Note: Descriptions are shown in the official language in which they were submitted.
15~DAM7
207786
- 1 - 17977
TTTLE OF THE INVENTION
INDENYL HYDROXAMIC ACIDS AND HYDROXY UREAS AS
INHIBITORS OF 5-LIPOXYGENASE.
BACKGROUND OF THE INVENTION
The leukotrienes and their biological
activities, especially their role in various disease
states, have been extensively studied. Their
properties are described in the book Leukotrienes and
Lipoxvgenases, Ed., J. Rokach, Elsevier, New York,
1989.
Inhibitors of the 5-lipoxygenase enzyme will
prevent the biosynthesis of the various leukotrienes,
and hence have a beneficial effect in those disease
states in which the leukotrienes contribute to the
disease.
20Q7786
15/DAM7 - 2 - 17977
Various derivatives of hydroxylamine have
been described as inhibitors of the 5-lipoxygenase
enzyme. Representative compounds are to be found in
the following patent documents: EP 196,184, EP
279,263, WP 87/04152 and U.K. 2, 191, 194. None of
the above-mentioned compounds contains an indene
nucleus, a distinguishing feature of the present
invention. U.S. Patents 3,647,858 and 3,654,349
describe certain indene derivatives, which differ
considerably from the present invention in that they
are carboxylic acids rather than hydroxamic acid
derivatives. Hydroxamic acids are distinguished from
carboxylic acids by being about 4 pKA units weaker as
acids. The pKA values of hydroxamic acids (8-9) are
such that they are largely un-ionized at
physiological pH, whereas carboxylic acids (pKA 4-5)
are fully ionized. Other physical-chemical
properties, such as chelation ability, are also
notably different between the two classes of
functional groups.
SUMMARY OF THE INVENTION
The present invention relates to compounds
having activity as inhibitors of the 5-lipoxygenase
enzyme, to methods for their preparation, and to
methods and pharmaceutical formulations for using
these compounds in mammals (especially humans).
Because of their activity as inhibitors of
5-lipoxygenase, 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
~pp7°786
15/DAM7 - 3 - 17977
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 fox 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
io cytoprotective agents and for the treatment of
migraine headache.
Thus, the compounds of the present invention
may also be used to treat or prevent mammalian
especially, human) disease states 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
2o 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
3o conditions such as asthma, psoriasis, pain, ulcers
and systemic anaphylaxis. Thus inhibition of the
synthesis of such compounds will alleviate these arid
other leukotriene-related disease states.
2p~;7786
15~DAM~ - 4 - 17977
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel
compounds of the Formula I:
O
~~R5)a) m N \Z
w R~ Re
)p / 3 n
to R I
wherein:
R1 and R5 are independently:
a) hydrogen;
b) lower alkyl;
R2 and R3 are independently
c) hydrogen;
d) lower alkyl;
e) phenyl substituted with c)-d)
hereinabove or R~;
where R~ is -OR8, -SR9, -S(0)2R9,
-CN, -C02R8, or halogen;
wherein R$ is hydrogen or R9;
R9 is lower alkyl;
f) heteroaryi substituted with c)-d)
hereinabove or R~;
g) lower alkyl monosubstituted with
e) to f) hereinabove;
2~0~~86
IS~nAM~ - 5 - i~9~~
R4 is hydrogen, lower alkyl, lower alkynyl,
lower alkenyl, -OR8, -C(0)R8, -N02,
N(R8)2, -NR$C(0)R8, -R10N(R82)~
S02N(R8)2~ -SR9, -R100H, _S(0)2R9, -CN,
-C02R8, -CON(R$)2, halogen, cycloalkyl,
-R10-halogen, or cycloalkoxy;
where R8 and R9 are defined hereinabove
and R10 is lower alkyl;
to R6 is hydrogen or OM;
M is hydrogen, a pharmacetically acceptable
cation or -C(0)R11;
where R11 is lower alkyl, or phenyl
substituted with hydrogen, lower alkyl
or R~;
m is 0 to 4;
n is 0 or 1;
p is 0 to 2;
Z is lower alkyl or NR12R13.
where R12 is OM or R13; R13 is
hydrogen, lower alkyl or R12 and R13
are joined to form a heterocyclic ring
of 3 to 6 carbon atoms and 1 or 2
heteroatoms selected from N, S or 0,
provided that R12 is OM when R6 is
hydrogen or n is 0;
3o and the dotted line between positions 3 and
3~ indicates an optional double bond.
Alkyl, alkenyl, and alkynyl are intended to
include linear and branched structures and
combinations thereof.
200~~86
15~DAM7 - 6 - 17977
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, undecyl, dodecyl,
tridecyl, tetradecyl, pentadecyl, eicosyl,
3,7-diethyl-2,2-dimethyl-4-propylnonyl, 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
l0 methyl, ethyl, propyl, isopropyl, butyl, sec- and
tert-butyl, pentyl, hexyl, heptyl, and the like.
