in
~.S. Pat. 4,237,160. They may al80 contain histidine
decarboxylase inhibitors such as
a-fluoromethylhistidine, described in U.S. Pat.
4,325,961. The compounds of the Formula I may also
be advantageously combined with an Hl or H2-receptor
Fl 1 337427
6/DAM2 - 26 - ~ 17940
antagoniæt, such as for instance acetamazole,
aminothiadiazoles disclosed in EP 40,696 (December 2,
1981), benadryl, cimetidine, famotidine, framamine,
histadyl, phenergan, ranitidine, terfenadine and like
compounds, such as those disclosed in ~.S. Patent
Nos. 4,283,408; 4,362,736; and 4,394,508. The
pharmaceutical compositions may also contain a K+/H+
ATPase inhibitor such as omeprazole, disclosed in
U.S. Pat. 4,255,431, and the like. Compounds of
Formula I may also be usefully combined with most
cell stabilizing agents, such as
1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane
and related compounds described in British Patent
Specifications 1,144,905 and 1,144,906. Another
useful pharmaceutical composition comprises the
Formula I compounds in combination with serotonin
antagonists such as methysergide, the serptonin
antagonists described in ~ature, Vol. 316, pages
126-131, 1985, and the like.
-
Other advantageous pharmaceutical
compositions comprise the Formula I compounds in
combination with anti-cholinergics such as
ipratropium bromide, bronchodilators such as the beta
agonist salbutamol, metaproterenol, terbutaline,
fenoterol and the like, and the anti-asthmatic drugs
theophylline, choline theophyllinate and
enprofylline, the calcium antagonists nifedipine,
diltiazem, nitrendipine, verapamil, nimodipine,
felodipine, etc. and the corticosteroids,
hydrocortisone, methylprednisolone, betamethasone,
dexamethasone, beclomethasone, and the like.
~'.
Fl 1 3 3 7 4 2 7
6/DAM2 - 27 - 17940
Compounds of the present invention can be
prepared according to the following methods.
Temperatures are in degree Celsius.
The starting methoxy phenylhydrazines II are
either commercially available or are deæcribed in the
chemical literature as are the acetamidophenols
ggVI. The benzyl phenylhydrazine starting materials
III are prepared as described in EP 166,591 (17102
IA) and the ketones IV are prepared as described in
EP 275,667 (17496 IA). The 2-(halomethyl)quinolines
VII are available from literature methods described
in "Quinolines" Parts I and II, G. Jones (ED.), John
Wiley & Sons, Toronto, 1977 and 1982. The
preparation of VII by halogenation of the
corresponding 2-methylquinolines is also described in
the Jones' volumes. The benzyl halides, (R10)2
PhCH2-Hal, are readily prepared and many such
compounds are described in the prior art, such as
U.S. Patent 4,808,608 (17323 IB). Hal in VII and
(R10)2 PhCH2-Hal represents Cl, Br or I.
Many syntheses of indoles are well-known in
the chemical literature: see for example,
"Heterocyclic compounds" Volume 25, Parts I, II, III,
W.J. Houlihan (Ed.), Interscience, J. Wiley ~ Sons,
N.Y., 1979, and "The Chemistry of Indoles" by R.J.
Sundberg, Academic Press, N.Y., 1970. One of the
most common syntheses is known as the Fischer Indole
Synthesis, and is abbreviated in the following
methods as "Fischer".
The -CO2H and -CO2R12 groups in the
intermediates and final products in the various
methods can be transformed to other representatives
of Q such as -CoNHS(0)2R14, -NHS(0)2R14, -CoNR15R15,
Fl ~ s37427
6/DAM2 - 28 - 17940
-CH2OH or tetrazol-5-yl by the methodology described
in U.S. Patent 4,808,608 (17323IV). The preparation
of the pro-drug forms (Q is -Co2R17) from the acids
may be effected by the methodology of EP 104,885
(published April 4, 1984) (16830 IA).
It will be apparent to one s~illed in the
art that the various functional groups (Rl, R2, Y, Q,
etc.) must be chosen 80 as to be compatible with the
chemistry being carried out. Such compatibility can
lo often be achieved by protecting groups, or by
specific variations in the sequence of the reactions.
When R5 is S-R7, the corresponding
sulfogides and sulfones can be prepared by oxidation
of the sulfides with one or two equivalents of an
oxidizing agent such as m-chloroperbenzoic acid or
monoperoxyphthalic ~cid or oxone (Trost, J. Org.
Chem.,~1988, pg.532).
Many of the following methods involve a
basic hydrolysis of an ester function to obtain the
corresponding carboxylic acid. In all cases, the
free acid i8 obtained by acidification of the
reaction mixture with a suitable acid such as
hydrochloric, sulfuric, acetic, trifluoroacetic acid,
etc.
Compounds VIII, XI, ~, XIX, XXXVI and their
precursor esters are all examples of the Formula I
compounds of the present invention.
,.. ~
1 337427
Fl
6/DAM2 - 29 - 17940
Method I
R4~ R4
M~O I ( Rlo)2pbcH2-H~l MeO ;~
~IHNH2 NE13/ Bu4N)3' / CH2C12 ~ 3~ - -3 H2
_5 .Il R ~/
R 1 0
~Rll Rll 1 ) F3scHER/~
p C02R~2
R4 R5 R4 R5
HO--~~'Rl~ R~l 1) N~s-l-E~ulHJ~3pA M~O ~ ~
R3 N ~ C02Mc 2 ) CH2N.2 ~ p C02H
3~10 ~ Vl
R] R5 S-R7
,~ 1 )K2C031DMFI VII I ~ ~3C13/EISH /CH,C12
~ ~ ~HAL 2 ) LiOH 2 ) CH23'2
R2 VII
R ' ~^~-- R4 R5 R4 H
2 0 ~_~ ~ ~ ~/ , COzH HO _ ~ p CO2M
R10~R10{~ ~X
R R10
VIII ( I ) 1 ) R'COC3 / A~C33 / C2H~C12
2 5 2 ) N OM I McOH
R4 R33 R31 1) K2CO3/DMF/VII R4 Cl~IORRll
"l~o ~N P C2H ) Li HO ~ 02~c
R10~ X~ ( I ) Rlo ~ X
1 337427
Fl
6/DAM2 - 30 - 17940
Method 1
Intermediate y is prepared by a Fischer
reaction between benzylphenylhydrazine III and ketone
IV, followed by hydrolysis with an aqueous golution
of an alkali hydroxide or other suitable hydroxide in
mixture with a suitable water miscible organic
solvent such as tetrahydrofuran (THF) or methanol
(MeOH). The methoxy acid V is demethylated by
heating with an alkali salt of an aliphatic thiol in
a suitable solvent such as hexamethylphosphorictri-
amide (HMPA) or N-methylpyrrolidone (NMP). The
reaction mixture is acidified and the crude acid so
obtained is converted to the methyl ester VI by
treatment with diazomethane. The phenol VI is
coupled to the 2-halomethylquinoline VII, by stirring
with a base (preferably an alkali hydride or
carbonate) in a suitable solvent such as dimethyl
formamide (DMF), NMP, acetone or the like. The
resulting ester is hydrolysed by base to yield VIII,
a compound of the present invention.
When intermediate V contains a sulfide group
attached to position 3, treatment with a Lewis acid,
such as AlC13, and an aliphatic thiol, simultaneously
effects demethylation and removes the sulfide group.
Suitable solvents for this reaction are methylene
chloride, 1,2-dichloroethane, etc. The resulting
acid is then converted to the methyl ester IX with
diazomethane. A Friedel-Crafts reaction between IX
and an acid chloride, R7COCl, simultaneously
introduces the acyl substituent into the 3-position
of the indole ring and onto the phenolic hydroxyl
group. The acyl group is removed from the phenol by
1 337427
Fl
6/DAM2 - 31 - 17940
treatment with sodium methoxide in MeOH to yield
acylphenol ~. Phenol X is coupled with VII as
described for the coupling of VI and VII above. In
these coupling reactionæ, it i8 at times advantageous
to add a catalyst such as potassium iodide or
tetraethylammonium bromide, especially when Hal is
chlorine. A final hydrolysis yields compound XI.