"Lower alkenyl" groups include those alkenyl
groups of 2 to 7 carbon atoms. Examples of lower
alkenyl groups include vinyl, allyl, isopropenyl,
pentenyl, hexenyl, heptenyl, 1-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-pentynyl, 2-heptynyl and the like.
The term "cycloalkyl" refers to a
hydrocarbon containing one or more rings having from
3 to 12 carbon atoms, with the hydrocarbon having up
to a total of 20 carbon atoms. Examples of
cycloalkyl groups are cyclopropyl, cyclopentyl,
cycloheptyl, adamantyl, cyclododecylmethyl,
2-ethyl-1-bicyclo(4.4.0]decyl and the like.
The term "cycloalkoxy" refers to an oxygen
attached to a hydrocarbon containing one or more
3o rings having from 3 to 12 carbon atoms with the
hydrocarbon having up to a total of 20 carbon atoms.
Examples of cycloalkoxy groups are cyclopropoxy,
cyclopentoxy, cyclododecyloxy, and the like.
20Q7_786
15/DAM7 - 7 - 17977
The term "heteroaryl" which defines R2 and
R3 refers to those monocyclic groups of 5 to 7
members containing only one heteroatom selected from
N, S, or 0 in the ring. Examples include furanyl,
pyridyl, thienyl and the like.
The term "suitably substituted hydroxylamine
hydrochloride" refered to in the Methods section
refers to hydroxylamine hydrochloride and lower alkyl
hydroxylamine hydrochloride, the latter which
includes methylhydroxylamine hydrochloride,
ethylhydroxylamine hydrochloride and the like.
Halogen includes F, C1, Br, and I.
It is intended that the definitions of any
substituent (e. g., R4, R5, etc.) in a particular
molecule be independent of its definitions elsewhere
in the molecule. Thus, -N(R$)2 represents -NHH,
-NHCH3, etc.
It is intended that the point of attachment
of the R1 substituent may be either at the 1-position
or the 2-position of the indene ring and that the
[C<R5)2 etc. substitutent is attached at the position
not occupied by Rl. It is intended that the R4
substituent(s) may occupy any of the nonfused
positions of the 6-membered ring of the indene.
The heterocycles formed when R12 and R13
join through N include pyrrolidine, piperidine,
morpholine, thiamorpholine, piperazine, and
N-methylpiperazine.
Some of the compounds described herein
3o 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
2oo~~ss
IS~nAM~ - 8 - 17977
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 pharmaceutically acceptable
salts thereof, and may also contain a pharmaceuti-
cally 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 sodium
salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts 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,NI-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. Thus M includes the above cations.
2a~7786
15~DAM7 - 9 - 17977
When the compound of the present invention
is basic, salts may be prepared from pharmaceutically
acceptable non-toxic acids, including inorganic and
organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric,
ethanesulfonic, fumaric, gluconic, glutamic,
hydrobromic, hydrochloric, isethionic, lactic,
malefic, malic, mandelic, methanesulfonic, mucic,
nitric, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric, p-toluenesulfonic acid and the
like. Particularly preferred are citric,
hydrobromic, hydrochloric, malefic, phosphoric,
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.
The ability of the compounds of Formula I to
inhibit the 5-lipoxygenase enzyme 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)
allergies and allergic reactions such as allergic
rhinitis, contact dermatitis, allergic
conjunctivitis, and the like, 3) inflammation such
asarthritis 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
20~~'786
iS~nAM~ - 10 - 1~9~~
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.
Two assays can be used to measure
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
willalso 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
3o 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
2~Q778fi
15/DAM7 - 11 - 17977
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 outside these limits in some
cases.
For use where a composition f or intravenous
administration is employed, a suitable dosage range
for anti-asthmatic, anti-inflammatory or
anti-allergic use is from about 0.001 mg to about 25
mg (preferably from 0.01 mg to about 1 mg) of a
l0 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.
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 arid for
cytoprotective use from 0.1 mg to about 100 mg
(preferably from about 1 mg to about 100 mg arid 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
3o acceptable ophthalmic formulation may be used.
The exact amount of a compound of the
Formula I to be used as a cytoprotective agent will
2007786
15~D'W - 12 - 17977
depend on, inter alia, whether it is being
administered to heal damaged cells or to avoid future
damage, 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 that might otherwise cause
1o such 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
15 NSAID, (for example, in a combination dosage form).
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,
2o 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
25 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
3o salts" refers to salts prepared from pharmaceutically
acceptable non-toxic bases or acids including
inorganic bases or acids and organic bases or acids.