Fl 1 337427
6/DAM2 - 32 - 17940
Method 2
R4 R5
FISCHER MeO ~/RIl R~
+ lV ~ , /~co2R~2
R- H
1 ) 1CHMDS /THF / 78~
2 ) R H~l/
0 4
R~ RR151 R~ cl3lE~sHlc2H4c~2 ~HR~I Rll
McO ~ C02R~2 R5 ~ s-R7 ' ~ C02R~2
R xnl xvl
1 , ~ LiOH 1 ) R7COCI /NE13 /THF
2 ) Na S-t-Bu / H~PA ~ 2 ) R7CoC3 / AIC13 / C2H~C12
3 ) CH2~2 , ~ X~II
R4 COR7
~/Rll Rl~ ~ ) NacNBH3lzsll2lc2H4cl2R7co2~ - Rll ~
>0 - ~N~ 2) NaOMe/MeOH R~ 18 p C02R12
R Xlv XVIII
I ) N~OMe / M~OH
1 ) K2CO3 / DMF / VII 2 ) K2C03 / DMF /
2 ) LiOH 3 ) LiOH
k ~CO~H ~ ~OIH
XV (}) XIX (1~
Fl 1 3 3 7 4 2 7
6/DAM2 - 33 - 17940
Method 2
Intermediate XII is prepared by a Fischer
reaction between methoxyphenyl hydrazine II and
ketone IV, followed by alkylation of the indole
nitrogen, after deprotonation using potassium
hexamethyldisilazane in an ether solvent such as
tetrahydrofuran (THF), with an alkyl or aralkyl
halide.
The methoxy group in XIII is removed using
the conditions of Method l. The corresponding phenol
XIV is now coupled with the 2-halomethylquinoline VII
by stirring with a base (preferably an alkali hydride
or carbonate) in a suitable solvent such as DMF, NMP
or the like. The resulting ester is hydrolysed using
base to yield XV a compound of the present invention.
When intermediate XIII contains a sulfide at
position 3, treatment with a Lewis acid such as AlCl3
and an aliphatic thiol simultaneously effects
demethylation and removes the sulfide group.
Suitable solvents for this reaction are
dichloromethane or dichloroethane. In a variation of
Method l, the phenolic hydroxyl in XVI is first
acylated with the reagent R7COCl (XVII) in the
presence of a weak base such as triethylamine. A
Friedel-Crafts reaction is then carried out on the
O-acylated intermediate, with an additional mole of
XVII and AlCl3, to yield the intermediate XVIII.
Acyl ester XVIII may then be reduced to a 3-alkyl
indole XIV using sodium cyan-
oborohydride in dichloroethane using a zinc iodidecatalyst.
Acyl ester XVIII is cleaved to the indole
phenol by hydrolysis with sodium methoxide in
methanol and is coupled to 2-halomethyl quinoline VII
Fl 1 3 3 7 4 2 7
6/DAM2 - 34 - 17940
using a base such aæ an alkali hydride or carbonate
in a solvent such as DMF or NMP. Hydrolysis of the
resulting compound using base yields the compound of
the present invention XIX.
~ THOD 3
10 R4 R4 R4
~ (CH3~3C~oCI ~ I ) HCI/N~N02 ~\
t~ !J~ ~(CH3~3CC021 11 , (CH3)3CCO+ ll
R3~ NH2 R3NH2 2 ) N~2S24 R~NHNH2
xx ~ x~a
/(R10)2PnCH2H~
l NE13 / Bu4NBr / CH2C12
R4 R5 R4
~RIl Rll PISCHER / IV
(CU33CC02-- ~`C02RI~ (CU33CC02~$~ ,N3
N~OMe / MeOH
as ~er l`~l~t h~ 1
Vl ~ Vm(I)
1 337427
Fl
6/DAM2 - 35 - 17940
Method 3
A suitably substituted aminophenol XX is
protected on oxygen by the use of pivaloyl chloride
dissolved in CH2C12 using triethyl amine as base.
The pivaloate ester XXI is then diazotized using
hydrochloric acid and sodium nitrite in an aqueous
solvent and the transient diazonium species reduced
in æitu to the hydrazine XXII using sodium
hydrosulfite in water. Benzylation of the hydrazine
is effected as described in Method 1.
The 0-pivaloyl-N-benzylhydrazine XXIII is
subjected to a Fischer indolization using the
appropriate ketone IV to produce the indole XXIV.
Cleavage of the 0-pivaloyl group using sodium
methoxide in methanol transforms the product into the
phenolic indole VI which is converted to the products
of this invention as described in Method 1.
~ THOD 4
R4 R5
X~ IV FISCHER ~ ~11 2 ) R8-H~ p Me~hDd 2
R3 N C02R12 3 ) ~OMelMeOH
XXV
1 337427
Fl
6/DAM2 - 36 - 17940
Method 4
The pivaloyloxyphenylhydrazine XXII is used
directly in the Fischer indolization using ketone
IV. N-Alkylation of the indole XXV, as described in
Method 2, followed by removal of the pivaloyl group
as described, yields the phenolic indole XIV which is
converted as described in Method 2 to the products of
this invention.
1 337427
Fl
6/DAM2 - 37 - 17940
Method 5
R4K2CO3 / DMF / VII R~ R4
~NHAc R~ ~NHAc
o R R3
XXVI XXVII
KOH t 4. ErOH / Heu
R~ I)HCI/NNO2 Rl ~_
R2 R32) N~2524 R2 R3 NH2
XX~ XXVIII
( Rl )2PhCH2-H~I
2 0 ( i-Pr)2NEI / Bu4NBr / CH2CI2
Rl
~ ,~I)FISCHER/ IV
R3 N~--O ,~``N'2 2 ) UOH vm ( I )
2 5 Rl~J
R10
Fl 1 33 7 4 2 7
6/DAM2 - 38 - 17940
Method 5
A suitable N-acetylated aminophenol XXVI is
reacted with VII using an alkali hydride or
carbonate, such as potassium carbonate as a base in a
polar solvent like DMF or NMP. The quinolinylmethoxy
acetanilide XXVII is then de-acetylated using
standard basic conditions, preferably using alcoholic
potassium hydroxide under reflux to produce the
quinolinylmethoxy aniline derivative XXVIII.
Conversion of the quinolinylmethoxy aniline
derivative to the hydrazine analogue XXIX is effected
through reduction of the intermediate diazonium salt
using sodium hydrosulfite in an aqueous medium.
The hydrazine XXIX is then N-benzylated
using a benzyl halide in an organic solvent such as
methylene chloride containing an amine base such as
diisopropylethylamine and preferably
tetra-n-butylammonium bromide as catalyst.
The hydrazine XXX is then processed using a
~ischer indolization with ketone IV according to
Methods 1, 2, 3 and 4 to produce compounds of the
present invention.
Fl 1 33 7 4 2 7
6/DAM2 - 39 - 17940
Method 6
R5~J~ 2 ) IUMD5/THl~/R8H~1 ~ ~C02R12
XXXI R8
X~
~H4 /THF /
/ RIlMgBr
15 ~ ~1 ,o~ ~u~
~WV XX~ '
Rll \ I ) N HtTHF/ XXXV
20S~ \ 2) LiOH
H CO2Me
X~V
2 5 ~'\~ ~ P Co2H
~CXVI ( I )
1 337427
Fl
6/DAM2 - 40 - 17940
Method 6
Hydrazine XXIX may also be transformed
directly to unsubstituted indoles by a Fischer
reaction with various ketones like XXXI.
N-Alkylation of the indoles is effected using the
conditions described in Method 2 to produce
quinolinylmethoxyindole alkanoate esters XXXII. Such
esters are transformed to ketones or carbinols via
Grignard conditions using alkyl magnesium halides in
ether solvents like diethyl ether or through the use
of lithium aluminum hydride in ether solvents like
THF. The carbinols XXXIV so produced may be further
transformed into ester compounds of the present
invention by reacting with a-halo esters XXXV using
sodium hydride as base in a suitable solvent like
THF. Subsequent hydrolysis of the esters using
Method 1 leads to acid compounds of the present
invention.