2~Q~~86
15~DAM7 - 13 - 17977
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.
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
2o inhalation is a metered dose inhalation (MDI)
aerosol, which may be formulated as a suspension or
solution 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
3o 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
2007786
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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, such as, for
example, suspensions, elixirs and solutions; or
carriers such ae 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
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.
2o In addition to the common dosage forms set
out above, the compounds of Formula I may also be
administered by controlled release means
and/ordelivery devices such 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 containing 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
B
~~0?~86
15~DAM7 - 15 - 17977
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 presentation. 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
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
andeach cachet or capsule contains from about 2.5 to
about 500 mg of the active ingredient.
30
200786
15/DAM7 - 16 - 17977
The following are examples of representative
pharmaceutical dosage forms for the compounds of
Formula I:
Compound of Formula I 10
Methylcellulose 5.0
Tween* 80 0. 5
Benzyl alcohol 9.0
Benz,3lkonium chloride 1.0
Water for injection to a total volume of 1 m1
Tablet mg/tablet
Compound of Formula I 25
Microcrystalline Cellulose 415
Providone* 14.0
Pregelatinized Starch 43.5
Magnesium Stearate 2-55
500
~'~sule m,e%psule
Compound of Formula I 25
Lactose Powder 573.5
Magnesium Stearate 1.5
600
Aerosol canister per
Compound of Formula I 24 mg
Lecithin, NF Liquid Concentrate 1.2 mg
Trichlorofluoromethane, NF 4.025 gm
Dichlorodifluoromethane, NF 12.15 gm
*Trademark
B
2oo~ass
15~DAM7 - 17 - 17977
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
1o 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, preferably 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.
2o 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
3o acid, carprofen, fenbufen, fenoprofen,
fluprofen,flurbiprofen, ibuprofen, indoprofen,
ketoprofen, miroprofen, naproxen, oxaprozin,
pirprofen, prano-profen, suprofen, tiaprofenic acid,
20p778fi
15/DAM7 - 18 - 17977
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
having a free -CH(CH3)COOH or -CH2CH2COOH group
(which optionally can be in the form of a
to pharmaceutically acceptable salt group, e.g.,
-CH(CH3)C00-Na+ or -CH2CH2C00-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,
2o 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.
-CHZC00-Na+), typically attached directly to aring
3o system, preferably to an aromatic or heteroaromatic
ring system.
2~Q7786
15/DAM7 - 19 - 17977
The fenamic acid derivatives which may be
used comprise: flufenamic acid, meclof enamic 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
l0 structure:
- H -
\ / N \ /
C02 H
2o which can bear a variety of substituents and in which
the free -COON group can be in the form of a
pharmaceutically acceptable salt group, e.g.,
-C00-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.
2pp7786
i5/naro - Zo - 1~9~~
Thus, "biphenylcarboxylic acid
derivatives" as defined herein are non-narcotic
analgesics/non-steroidal anti-inflammatory drugs
which contain the basic structure:
C02 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.,
-C00-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 axe
non narcotic analgesics/non-steroidal
anti-inflammatory drugs which have the general
formula:
OH
3 0 ~ ~ ( O)
I
O O
~~0~~86
15~DAM7 - 21 - 17977
wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used:
amfenac sodium, aminoprofen, anitrazafen,
antrafenine, auranofin, bendazac lysinate,
benzydanine, beprozin, broperamole, bufezolac,
cinmetacin, ciproquazone, cloximate, dazidamine,
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
HCI, 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 HC1,
tiflamizole, tirnegadine, tolpadol, tryptamid and
ufenamate.
The following NSAIDs, designated by
company code number (see e.g., Pharmaprojects), may
also be used:
4801565, AA861, AD1590, AFP802, AFP860, AI77B, AP504,
AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382,
EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4,
2no~786
15/DAM7 - 22 - 17977
LA2851, MR714, MR897, MY309, ON03144, PR823, PV102,
PV108, 8830, RS2131, SCR152, SH440, SIR133, SPAS510,
SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-
indancarbosylic acid), TV82706, U60257, UR2301, and
WY41770.
Finally, NSAIDs which may also be used
include the salicylates, specifically acetyl
salicylic acid and the phenylbutazones, and
pharmaceutically acceptable salts thereof.
In addition to indomethacin, other preferred
NSAIDS are acetyl salicylic acid, diclof enac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen,
ketoprofen, naproxen, phenylbutazone, pirozicam,
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),
Pharmaceutical compositions comprising
the Formula I compounds may also contain as the
B
~Q~786
15/DAM7 - 23 - 17977
second active ingredient, prostaglandin antagoniete
such as those disclosed in EP 11,067 (May 28, 1980)
or thrombogane antagonists such as those disclosed in
U.S. Pat. 4,237,160. They may also contain histidine
decarbosylase inhibitors such as
a-f luoromethylhistidine, described in U.S. Pat.