Fl 1 3 3 7 4 2 7
6/DAM2 - 41 - 17940
Representative Compounds
Table I illustrates compounds ha~ing the formula
Ia representative of the present invention. "Attach
point" is the position on the indole nucleus where
the quinolylmethoxy moiety is attached.
~ ~5
8 Ia
R
Assays for Determining Biological Ac~ivity
Compounds of Formula I can be tested using the
following assays to determine their mammalian
leukotriene biosynthesis inhibiting activity.
Rat Peritoneal Polymorphonuclear (PMN) Leukocyte
Assay
Rats under ether anesthesia are injected
(i.p.) with 8 mL of a suspension of sodium caseinate
(6 grams in ca. 50 mL water). After 15-24 hr. the
rats are sacrificed (CO2) and the cells from the
peritoneal cavity are recovered by lavage with 20 mL
of buffer (Eagles MEM containing 30 m~ HEPES adjusted
to p~ 7.4 with NaOH). The cells are pelleted (350 x
g, 5 min.), resuspended in buffer with vigorous
shaking, filtered through lens paper, recentrifuged
and finally ~uspended in buffer at a concentration of
10 cells/mL. A 500 mL aliquot of PMN
1 337427
Fl
6/DAM2- 42 - 17940
TABLE I
R~CH20 ~ CHz-Y-~CR~lR~1)p-COzH
R~ I~
Ex Rl R2 R3 ATTACH R8 R5 Y (cRllRll
No. POINT
1 H,H H 5 -CH2Ph-1 Cl -S-t-Bu C(Me)2
2 H,H H 5 -CH2Ph 1 Cl Me C(Me)2
3 H,H H 5 -CH2Ph-4-S-t-Bu -S-t-Bu C(Me)2
4 H,H H 5 -CH2Ph ~ Cl -SPh C(Me)2
6 H,H H 5 -CH2Ph ~ Cl _S(0)2Ph C(Me)2
7 H,H H 5 -CH2Ph 1 Cl -S(O)Ph C(Me)2
2 0 8 H,H H 5 -CH2Ph ~ Cl H C(Me)2
9 H,H H 5 -CH2Ph-1 Cl -C(O)Ph C(Me)z
lû H,H H 5 -CH2Ph ~ Cl -CH2Ph C(Me)2
11 H,H H 5 -CH2Ph 1 Cl -C(O)CH2-t-Bu C(Me)2
12 H,H H 5 -CH2Ph ~ Cl -S-t-Bu CH20CH
13 H,H H 5 -CH2Ph-4-Cl -CH2CH2-t-BU C(Me)2
14 H,H H 5 -CH2Ph 1-Cl -S-t-Bu CH(Me)
3 0
- 1 337427
Fl
6/DAM2 - 43 - 17940
Ex Rl R2 R3 ATTACH R8 R5 Y-(cRl lpl 1
No. POINT
6-Cl, 7-Cl H 5 -CH2Ph~Cl Me C(Me)2
16 H, 7-Cl H 5 -CH2Ph 1 Cl Me C(Me)2
17 H,H 4-allyl 5 -CH2Ph l Cl -S-t-Bu C(Me)z
18 H,H 4-al lyl 5 -CH2Ph~Cl H C(Me)z
19 H,H H 6 -CH2Ph 1 Cl -S-t-Bu C(Me)2
2û H,H H 4 -CH2Ph 'I Cl -S-t-Bu C(Me)2
21 H,H H 7 -CH2Ph 'I Cl -S-t-Bu C(Me)2
22 H,H H 5 -CH2Ph 1 Cl -S-t-Bu CH20CH(Me)
23 H,H H 4 -CH2Ph 1 Cl H C(Me)2
24 H,H H 6 Me -C(O)Ph-4-Cl C(Me)2
25 H,H H 6 Me -CH2Ph 1 Cl C(Me)2
26 H,H H 5 -CH2Ph 1 Cl -O-i-Pr C(Me)2
Fl 1 337421
6/DAM2 - 44 - 17940
suspension and test compound are preincubated for 2
minutes at 37-C, followed by the addition of 10 mM
A-23187. The suspension iB stirred for an additional
4 minutes then bioassayed for LTB4 content by adding
an aliquot to a second 500 mL portion of the PMN at
37C. The LTB4 produced in the first incubation
causes aggregation of the ~econd PMN, which is
measured as a change in light transmission. The size
of the assay aliquot is chosen to give a submaximal
transmission change (usually -70%) for the untreated
control. The percentage inhibition of LTB4 formation
is calcuated form the ratio of transmission change in
the sample to the transmission change in the
compound-free control.
~uman Polymorphonuclear (PMN) Leukocyte LTB/, Assay
A. Preparation of Human PMN. ~uman blood was
obtained by antecubital venepuncture from consenting
volunteers who had not taken medication within the
previous 7 days. The blood was immediately added to
10% (v/v) trisodium citrate (0.13 M) or 5% (v/v)
sodium heparin (1000 IU/mL). PMNs were isolated from
anticoagulated blood by dextran sedimentation of
erythrocytes followed by centrifugation through
Ficoll-Hypaque' (specific gravity 1.077), as described
by Boyum (Scand. J. Clin. Lab. Invest., ~1 (Supp.
~1~. 77(1968)). Contaminating erythrocytes were
removed by lysis following ezposure to ammonium
chloride (0.16 M) in Tris buffer (pH 7.65), and the
PMNs resuspended at 5 z 105 cell~/mL in EEPES (15
mM)-buffered Hanks balanced salt solution containing
Ca2+ (1.4 mM) and Mg2+ (o 7 mM), pH 7.4. Viability
was assessed by Trypan blue exclusion and was
typically greater than 98Z.
A
Fl 1 3 3 7 4 2 7
6/DAM2 - 45 - 17940
B. Generation and Radioimmunoassay of LTB4.
PMNs (0.5 mL; 2.5 x 105 cells) were placed in plastic
tubes and incubated (37C, 2 min) with test compounds
at the desired concentration or vehicle (DMS0, final
concentration 0.2%) as control. The synthesis of
LTB4 was initiated by the addition of calcium
ionophore A23187 (final concentration 10 mM) or
vehicle in control samples and allowed to proceed for
5 minutes at 37C. The reactions were then
terminated by the addition of cold methanol (0.25 mL)
and samples of the entire PMN reaction mixture were
removed for radioimmunoassay of LTB4.
Samples (50 mL) of authentic LTB4 of known
concentration in radioimmunoassay buffer (RIA) buffer
(potassium phosphate 1 mM; disodium EDTA 0.1 mM;
Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN
reaction mixture diluted 1:1 with RIA buffer were
added to reaction tubes. Thereafter [3H]-LTB4 (10
nCi in 100 mL RIA buffer) and LTB4-antiserum (100 mL
Of a 1:3000 dilution in RIA buffer) were added and
the tubes vortexed. Reactants were allowed to
equilibrate by incubation overnight at 4C. To
separate antibody-bound from free LTB4, aliquots (50
mL) of activated charcoal (3% activated charcoal in
RIA buffer containing 0.25% Dextran T-70) were added,
the tubes vortexed, and allowed to stand at room
temperature for 10 minutes prior to centrifugation
(1500 x g; 10 min; 4C). The supernatants containing
antibody-bound LTB4 were decanted into vials and
Aquasol 2 (4 mL) was added. Radioactivity was
quantified by liquid scintillation spectrometry.
Preliminary studies established that the amount of
methanol carried into the radioimmunoassay did not
- 1 337427
Fl
6/DAM2 - 46 - 17940
influence the results. The specificity of the
antiserum and the sensitivity of the procedure have
been described by Rokach et al. (Prostaglandins
Leukotrienes and Medicine 1984, 13, 21.) The amount
of LTB4 produced in test and control (approx. 20
ng/106 cells) samples were calculated. Inhibitory
dose-response curves were constructed using a
four-parameter algorithm and from these the IC50
values were determined.
Asthmatic Rat Assay
Rats are obtained from an inbred line of
asthmatic rats. Both female (190-250 g) and male
(260-400 g) rats are used.
Egg albumin (EA), grade V, crystallized and
lyophilized, is obtained from Sigma Chemical Co., St.
Louis. Aluminum hydroxide is obtained from the Regis
Chemical Company, Chicago. Methysergide bimaleate
was supplied by Sandoz Ltd., Basel.
The challenge and subsequent respiratory
recordings are carried out in a clear plastic box
with internal dimensions 10 x 6 x 4 inches. The top
of the box is removable; in use, it is held firmly in
place by four clamps and an airtight seal is
maintained by a soft rubber gasket. Through the
center of each end of the chamber a Devilbiss
nebulizer (No. 40) is inserted via an airtight seal
and each end of the box also has an outlet. A
Fleisch No. 0000 pneumotachograph is inserted into
one end of the box and coupled to a Grass volumetric
pressure transducer (PT5-A) which is then connected
to a Beckman Type R Dynograph through appropriate
couplers. While aerosolizing the antigen, the
Fl t 337427
6/DAM2 - 47 - 17940
outlets are open and the pneumotachograph is isolated
from the chamber. The outlets are closed and the
pneumotachograph and the chamber are connected during
the recording of the respiratory patterns. For
challenge, 2 mL of a 3% solution of antigen in saline
is placed into each nebulizer and the aerosol is
generated with air from a small Potter diaphragm pump
operating at 10 psi and a flow of 8 liters/minute.
Rats are sensitized by injecting
(subcutaneously) 1 mL of a suspension containing 1 mg
EA and 200 mg aluminum hydroxide in saline. They are
used between days 12 and 24 postsensitization. In
order to eliminate the serotonin component of the
response, rats are pretreated intravenously 5 minutes
prior to aerosol challenge with 3.0 mgm/kg of
methysergide. Rats are then exposed to an aerosol of
3~/O EA in saline for exactly 1 minute, then their
respiratory profiles are recorded for a further 30
minutes. The duration of continuous dyspnea is
measured from the respiratory recordings.
Compounds are generally administered either
orally 1-4 hours prior to challenge or intravenously
2 minutes prior to challenge. They are either
dissolved in saline or 1% methocel or suspended in 1%
2s methocel. The volume injected is 1 mL/kg
(intravenously) or 10 mL/kg (orally). Prior to oral
treatment rats are starved overnight. Their activity
is determined in terms of their ability to decrease
the duration of symptoms of dyspnea in comparison
with a group of vehicle-treated controls. Usually, a
compound is evaluated at a series of doses and an
ED50 is determined. This is defined as the dose
Fl 1 3 3 7 4 2 7
6/DAM2 - 48 - 17940
(mg/kg) which would inhibit the duration of symptoms
by 50%.
The invention is further defined by
reference to the following examples, which are
intended to be illustrative and not limiting. All
temperatures are in degrees Celsius.
Example 1
3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]-2,
2-dimethylpropanoic acid
Step A: 3-[N-p-Chlorobenzyl-3-(t-butylthio)-5-
methoxyindol-2-yl]-2,2-dimethylpropanoic
acid methyl ester
To a solution of 39 g of methyl
5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in a
mixture of 300 mL of toluene and 150 mL of glacial
acetic acid was added 15 g of NaOAc and 50 g of
1-(4-methoxyphenyl)-1-(p-chlorobenzyl)hydrazine
hydrochloride. The reaction was maintained with
stirring at room temperature for 3 days under argon
in the dark. The mixture was poured into 3 L of H2O
and extracted with 3 x 500 mL of EtOAc. The ethyl
acetate was washed with 3 x 500 mL of water then
solid NaHCO3 was added. The mixture was filtered and
the filtrate washed twice with water . The organic
phase was dried over MgSO4 and evaporated to dryness
to provide the title compound. m.p. 102-103 C.
1 337427
Fl
6/DAM2 - 49 - 17940
Step B: 3-tN-(p-Chlorobenzyl)-3-(t-butylthio)-5-
methoxyindol-2-yl]-2,2-dimethylpropanoic
acid
The compound from Step A was hydrolysed
using 325 mL of THF, 600 mL of MeOH and 325 mL of
l.OM LiOH. The æolution was heated to 80 C for 3
h. The æolution was acidified with lN HCl and
extracted with 3 x 200 mL of EtOAc. The organic
phase was washed with water (2 x 150 mL) and dried
over MgSO4. The solution was evaporated to dryness
to provide the title compound. m.p. 190-191 C.
Anal C, H, N: Calc. C 65.27; H 6.57; N 3.04,
Found C 65.28; H 6.58; N 3.04
Step C: Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-
(t-butylthio)indol-2-yl]-2,2-dimethyl-
propanoate0
A solution of 61 mL of t-butylthiol in 650
mL of dry HMPA at 0 C was treated portionwise with
26 g of 50% NaH in mineral oil after removal of oil
with hexane. The reaction was stirred at RT for 305 mins and 46 g of the compound from Step B was added.
The reaction was then heated under N2 at
175 C for 5 hours. The solution was cooled, and
poured onto crushed ice, after which it was treated
with 2 N HCl to pH 5 and extracted with EtOAc (3 x
500 mL). The organic phase was washed with H2O (3 x
200 mL) dried (MgSO4) and evaporated.
El 1 3 3 7 4 2 7
6/DAM2 - 50 - 17940
The residue was dissolved in 300 mL of ether and
ethereal diazomethane was added until all acid was
consumed. The excess solvent was removed and the
oily residue triturated with hexane to leave a
crystalline mass which was recrystallized from
EtOAc/hexane to provide the title compound as a white
crystalline solid, m.p. 170-171 C. From the mother
liquors was isolated methyl 3-[N-(p-t-butylthio-
benzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-di-
lo methyl propanoate which was used as such in Example 3.
Step D: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-
5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-
dimethylpropanoate.
Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-
(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate (33.6
g) from Step C was dissolved in 500 mL of dry DMF and
the solution was charged with 2.4 g of KI, 30.3 g of
K2C03, 4.77 g of Cs2C03 and 23.5 g of
2-(chloromethyl)quinoline hydrochloride. The
reaction was stirred at RT, under N2, for 72 hours
then it was poured into water (1.5 L), acidified with
lN HCl and extracted (3 x 200 mL) with CH2C12. The
organic phase was washed with H20 (3 x 150 mL), dried
and evaporated. The residue was dissolved in hot
EtOAc and upon cooling crystallized to deposit 22.0 g
of the title compound, m.p. 166-167 C
Step E: 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]-2,
2-dimethylpropanoic acid
1 337427
Fl
6/DAM2 - 51 - 17940
Using the hydrolytic procedure of Step B but
substituting the ester of Step D for the ester of
Step A provided the title compound, which was
recrystallized from 1:1 EtOAc/hexane. m.p. 208C.
Anal C, H, N: Calc. C 69.55; H 6.01; N 4.77,
Found C 69.77; H 6.05; N 4.70
Example lA
3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]-2,2-
dimethylpropanoic acid
Step A: N-Acetyl-4-(guinolin-2-ylmethoxy)aniline
A mixture containing 2-(chloromethyl)-
quinoline hydrochloride (100.0 g), 4-acetamido-
phenol (70.69 g) and milled anhydrous potassium
carbonate (194 gj was stirred in DMF (1.2 L) using a
mechanical stirrer for 48 hours. The mixture was
carefully poured onto ice/water (3 L) with vigourous
ætirring. After the ice had melted, the solid was
filtered and rinsed thoroughly with water. It was
recrystallized from 95% ethanol and filtered to give
the title compound in three crops.
Step B: 4-(Quinolin-2-ylmethoxy)aniline
A suspension of N-acetyl-4-(quinolin
-2-ylmethoxy)aniline (Step A, 108.9 g) in 1 L of 95%
ethanol containing 10 M KOH (120 mL) was heated at
reflux under nitrogen in a heating mantle. When the
hydrolysis was complete (approx. 36 h), the
1 337427
Fl
6/DAM2 - 52 - 17940
reaction mixture was cooled and ethanol was partially
removed under vacuum. The mixture was then diluted
with water (200 mL) and the fine off-white crystals
were collected and thoroughly rinsed with water. The
material, after air-drying, yielded the title
compound which was used as such in the next step.