4,325,961. The compounds of the Formula I may also
be advantageously combined with an H1 or
H2-receptorantagonist, 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 U.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-carboxy-chromon-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 serotonin
antagonists described in Nature, Vol. 316, pages
126-131, 1985, and the like.
3o Other advantageous pharmaceutical
compositions comprise the Formula I compounds in
combination with anti-cholinergics such as
ipratropium bromide, bronchodilators such as the beta
B
20Q7786
15~DAM7 - 24 - 17977
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.
to Representative Comvounds
Tables 1, 2 and 3 illustrate compounds
representative of the present invention.
20
30
2~07~86
15/DAM7 - 25 - 17977
Table 1
O
C R5 y ~Z
2~ m
R4
\ R~
Ia
R3
EX_. .jSR~2lmY _Z R RZ R3 R4
1
1 CH2 - - N(OH)CH3 _ H C6H4-4-SCH3 F
- CH3
2 (CH2)2 NOH CH3 CH3 H C6H4-4-SCH3 F
3 (CH2)2 NOH NHZ CH3 H C6H4-4-SCH3 F
4 (CH2)2 NOH NHCH3 CH3 H C6H4-4-SCH3 F
(CHZ)2 NOH NH(CH3)3 CH3 H C6H4-4-SCH3 F
5
6 CH2 NH N(OH)CH3 CH3 H C6H4-4-SCH3 F
7 (CH2)2 NOH NH2 CH3 H C6H4-4-S(0)CH3F
8 (CH2)2 NOH NHZ CH3 H C6H4-4-S(0)2CH3F
9 CH2 NOH NH2 CH3 H C6H4-4-SCH3 F
10 CHCH NOH NH2 CH3 H C6H4-4-SCH3 F
~
11 (CH2 NOH NH2 CH3 H C6H4-4-SCH3 F
3
12 (CHZ)4 NOH NH2 CH3 H C6H4-4-SCH3 F
13 (CH2)2 NOH NH2 H C6H4-4-SCH3H H
14 (CH2)Z NOH NH2 H C4H30* H H
15 (CHZ)2 NOH NHZ H C4H3S** H H
* 2-FURYL
** 2-THIENYL
30
2pp7786
15/DAM7 - 26 - 17977
Tabl~ 2
C H~
O
N
~2
OH
to I b
EX R3
16 C6H4-4-SCH3
17 C6H4-4-S(0)CH3
18 C6H4-4-S(0)ZCH3
Table 3
HO
N NH2
\ R~
i
CHzR3
200 7786
15/DAM7 - 27 - 17977
Table 3 (Cont'd)
EX R1 -CH2R3
19 CH3 CH2C6H4-4-SCH3
20 H CH2CH3
l0 Assays for Determining Biological ActivitX
Compounds of Formula I can be tested using
the following assays to determine their ability to
inhibit the 5-lipoxygenase enzyme.
20
30
20~~~s6
15/DAM7 - zs - 17977
Determination of Inhibition of 5-Lip~$enase
The activity of 5-lipoxygenase was measured
from the conversion of [14C]-arachidonic acid to
5-HETE and 5,12-diHETEs catalyzed by the 10,000 x g
supernatant fraction from rat PMN leukocytes, using
the procedure of Riendeau and Leblanc (Biochem.
Bioph~. Res. Common. X41, 534-540, 1986) with minor
modifications. The incubation mixture contained 25
mM Na+/K+ phosphate buffer, pH 7.3, 1 mM ATP, 0.5 mM
l0 CaCl2, 0.5 mM mercaptoethanol and an aliquot of the
enzyme preparation in a final volume of 0.2 m1. The
enzyme was pre-incubated with the inhibitor for 2 min
at 37°C before initiation of the reaction with the
addition of 2 ~1 of [14C]-arachidonic acid (25,000
DPM) in ethanol to obtain a final concentration of 10
~,M. Inhibitors were added as 500-fold concentrated
solutions in DMSO. After incubation for 10 min at
37°C, the reaction was stopped by adding 0.8 mL of
diethyl ether/methanol/1 M citric acid (30:4:1). The
samples were centrifuged at 1,000 x g for 5 min and
the organic phases analyzed by TLC on Baker Si250F-PA
or Whatman silica gel 60A LKGF plates using diethyl
ether/petroleum ether/acetic acid (50:50:1) as
solvent. The amount of radioactivity migrating at
the positions of arachidonic acid, 5-HETE and
5,12-diHETEs was determined using a Berthold TLC
analyzer LB 2842. The activity of 5-lipoxygenase was
calculated from the percentage of conversion of
arachidonic acid to 5-HETE and 5,12-diHETEs after the
10 min incubation.