Step C: 4-(Quinolin-2-ylmethoxy)phenylhydrazine
A quantitiy of 84 g of 4-(quinolin-2-
ylmethoxy)aniline from Step B was suspended in 300 mL
of deionized H2O and 84 mL of 12 M HCl. The
suspension was stirred vigourously to obtain a fine
particle suspension. Then a precooled solution (5C)
of 23.88 g of sodium nitrite dissolved in 75 mL of
deionized H2O was added dropwise to the suspension at
5C over 25 minutes. The solution was stirred at 5C
for 60 min to obtain the diazonium salt as a clear
brown solution. The presence of excess HNO2 was
confirmed by KI-starch paper, and the pH of the
solution was about 3Ø If a white suspension
persisted after 1 h, the mixture was filtered through
a glass wool plug, to give the diazonium salt in the
filtrate.
In the meantime a sodium hydrosulfite
solution was prepared by dissolving 321 g of sodium
hydrosulfite (approx. 85~/o purity) in 2 L of deionized
water, and cooled at 0 to 5C. To this solution
were added 15 mL of 2N NaOH and 2 L of ether. The
biphasic solution was kept near 0C by additon of
crushed ice and was stirred vigorously. To this
solution was added dropwise the diazonium salt
Fl 1 3 3 7 4 2 7
6/DAM2 - 53 - 17940
solution with stirring maintained throughout. At the
end of the addition an orange solid was formed and
600 mL of NaOH (2N) was added over 30 minutes. The
reaction was finally stirred for 60 minutes at 25C.
The solid was collected, æuspended in ether (1 L) and
filtered. The process was repeated with 2 L of water
to yield the title compound as a pale yellow solid
after freeze-drying overnight. m.p. 73-85C (dec).
O Step D: l-(p-chlorobenzyl)-l-[4-(quinolin-2
methoxy)phenyl]hydrazine
A quantity of 10 g of 4-(quinolin-2-
ylmethoxy)phenylhydrazine from Step C was added to a
solution of 10.5 mL of diisopropylethylamine and 150
mL of CH2C12. To the yellow suspension was added
9.11 g of p-chlorobenzyl chloride followed by 3.64 g
of Bu4NBr and 50 mL of CH2C12. The reaction was
stirred for approximately 24 hours. When no starting
material remained, the reaction was diluted with H20
and extracted 3 times with CH2C12. The combined
organic phase was washed once with water and dried
(MgS04), filtered and evaporated to dryness. The
solid residue was dried under vacuum overnight prior
to being swished in ether/methanol 90/10 to give the
title compound as a pale yellow solid. m.p. 130C.
Step E: 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]-2,2-
dimethylpropanoic acid
The methyl ester of the title compound was
prepared according to the method described in Step A
1 337427
Fl
6/DAM2 - 54 - 17940
of Example 1 but using the phenylhydrazine from Step
D of Example lA as starting material.
The title compound was prepared under the
conditions described in Step B of Example 1.
Example 2
3-tN-(p-Chlorobenzyl)-3-methyl-5-(quinolin-2-yl-
methoxy)indol-2-yll-2.2-dimethylpropanoic acid
The title compound was prepared according to
the method of Example 1, but using methyl 2,2-
dimethyl-4-oxohexanoate as starting material in Step
A in place of methyl 5-t-butylthio-2,2-dimethyl-
4-oxopentanoate. m.p. 215-217 C.
Example 3
3-[N-(p-t-Butylthiobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-
propanoic acid
The methyl ester byproduct from Step C of
Example 1 was reacted 2-(chloromethyl)quinoline
according to the conditions of Steps D & E of Example
1 to provide the title compound. m.p. 172-173 C.
Example 4
3-[N-(p-Chlorobenzyl)-3-(phenylthio)-5-(quinolin-
2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid
The title compound was prepared according to
the method described for Example 1, but substituting
methyl-5-phenylthio-2,2-dimethyl-4-oxopentanoate for
1 337427
Fl
6/DAM2 - 55 - 17940
methyl 5-t-butylthio-2,2-dimethyl-4-oxopentonoate in
Example 1 (Step A).
Anal. C, H, N for sodium salt- 2 H20:
Calc. C 64.91; H 5.30; N 4.20
Found C 64.94; H 5.04; N 4.15
Example 5
3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-
(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-
propanoic acid. N-oxide
Methyl 3-[N-(p-chlorobenzyl)-3-
(phenylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-
dimethyl propanoate (430 mg) from Step D of Example 4
was dissolved in 5 mL cold CH2C12 and treated with a
solution of 448 mg of 80% m-chloroperbenzoic acid
(MCPBA) in CH2C12. After 24 hours, the solution was
poured onto 10 mL of sat. aqueous NaHC03 solution,
extracted with 3 x 10 mL of CH2C12, washed with 2 x
10 mL of H20, dried with magnesium sulfate and
evaporated to dryness. ~he residue was crystallised
from 2:1 CH2C12/EtOAc to yield 280 mg of the title
compound as its methyl ester. Hydrolysis using the
conditions described in Example 1 (Step B) provided
the title compound, m.p. 197 C (dec.)
Anal. C, H, N: Calc. C 66.0; H 4.77; N 4.28
Found C 66.06; H 4.77; N 4.19.
1 337427
Fl
6/DAM2 - 56 - 17940
Examples 6 and 7
3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quino-
lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic
acid and
3-[N-(p-Chlorobenzyl)-3-(phenylsulfinyl)-5-(quino-
lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic
acid
Methyl 3-[N-p-chlorobenzyl-3-(phenyl
lo thio)-5-(quinolin-2-methoxy)indol-2-yl]-2,2-
dimethyl propanoate (430 mg) from Example 4 (Step D)
was dissolved in 5 mL of cold methylene chloride and
a solution of 150 mg of 80% (MCPBA) in methylene
chloride was added. After 24 hours, the reaction
solution was poured onto 10 mL of saturated aqueous
sodium bicarbonate solution and this mixture was
extracted 3 times with 10 mL of methylene chloride.
The combined organic phases were washed twice with 10
mL of water, dried with magnesium sulfate and
evaporated under vacuum.
Chromatography over silica gel (2 hexane: 1
ethyl acetate) provided two compounds which were
separately hydrolyzed using the procedure described
in Example 1 (Step B).
3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quinolin-
2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid:
Anal . C, H, N f or sodium salt H2O:
Calc. C 63.57; H 4.89; N 4.12
Found C 63.28; E 4.77; N 3.90
Fl t 3 3 7 4 2 7
6/DAM2 - 57 - 17940
3-[N-(p-Chlorobenzyl)-3-(phenylsulfinyl)-5-(quino-
lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic
acid:
Anal. C, H, N for sodium salt- H20:
Calc. C 63.38; H 5.17; N 4.11
Found C 63.28; H 4.89; N 3.97
Example 8
3-[N-(p-Chlorobenzyl)-5-(quinolin-2-ylmethoxy)-
indol-2-yl~-2~2-dimethylpropanoic acid
Step A: Methyl 3-[N-(p-chlorobenzyl)-5-hydroxyindol-
2-yll-2,2-dimethylpropanoate
A suspension of 1.0 g of 3-tN-(p-chloro-
benzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-
dimethylpropanoic acid (from Example 1 Step B) in 50
mL of CH2C12 was treated with 1.3 mL of ethanethiol
and 3.47 g of AlC13 at 0C under argon. After 40 min
the mixture was poured onto 50 mL lN HCl, extracted
with 3 x 50 mL of CH2C12 washed with 2 x 50 mL of
H20, dried with MgS04 and the solvent removed. The
residue was dissolved in 10 mL ether and ethereal
diazomethane added until all the acid was consumed.
The excess solvent was removed and the residue
chromatographed on silica gel to afford the title
compound.
Step B: 3-[N-(p-Chlorobenzyl)-5-(quinolin-2-yl-
methoxy)indol-2-yl]-2,2-dimethylpropanoic
acid
The title compound was prepared by treating
1 ~37427
Fl
6/DAM2 - 58 - 17940
the ester from Step A with 2-(choromethyl)quinoline
hydrochloride under the conditions of Step D and
effecting hydrolysis under the conditions of Example
1 (Step B), m.p. 193-194C.