2pp7~86
15/DAM7 - 29 - 17977
Rat Peritoneal Polymarphonuclear (PMN) Leukocyte Ass~~
Rats under ether anesthesia are injected
(i.p.) with 8 mL of a suspension of sodium caseinate
(6 grams in ~. 50 mL water). After 15-24 hr. the
rats are sacrificed (C02) and the cells from the
peritoneal cavity are recovered by lavage with 20 mL
of buffer (Eagles MEM containing 30 mM_ HEPES adjusted
to pH 7.4 with NaOH). The cells are pelleted (350 x
g, 5 min.), resuspended in buffer with vigorous
l0 shaking, filtered through lens paper, recentrifuged
and finally suspended in buffer at a concentration of
cells/mL. A 500 ~,L aliquot of PMN suspension and
test compound are preincubated for 2 minutes at 37°,
followed by the addition of 10 ~,M A-23187. The
suspension is stirred for an additional 4 minutes
then bioassayed for LTB4 content by adding an aliquot
to a second 500 y.L portion of the PMN at 37°C. The
LTB4 produced in the first incubation causes aggre-
gation of the second PMN, which is measured as a
2o 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 calculated
from the ratio of transmission change in the sample
to the transmission change in the compound-free
control.
Iceman Polvmorphr onu_clP,~~~?MN) Leukoc_~~TB4 Assay
A. Preparation of Human PMN. Human 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
2oo~7ss
15/DAM7 - 30 - 17977
lOx (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.l Contaminating erythrocytes were removed
by lysis following exposure to ammonium chloride
(0.16 M) in Tris buffer (pH 7.65), and the PMNs
resuspended at 5 x 105 cells/mL in HEPES (15
~)-buff Bred Hanks t~alanced salt solution containing
Ca2+ (1.4 mM) and Mg2+ (0.7 mM), pH 7.4. Viability
was assessed by Trypan blue exclusion and was
typically greater than 98~.
B. Generation and Radioimmunoassay of LTB4.
pas (0.5 mL; 2.5 x 105 cells) were placed in plastic
tubes and incubated (37°C, 2 min) with test compounds
at the desired concentration or vehicle (DMSO, final
concentration 0.2~G) as control. The synthesis of
LTB4 was initiated by the addition of calcium
ionophore A23187 (final concentration 10 EtM) or
vehicle in control samples and allowed to proceed for
5 minutes at 37~C. 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 N.L) 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
3o reaction mixture diluted 1:1 with RIA buffer were
added to reaction tubes. Thereafter [3H]-LTB4 (10
nCi in 100 ~,L RIA buff er) and LTB4-antiserum (100 ~.L
of a 1:3000 dilution in RIA buffer) were added and
* Trademark
g
2pp7786
15/DAM7 - 31 - 17977
the tubes vorteged. Reactants were allowed to
equilibrate by incubation overnight at 4'C. To
separate antibody-bound from free LTB4, aliquots (50
~,L) 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; 4°C). The supernatants containing
antibody-bound LTB4 were decanted into vials and
to Aquasol 2 (4 mL) was adc;ed. Radioactivity was
quantified by liquid scintillation spectrometry.
Preliminary studies established that the amount of
methanol carried into the radioimmunoassay did not
influence the results. The specificity of the
15 antiserum and the sensitivity of the procedure have
been described by Rokach ~ ~.2 The amount of LT84
produced in test and control (approu. 20 ag/106
cells) samples were calculated. Inhibitory
dose-response curves were constructed using a
2o four-parameter algorithm and from these the IC50
values were determined.
25 (1) Boyum, A. Stand. J. Clin. Lab Inv at_, ~;
(Supp 97), 77 (1968).
(2) Rokach, J.; Hayes, E.C.; Girard, Y.; Lombardo, D.L.;
Maycock, A.L.; Rosenthal, A.S.; Young, R.N.;
Zamboni, R.; Zweerink, H.J. Prostaglandins
30 I~euk~trienes and Medicine, ~: 21 (1984).
* Trademark
B
20p~786
15/DAM7 - 32 - 17977
Asthmatic Rat Ass~i
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
2o 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
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
3o 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.
2pp7786
15/DAM7 - 33 - 17977
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% EA in saline for exactly 1 minute, then their
l0 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
15 2 minutes prior to challenge. They are either
dissolved in saline or 1% methocel or suspended in 1%
methocel. The volume injected is 1 mL/kg
(intravenously) or 10 mL/kg (orally). Prior to oral
treatment rats are starved overnight. Their activity
20 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
25 (mg/kg) which would inhibit the duration of symptoms
by 50°!0.
Compounds of the present invention can be
prepared according to the following methods.
Temperatures are in degree Celsius.