Example 9
3-[N-(p-Chlorobenzyl)-3-benzoyl-5-(quinolin-2-yl-
methoxy~indol-2-yll-2,2-dimethylpropanoic acid
Step A: Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-
benzoyloxyindol-2-yll-2~2-dimethylpropanoate
Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy
indol-2-yl~-2,2-dimethylpropanoate (609 mg) from
Example 8 (Step A) was dissolved in 10 mL of
1,2-dichloroethane and the solution charged with 0.5
mL of benzoyl chloride and 680 mg of AlC13. The
reaction was heated to 80 C under argon for 1.5 h,
then quenched with 20 mL of 0.5N Na, K tartrate
solution, extracted with 3 x 20 mL of ether, washed
with 10 mL of H2O and dried (MgSO4). Removal of
solvent provided an oily residue which was
chromatographed on silica gel to give the title
compound.
5 Step B: Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-
hydroxyindol-2-yll-2.2-dimethylpropanoate
The compound from Step A (300 mg) was
dissolved in 4 mL of MeOH and treated with 1 mL of a
1.4 M solution of NaOMe in MeOH under argon for 3
hrs. The mixture was poured onto 20 mL of NH40Ac
(25Z solution), extracted with 3 x 15 mL of ether,
1 337427
Fl
6/DAM2 - 59 - 17940
washed with 10 mL of H20, dried over MgS04 and the
solvent removed under vacuum. The resulting oil was
purified by chromatography on silica gel to afford
the title compound.
Step C: 3-[N-(p-Chlorobenzyl)-3-benzoyl-5-(quinolin-
2-yl-methoxy)indol-2-yl]-2,2-dimethyl-
propanoic acid
The title compound was prepared using the
conditions described in Step D and Step E of Example
1, but substituting the ester from Step B for the
ester of Example 1 , Step C; m.p. 165-166C.
Example 10
3-[N-(p-Chlorobenzyl)-3-benzyl-5-(quinolin-
2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic
acid
Step A: Methyl 3-[N-(p-Chlorobenzyl)-3-benzyl-5-
(benzoyloxy)indol-2-yl]-2,2-dimethyl-
propanoate
Methyl 3-[N-(p-chlorobenzyl)-3-
benzoyl-5-(benzoyloxy)indol-2-yl]-2,2-dimethyl-
propanoate (360 mg) (prepared in Step A of Example
9), 800 mg of ZnI2, and 500 mg of sodium
cyanoborohydride were stirred in 5 mL of
dichloroethane at RT under argon for 30 min. The
temperature was then raised to 65 C for 3 hr. After
the solution had cooled, it was poured onto 10 mL of
NH40Ac (25% solution), extracted with 3 x 15 mL of
ether, washed with 10 mL of ~2 and dried (MgS04).
1 337427
Fl
6/DAM2 - 60 - 17940
The solution was evaporated to dryness and the
residue was chromatographed on silica gel to yield
the title compound as a white foam.
Step B: 3-[N-(p-Chlorobenzyl)-3-benzyl-5-(quinolin-
2-yl-methoxy)indol-2-yl]-2,2-dimethyl-
propanoic acid
The title compound was prepared under the
lo conditions described in Step B and Step C of Example
9 but substituting the ester from Example 10 (Step A)
for the ester of Example 9 (Step A), m.p. 178C.
Example 11
3-[N-(p-Chlorobenzyl)-3-(3,3-dimethyl-1-oxo-1-
butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,
2-dimethylpropanoic acid
The title compound was prepared according to
2~ the method described in Example 9, but using
t-butylacetylchloride in place of benzoyl chloride in
Step A, m.p. 183-184C.
Example 12
2s 2-tN-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-
2-ylmethoxy)indol-2-yl~ethoxyethanoic acid
Step A; Methyl 2- [n- ( p-Chorobenzyl)-3-(t-butylthio)-
5-(quinolin-2-ylmethoxy)indol-2-yl]
ethanoate
The title compound was prepared according to
the method outlined in Steps A-D of Example 1, but
1 337427
Fl
6/DAM2 - 61 - 17940
using methyl 4-t-butylthio-3-oxo-butanoate in Step A
instead of methyl 5-t-butylthio-2,2-dimethyl-
4-oxopentanoate.
Step B: 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yllethanol
The compound from Step A (192 mg) was
dissolved in 3 mL of THF at RT under an argon
lo atmosphere and treated with 30 mg of lithium aluminum
hydride. After 1 hr, the reaction was poured onto 10
mL of 0.5 N Na,K tartrate solution and extracted with
3 x 10 mL of EtOAc. The organic layer was washed
with 10 mL of H20, dried (MgS04) and evaporated to
dryness to yield the title compound.
Step C: 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]ethoxy-
ethanoic acid
To 91 mg of 2-[N-(p-chlorobenzyl)-3-(t-
butylthio)-5-(quinolin-2-ylmethoxy)indol-2-
yl]ethanol from Step B in 2 mL THF at 0 C under an
argon atmosphere was added 40 mg of 80% sodium
hydride over 30 min. Ethyl bromoacetate (0.3 ml) was
added to the solution and the reaction stirred at RT
overnight. The reaction was poured onto 10 mL of
NH40Ac (25~/o solution), extracted with 3 x 10 mL of
EtOAc, washed with 20 mL of H20 and dried over 4
MgS04. Removal of the solvent followed by column
chromatography on silica gel afforded the ethyl eæter
of title compound. Hydrolysis of this ester under
1 ~37427
Fl
6/DAM2 - 62 - 17940
the conditions described in Step B of Example 1
provided the title compound, m.p. 185C (dec.).
Example 13
3-[N-(p-Chlorobenzyl)-3-(3,3-dimethyl-1-
butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-
2.2-dimethylpropanoic acid
The title compound was prepared according to
the method described in Example 10 but using methyl
3-[N-(p-chlorobenzyl)-3-(3,3-dimethy-1-oxo-
l-butyl)-5-(t-butylacetyloxy)-indol-2-yl]-2,2-
dimethylpropanoate (obtained as an intermediate from
Example 11) as starting material, m.p. 188C (dec.).5
i Example 14
3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-
2-ylmethoxy)indol-2-yl~-2-methylpropanoic acid
- The title compound was prepared according to the
method of Example 1 using methyl 5-t-butyl-
thio-2-methyl-4-oxopentanoate as starting material in
Step A in place of methyl 5-t-butylthio-2,2-
dimethyl-4-oxopentanoate.
2s lH NMR (250 MHz, acetone-d6) ~ 1.05 (3H, d, J = 6Hz),
1.15 (9H, s), 2.7 (lH, m), 3.2 (2H, d, J = 7Hz), 5.4
(2H, s), 5.6 (2H, s), 6.9 (lH, dd), 7.0 (2H, d), 7.3
(4H, m), 7.6 (lH, td), 7.7 (lH, d), 7.8 (lH, td), 7.9
(lH, d), 8.1 (lH, d), 8.3 ppm (lH, d).
Fl 1 3 3 7 4 2 7
6/DAM2 - 63 - 17940
Example 15
3-[N-(p-Chlorobenzyl)-3-methyl-5-(6,7-dichloro-
quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-
propanolc acid
The title compound was prepared according tothe method described in Example 1 but using methyl
2,2-dimethyl-4-oxohexanoate as starting material in
Step A and 2-(bromomethyl)-6,7-dichloroquinoline in
Step D.
Anal. C, H, N: Calc. C 63.21; H 4.74; N 4.91
Found C 63.47; H 4.94; N 4.67
- - Example 16
3-[N-(p-Chlorobenzyl)-3-methyl-5-(7-chloroquino-
lin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-
propanoic acid
The title compound was prepared according to
the method described in Example 15 but using
2-(bromomethyl)-7-chloroquinoline instead of
2-(bromomethyl)-6,7-dichloroquinoline. m.p.
105-107C.