30 It will be apparent to one skilled in the
art that the various functional groups (Rl, R2, R6
etc.) must be chosen so as to be compatible with the
chemistry being carried out. Such compatibility can
2nQ7786
15~DAM7 - 34 - 17977
often be achieved by protecting groups, or by
specific variations in the sequence of the reactions.
When R4 or R7 is S-R9, the corresponding
sulfoxides and sulfones can be prepared by oxidation
of the sulf ides with one or two equivalents of an
oxidizing agent such as m-chloroperbenzoic acid or
monoperoxyphthalic acid or oxone (Trost, J. Org.
Chem., 1988, pg. 532).
Many of the following methods involve a
1o basic hydrolysis of an ester function to obtain the
corresponding carboxylic acid. In all cases, the
free acid is obtained by acidification of the
reaction mixture with a suitable acid such as
hydrochloric, sulfuric, acetic, trifluoracetic acid,
etc.
25
2~4~~86
15/DAM7 - 35 - 17977
METHOD 1
( Ra) p ~ \ R~
- I ND
Ra
Ra
IND- CHaCOZH ~ IND- CcHz)aOH --'' IND- (cHa)zI
II III ~ IV
I ND- cH2coa r~ I ND- ( cHa) acN I ND- ( cHa) aCH( COaMe) a
X V XI
IND- <cHa)rcHO ' IND- (cHa)scOaMe
VI XII
IND- CcHz)y~-~=rroH
VII
I ND- ( cHa) rcHaNHOH
~ VIII
OH
I
I ND- CcHz)rcHaNCOrrHR
IX
2oo~~ss
15/DAM7 - 36 - 17977
METHOD 1
Intermediate I_~I_ is prepared by reduction of
the indene carboxylic acid I_~ with a reducing agent,
such as borane or lithium aluminum hydride, in a
suitable organic solvent, such as tetrahydrofuran
(THF). The hydroxyethylindene III is converted to
the iodoethylindene IV by treatment with an iodine
source, such as tetrabutylammonium iodide, in the
io presence of a hydroxyl-activating agent, such as
trifluoromethane sulfonic anhydride, in a suitable
organic solvent, such as methylene chloride. The
intermediate ~V so obtained is converted to the
cyanoethylindene V_ by treatment with a cyanide
source, such as potassium cyanide or
tetrabutylammonium cyanide, in a suitable organic
solvent, such as acetonitrile or dimethylformamide
(DMF). The nitrite V is then reduced to the aldehyde
VI_ (r=2) by treatment with a reducing agent, such as
2o diisobutyl aluminum hydride, in a suitable organic
solvent such as toluene.
The aldehyde VI so obtained is treated with
hydroxylamine hydrochloride in the presence of an
organic nitrogen base, such as triethylamine, in a
suitable organic solvent, such as ethanol, to provide
the oxime V~ (r=2). The oxime VT? is converted to
the hydroxaminoethylindene VIII (r=2) by reducing it
with a suitable reducing agent, such as
pyridine-borane complex, in the presence of a proton
3o source, such as aqueous hydrochloric acid,
2007786
15/DAM7 - 37 - 17977
in a suitable water-miscible organic solvent, such as
ethanol. The hydroxamine VIII so obtained is treated
with trimethylsilyl isocyanate in a suitable organic
solvent, such as THF, followed by treatment with
water to provide a compound ~ (r=2, R=H) of the
present invention.
Alternatively, the indene carboxylic acid
may be esterified by treating it with thionyl
chloride with methanol to provide the ester X_. This
ester X_ is converted to the aldehyde VI (r=1) by
treatment with a suitable reducing agent, such as
diisobutyl aluminum hydride, in a suitable organic
solvent, such as toluene. The aldehyde VI so
obtained may undergo the sequence of reactions
described above to provide a compound IX (r=1, R=H)
of the present invention.
Alternatively, the iodoethylindene
described above is treated with the sodium salt of
dimethyl malonate in a suitable organic solvent, such
as DMF, to provide the malonate .X~. The dimethyl
malonate XI is converted to the methyl ester X~T by
treatment with lithium chloride and water in a
suitable water miscible organic solvent, such as
dimethyl sulfoxide (DMSO). This ester X~ is
converted to the aldehyde VI (r=3) as described for
ester X. The aldehyde so obtained is converted to a
compound ~ (r=3, R=H) of the present invention by
the sequence of reactions described above.
Reacting compound VIII (r=1) with methyl
3o isocyanate or with t-butyl isocyanate in THF
provides compound IX (r=1, R = methyl or t-butyl) of
the present invention.
200786
15/DAM7 - 38 - 17977
METHOD 2
CR')p ~ ~ R' - IND
R3
Rz
IND- C~Hz)zoH -' IND- C~Ha)aHr IND- C~Hz)a~T~'
I I I XI I I ~ XI V
OH OC( O) R
IND- C~F';a)a~Co)R '--IND- C~Ha)a~Co)R ''-IND- C~Ha)a~H
XVI XV VIII
25
2007786
15/DAM7 - 39 - 17977
METHOD 2
Intermediate XIII is prepared by treatment
of the hydroxyethylindene III with carbon
tetrabromide and 1,2-bis(diphenylphosphino)ethane in
a suitable organic solvent, such as methylene
chloride. The bromoethylindene XIII so obtained is
treated with a suitably protected hydroxylamine such
as 0-(tetrahydropyran-2-yl)hydroxylamine and
potassium iodide in a suitable organic solvent, such
as DMF or acetone, to provide intermediate ~. The
intermediate XIV is deprotected by treatment with an
organic acid such as camphorsulfonic acid in a
suitable organic solvent such as methanol to provide
the hydroxylaminoethylindene VIII. The intermediate
VIII is converted to the acyloxyacylamide ~ by
treating VIII with a suitable acylating agent, such
as an acid chloride (RCOC1) or an acid anhydride
((RCO)20), and a suitable organic base, such as
2o pyridine, in a suitable organic solvent, such as
methylene chloride. The intermediate ~V_ is converted
to a compound X~. of the present invention by
treatment of ~ with a suitable weak base, such as
potassium carbonate, in a suitable organic solvent,
such as methanol. R is Z in the Formula I compounds.
2aQ~aas
15/DAM7 - 40 - 17977
METHOD 3
CR4)p ~ ~ R' - IND
R3
Ra
OH
I
I ND- cHacoaH ~ I ND- cHarrco ~ I ND- cH2NHC( o) rrR
II XVII XXVI
OH
I
I ND- cHac( o) r~R I ND- cHarrHa
XXV
XVIII
H3c ~ I ND- cHo
I
I ND- cHOH XI X
XX
I ND- cHaoH
H3C
I , XXIII
I ND- c~HO'rHP
OH
XXI ~ I
I ND- CHaI~( O) NHR
OH
XXI V
I ND- CH-NC( o) NHR
H3c XXII
2~p'7786
15~DAM7 - 41 - 17977
METHOD 3
The indene carboxylic acid 1~ is treated
with oxalyl chloride and DMF in a suitable organic
solvent such as methylene chloride and the resulting
acid chloride is treated with an azide source, such
as trimethylsilyl azide or sodium azide, in a
suitable organic solvent, such as carbon tetra-
chloride or acetonitrile, to provide the isocyanate
to ~. The isocyanate thus obtained is hydrolyzed to
the aminomethylindene XVIIL, as the hydrochloride
salt, with acetic acid and aqueous hydrochloric
acid. The free amine XVIII is obtained by
neutralizing the hydrochloride salt with an alkali
15 base, such as sodium hydroxide, in a mixture of water
and a suitable organic solvent, such as ethyl acetate
(EtOAc). The aminomethylindene xvilz is converted to
the aldehyde by first treating the amine with a
suitable chlorinating agent, such as t-butyl hypochlo-
20 rite, in a suitable organic solvent, such as diethyl
ether or tetrahydrofuran, followed by a suitable
organoalkali base, such as potassium t-butoxide, in a
suitable organic solvent, such as ethanol.
The aldehyde IX~ thus obtained is reduc-
25 tively alkylated to the hydroxyethylindene ~X by
treating compound with a suitable methylating
agent, such as methyl lithium, in a suitable organic
solvent, such as THF and ether, followed by
contacting the intermediate with a suitable proton
3o source, such as ammonium chloride in water. The
alcohol XX thus obtained is converted to intermediate
XXI by treating it with 0-<tetrahydropyran-2-yl)-
2~p778fi
i5/DAM~ - 42 - i~9~~
hydroxylamine and a suitable organic acid, such as
trifluoroacetic acid, in a suitable organic solvent,
such as methylene chloride. The intermediate X,~ is
deprotected as described in Method 2 for intermediate
~ and is then converted to a compound xxzz of the
present invention by derivatizing as described in
Method 1 for hydroxamine VIII.
Alternately, the aldehyde X~ is reduced by
contacting the aldehyde with a suitable reducing
agent, such as a combination of cerous chloride and
sodium borohydride, in a suitable organic solvent,
such as ethanol and THF, to provide the hydroxy-
methylindene XXIII. The intermediate XXIII is then
converted to a compound XXIV of the present invention
by the same sequence of reactions as described in
Method 2 to provide intermediate VIII followed by the
reactions as described in Method 1 to convert
intermediate VIII to compound ~X.