Anal. C, H, N: Calc. C 67.41; H 5.24; N 5.24
Found C 67.82; H 5.12; N 4.32
Example 17
3-[N-(p-Chlorobenzyl)-4-allyl-5-(quinolin-2-yl-
methoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-
propanoic acid
- 1 337427
Fl
6/DAM2 - 64 - 17940
Step A: Methyl 3-cN-(p-chlorobenzyl)-5-allyloxy
-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-
propanoic acid
500 mg. of methyl 3-[N-(p-chlorobenzyl)-5-
hydroxy-3-(t-butylthio)indol-2-yl]-
2,2-dimethylpropanoate from Step C of Example 1 was
dissolved in 5 mL of DMF and 20 mg of K2C03 and 150
mg of allyl bromide were added. The reaction was
stirred for 16 hrs. Water was added and the organic
phase extracted with EtOAc (3 x 5mL). The organic
phase was dried with MgSO4 and evaporated to yield,
after chromatography on silica gel (EtOAc:hexane
1:5), the title compound.
Step B: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-
4-allyl-5-hydroxyindol-2-yl]-2,2-dimethyl-
propanoate
500 mg of the ester of Step A was converted
to the title compound by heating to 180 in m-xylene
for 4 hours.
Step C: 3-[N-(p-Chlorobenzyl)-4-allyl-5-(quinolin-2-
ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-
dimethylpropanoic acid
The title compound was prepared from the
compound of Step B using the methodology of Example
30 1, (Steps D and E), m.p. 103-105C.
Anal. C, H, N: Calc. C 69.09; H 6.11; N 4.35
Found C 70.55; H 6.31; N 4.29
1 337427
Fl
6/DAM2 - 65 - 17940
Example 18
3-~N-(p-Chlorobenzyl)-4-allyl-5-(quinolin-2-yl-
methoxy)indol-2-yll-2.2-dimethylpropanoic acid
The methyl ester of the title compound was
prepared according to the method of Example 17 but
substituting methyl 3-[N-(p-chlorobenzyl)-5-
hydroxyindol-2-yl]-2,2-dimethylpropanoate as starting
material (obtained in Step A Example 8) for the ester
0 in Example 17 (Step A). Hydrolysis was then effected
according to the conditions of Step B of Example 1 to
provide the title compound, m.p. 196-197C (dec.).
Example 19
3-[N-(p-Chlorobenzyl)-6-(quinolin-2-ylmethoxy)-3-
(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic
acid
The title compound was prepared according to the
conditions of Example 1, Steps A to E, but
substituting 1-(3-methoxyphenyl)-1-(p-chloro-
benzyl)hydrazine hydrochloride for the starting
material in Example 1 (Step A). Chromatographic
separation of the desired regioisomer was achieved at
2s Step A by iæolating the most polar product, methyl
3-[N-(p-chlorobenzyl)-3-(t-butylthio)-6-methoxy-
indol-2-yl]-2,2-dimethylpropanoate. The properties
of the title compound were as follows: m.p.
165-167C.
Anal C, H, N: Calc. C 69,54; H 6.01; N 4.77
Found C 69.46; H 6.18; N 4.96
1 337427
Fl
6/DAM2 - 66 - 17940
Example 20
3-[N-(p-Chlorobenzyl)-4-(quinolin-2-ylmethoxy)-3-
(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic
acid
Methyl 3-tN-(p-chlorobenzyl)-3-(t-butylthio)-
4-methoxyindol-2-yl]-2,2-dimethylpropanoate was
obtained as a by-product from Step A of Example 19
and isolated by chromatography as the less polar
product. The compound was used as starting material
for the preparation of the title product using the
methodology of Steps B to E of Example 1.
Anal C, H, N: Calc. C 69.54; H 6.01; N 4.77;
Found C 69.80; H 6.24; N 4.86
Example 21
3-~N-(p-Chlorobenzyl)-3-(t-butylthio)-7-(quinolin-
2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic
acid
The title product was prepared according to
Steps A to E of Example 1 but substituting
1-(2-methoxyphenyl)-1-(p-chlorobenzyl)hydrazine
hydrochloride for 1-(4-methoxyphenyl)-1-(p-
chlorobenzyl hydrazine hydrochloride in Example 1
~Step A), m.p. 206C.
Anal. C, H, N: Calc. C 69.54; H 6.01; N 4.77,
Found C 69.40; H 5.88; N 4.65
1 337427
Fl
6/DAM2 - 67 - 17940
Example 22
2-[2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quino-
lin-2-ylmethoxy)indol-2-yl]ethoxy]propanoic acid
sodium salt dihydrate Step A: Methyl 2-[2-[N-(p-chlorobenzyl)-3-(t-butyl-
thio)-5-quinolin-2-ylmethoxy)indol-2-yl]-
ethoxylpropanoate
The title compound was prepared from 251 mg
of 2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]ethanol (Step B of
Example 12) under the conditions described in Step C
of Example 12 using methyl P,L-2-bromopropanoate
instead of ethyl bromoacetate.
Step B: 2-[2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-
(quinolin-2-ylmethoxy)indol-2-yl]ethoxy]-
propanoic acid sodium salt dihydrate
The acid corresponding to the title compound
of Example 22 was prepared from the ester of Step A
of Example 22 under the conditions described in Step
B of Example 1. A quantity of 204 mg of the acid was
suspended in 1.5 mL of EtOH and treated with 1 equiv.
of lN aq. NaOH and freezed dried for 2 days to afford
the title compound.
Anal. C, H, N: Calc. C 61.25; H 5.61; N 4.33,
Found C 61.75; H 5.70; N 3.97
1 337427
Fl
6/DAM2 - 68 - 17940
Example 23
3-[N-(p-Chlorobenzyl)-4-(quinolin-2-ylmethoxy)-
indol-2-yll-2.2-dimethylpropanoic acid
Step A: Methyl 3-[N-(p-chlorobenzyl)-4-
hydroxyindol-2-yll-2,2-dimethylpropanoate
The title compound was prepared using
methodology from Step A of Example 8 but substituting
lo 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-4-methoxy
indol-2-yl]-2,2-dimethylpropanoic acid (Step B of
Example 20) for the propanoic acid in Example 8 (Step
A).
5 Step B: 3-[N-(p-Chlorobenzyl)-4-(quinolin-2-yl-
methoxy)indol-2-yl]-2,2-dimethylpropanoic
- acid
The title product was prepared according to
conditions described in Steps D and E of Example 1
substituting methyl 3-[N-(p-chlorobenzyl)-4-hydroxy
indol-2-yl]-2,2-dimethylpropanoate for the propanoate
in Example 1 (Step D), m.p. 158-160C.
Anal. C, H, N: Calc. C 72.20; H 5.45; N 5.61
Found C 72.25; H 5.60; N 5.75
Example 24
3-[N-Methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-yl-
methoxy)indol-2-yll-2.2-dimethylpropanoic acid
1 337427
Fl
6/DAM2 - 69 - 17940
Step A: Methyl 3-[6-methoxy-3-(t-butylthio)
indol-2-yll-2.2-dimethylpropanoate
A mixture of 4.2 g of 3-methoxyphenyl-
hydrazine hydrochloride and 4.9 g of methyl
5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in 100
mL of t-butanol was refluxed for 18 hours. The
mixture was cooled to R.T., and evaporated to
dryness. The residue was suspended in ether (150 ml)
and stirred for 30 min. The salts were filtered and
the filtrate evaporated to dryness to give a residue
which was chromatographed on flash silica gel using
as eluant ethyl acetate:toluene (1:99) to isolate the
title compound as the most polar product; m.p. 133C.
Step B: Methyl 3-[N--methyl-3-(t-butylthio)-6-
methoxyindol-2-yll-2.2-dimethylpropanoate
A solution of 1.75 g of the indole from Step
A in 30 mL of THF and 3 mL HMPA was cooled to -78C
and to this solution was slowly added a solution of
O.54M KHMDS in toluene (10.2 mL). The mixture was
stirred at this temperature for 15 min. and treated
with 0.34 mL of iodomethane. The mixture was stirred
at -78C for 5 h, quenched with lN HCl (100 mL),
extracted with ethyl acetate, and the organic layer
washed with H20, dried over Na2SO4 and evaporated to
dryness. The residue was chromatographed on flash
silica gel using ethyl acetate:hexane (20:80) as
eluant to afford the title compound as a solid; m.p.
97-98C.
1 337427
Fl
6/DAM2 - 70 - 17940
Step C: Methyl 3-[N-methyl-6-hydroxyindol-2-yl]-
2~2-dimethylpropanoate
To a cold solution of 940 mg of the indole
ester from Step B and 1.6 mL of ethanethiol in CH2C12
(50 mL) was added portion-wiæe 4.3 g of AlC13. After
complete addition, the mixture was stirred at R.T.
for 2 h. The mixture was then cooled to 0C and
carefully quenched with a solution of 0.5 M Na,K
tartrate (200 mL) and extracted with CH2C12. The
organic layer was dried over Na2S04 and evaporated to
dryness to give a solid which was chromatographed on
flash silica gel using ethyl acetate:hexane (30:70)
as eluant to afford the title compound; m.p.
125-126C.
Step D: Methyl 3-[N-methyl-6-(p-chlorobenzoyloxy)-
3-(p-chlorobenzoyl)indol-2-yl]-2,2-di-
methylpropanoate
0
To a cold solution of 393 mg of hydroxy
indole from Step C in 5 mL of THF were added 0.31 mL
of Et3N followed by 0.21 mL of p-chlorobenzoyl
chloride. The mixture was stirred at R.T for 15 min
and quenched with H20. The mixture was extracted
with ethyl acetate which was dried over Na2S04 and
evaporated to dryneæs to give a solid which was
dissolved in 10 mL of 1,2-dichloroethane. To this
mixture were added successively at R.T. 0.38 mL of
p-chlorobenzoyl chloride and 803 mg of AlC13. The
mixture was heated at 80C for 3 h, cooled to R.T.
and quenched with 50 mL of 0.5 N HCl. The mixture
was extracted with CH2C12, washed with H20,
1 337427
Fl
6/DAM2 - 71 - 17940
dried over Na2S04 and evaporated to dryness. The
residue was chromatographed on flash silica gel using
ethyl acetate:hexane (20:80) as eluant to afford the
title compound as a white solid. m.p. 138C.
Step E: Methyl 3-[N-methyl-3-(p-chlorobenzoyl)-6-
hydroxyindol-2-yll-2~2-dimethylpropanoate
To a suspension of 270 mg of the p-chlorobenzoate
from Step D in 3 mL of MeOH was added 1.2 mL of a
solution of 1.3M NaOMe in MeOH and the mixture was
stirred at R.T. for 2 hr. The reaction mixture was
poured onto 25% aq. NH40Ac and extracted with ethyl
acetate. The organic extract was dried over Na2S04,
evaporated to dryness and the residue chromatographed
on flash silica gel using ethyl acetate:hexane
(40:60) as eluant to afford the title compound as a
yellow foam.
0 Step F: Methyl 3-[N-methyl-3-(p-chlorobenzoyl)-6-
(quinolin-2-ylmethoxy)indol-2-yl]-
2~2-dimethylpropanoate
To a solution of 180 mg of the phenol from
Step E in 5 mL of DMF were added 124 mg of milled
K2C03 followed by 150 mg of 2-(bromomethyl)
quinoline. The mixture was 8tirred at R.T. for 18 h,
poured onto 25% aq. NH40Ac and extracted with ethyl
acetate. The extract was dried over Na2S04 and
evaporated to dryness to give an oil which was
chromatographed on flash silica gel using ethyl
acetate:hexane (30:70) as eluant to give the title
compound as a foam.
1 337427
Fl
6/DAM2 - 72 - 17940
Step G: 3-~N-Methyl-3-(p-chlorobenzoyl)-6-(quinolin-
2-ylmethoxy)indol-2-yl]-2,2-dimethyl-
propanoic acid
To a æolution of 230 mg of ester from Step F
in 1.5 mL of THF and 3 mL of MeOE was added lM aq.
LiOH and the mixture stirred at 80C for 4 h. The
mixture was cooled to R.T. and evaporated to dryness
in vacuo. The residue was dissolved in a mixture of
20 mL of 25% aq. NH40Ac and 20 mL of ethyl acetate
using vigourous stirring. The organic layer was
separated, dried over Na2SO4 and evaporated to
dryness to give a yellow solid (216 mg). This solid
was swished for 2 h in 5 mL of a mixture of
Et2O:hexane (1:1). The solid was filtered and rinsed
with a 1:2 mixture of Et2O:hexane to give the title
product as a yellow solid, m.p. 203-205C:
Anal. C, H, N: Calc. C 70.65; H 5.16; N 5.32;
Found C 70.42; H 5.25; N 5.40
Example 25
3-[N-Methyl-3-(p-chlorobenzyl)-6-(quinolin-2-yl-
methoxy)indol-2-yl]-2,2-dimethylpropanoic acid,
sodium salt hemihydrate
Step A: Methyl 3-~N-methyl-3-(p-chlorobenzyl)-6-
(p-chlorobenzoyloxy)indol-2-yl]-2,2-dimethyl-
propanoate0
To a solution of 500 mg of the benzoyl
derivative from Step D of Example 24 in 10 mL of
Fl ~ ~3 742 7
6/DAM2 - 73 - 17940
1,2-dichloroethane were added 1.19 g of ZnI2 and 700
mg of NaBH3CN. The mixture was heated at 65C for 5
hours and cooled to R.T. The mixture was quenched
with lN aq. ~Cl and extracted with CH2C12. The
extracts were washed with brine, dried over Na2S04
and evaporated to dryness to give an oil which was
chromatographed on flash silica gel using ethyl
acetate:hexane (15:85) as eluant to isolate the title
compound as a white foam.
Step B: Methyl 3-[N-methyl-3-(p-chlorobenzyl)-
6-hydroxyindol-2-yl~-2.2-dimethylpropanoate
To a suspension of 425 mg of
p-chlorobenzoate from Step A in 3 mL of MeOE was
added 1.9 mL of a solution of 1.3M NaOMe in MeOH.
The mixture was stirred at R.T. for 1 h, poured into
20 mL of 25% aq. N~40Ac, and extracted with ethyl
acetate. The organic extract was dried over Na2S04
and evaporated to dryness to give an oil which was
chromatographed on flash silica gel using ethyl
acetate:hexane (30:70) as eluant to give the title
compound as a white foam.
5 Step C: Methyl 3-tN-methyl-3-(p-chlorobenzyl)-
6-(quinolin-2-ylmethoxy)indol-2-yl3-2,2-
dimethylpropanoate
To a solution of 315 mg of the ester from
Step B in 3 mL of DMF were added 225 mg of milled
K2C03 and 272 mg of 2-(bromomethyl)quinoline. The
mixture was stirred at R.T. for 18 h, poured into 25%
aq. NH40Ac, and extracted with ethyl
? 337427
Fl
6/DAM2 - 74 - 17940
acetate. The organic extract was dried over Na2SO4
and evaporated to dryness to give an oil which was
chromatographed on flash silica gel using ethyl
acetate:hexane (30:70) as eluant to give the title
compound as a foam.
Step D: 3-~N-Methyl-3-(p-chlorobenzyl)-6-(quinolin-
2-ylmethoxy)indol-2-yl]-2,2-dimethyl
propanoic acid, sodium salt hemihydrate
0
To a solution of 367 mg of the ester from
Step C in 3 mL of THF and 6 mL of MeOH was added 1 M
aq. LiOH and the mixture was heated at 80C for 2 h.
The mixture was cooled to R.T. and evaporated to
dryness. The residue was dissolved in a mixture of
20 mL of 25% aq. NH40Ac and 20 mL of ethyl acetate
(vigourous stirring required). The organic layer was
separated, dried over Na2SO4 and evaporated to
dryness to give a white solid (346 mg). The solid
was swished at R.T. for 2 h with 10 mL of a mixture
of Et2O:hexane (1:1), filtered, rinsed with a mixture
of (1:2) Et2O:hexane and the solid collected to give
the title compound as its free acid, a white solid:
m.p. 185C.
The title compound was prepared by
dissolving the above acid in 1 mL of EtOH to which
0.63 mL of lN aq. NaOH was added. The mixture was
freeze dried for 2 days to give the title product as
a white solid.
Anal. C, H, N: Calc. C 67.32; H 5.29; N 5.07;
Found C 67.15; H 5.35; N 5.17