Alternately, the indene carboxylic acid
is treated with oxalyl chloride and DMF in a suitable
organic solvent, such as methylene chloride, and this
solution is added to a mixture of a suitable hydroxyl-
amine hydrochloride, such as N-methyl hydroxylamine
hydrochloride, and a suitable organic nitrogen base,
such as triethylamine, in a suitable organic solvent,
such as THF, to provide a compound ~V_ (R=Me) of the
present invention.
Alternately, the indene isocyanate XVII is
treated with a suitable hydroxylamine hydrochloride,
such as N-methylhydroxylamine hydrochloride, and a
suitable organic nitrogen base, such as
triethylamine, in a suitable organic solvent, such as
THF, to provide XXVI (R=Me) of the present invention.
~oo~~8s
15/DAM7 - 43 - 17977
METHOD 4
r~
COaMs
I
i i
I XXVI I o XXI X ~ o
XXVI I I
coar~ co,r~
I ~ i XXXVII I ~ ~ --~ I
oarts ~ XXX ~ XXXV
R 1~SC6F3a
I
CO)a
R
I i ~ XXXVIII ~ ~ off
I
~ CHz)zNHOH I ~ ~ CHa)zI~(O)NHR
oaMe
XXXI ~ XXXVI
R R MeSC6H,~
I
XXXIX (o)z
2 0 ~ R=
NC( O) NHa OH
I -C6H4SMs ~ I
OH I ~ ~ Cf'ia)z~CO)NHR
~ XXXII
R
CHa) a~H
XXXI I I
r~sC6H,~
I
C o>
OH
I
CHz ) z NC( O) NHR
~ XXXI V
rissc6H4
I
( o)
2007786
15/DAM7 - 44 - 17977
METHOD 4
Intermediate XXVI~ is treated With
glyoxylic acid hydrate and a suitable strong acid,
such as sulfuric acid, in a suitable organic solvent,
such as dioxane. The product from this reaction is
treated with methanol and thionyl chloride to provide
the methyl ester XXIX The intermediate ~ is
treated with a suitably substituted methylmagnesium
1o halide, such as 4-methylthiobenzylmagnesium bromide,
in a suitable organic solvent, such as ether, to
provide the intermediate X~X
Intermediate X~X is reduced by contacting it
with a suitable reducing agent, such as diisobutyl
aluminum hydride, in a suitable organic solvent, such
as THF and toluene. The alcohol obtained this way is
oxidized with a suitable oxidizing agent, such as a
chromium trioxide/pyridine mixture, in a suitable
organic solvent, such as methylene chloride. The
2o aldehyde obtained in this way undergoes the procedure
described in Method 1 for aldehyde VI to provide the
hydroxamine XXXI. The intermediate XXXI is then
treated as described in Method 1 for intermediate
V II to provide a compound XX I of the present
invention.
When the R group in intermediate XXXI is a
methylthiophenyl group oxidation of xxxl with
approximately one molar equivalent of a suitable
oxidizing agent, such as m-chloroperoxy benzoic acid,
3o in a suitable organic solvent, such as methylene
chloride provides the sulfoxide XXXI~. The
intermediate tXIXIII is then treated as described in
Method 1 for intermediate VIII to provide a compound
XXXIV of the present invention.
2oo~7ss
15/DAM7 - 45 - 17977
When the R group in intermediate is a
methylthiophenyl group oxidation of intermediate L
with greater than 2 molar equivalents of a suitable
oxidizing agent, such as m-chloroperoxy benzoic acid,
in a suitable organic solvent, such as methylene
chloride, provides the sulfone XXXV. The
intermediate XXXV is then treated as described in
Method 1 for intermediate ~ to provide a compound
XVI of the present invention.
1o Intermediate XXVII is treated with zinc,
methylbromoacetate and iodine in a suitable organic
solvent, such as ethyl ether, and after the mixture
is refluxed for a sufficient time, such as 3 hours,
the mixture is treated with a suitable strong acid,
such as aqueous hydrochloric acid, to decompose the
zinc complex. The product from this reaction is
treated with formic acid which provides the ester
intermediate ~XVII. The ester LV I_ is treated
with a suitable strong base, such as lithium
2o diisopropyl amide, in a suitable organic solvent,
such as THF, then a suitably substituted aldehyde,
such as 4-methylthiobenzaldehyde, 2-furaldehyde or
2-thiophene carboxaldehyde, is added. The compound
so produced is treated with a suitable strong base,
such as Triton B, in a suitable organic solvent, such
as methanol, which provides, after acidification with
a suitable aqueous acid, such as aqueous hydrochloric
acid, and subsequent treatment with diazomethane,
provides the intermediate XXXVIII. The intermediate
3o XXXVIII is then treated as described in Method 1 for
intermediate X_ which provides a compound XXXIX of the
present invention.
2007'786
15/DAM7 - 46 - 17977
METHOD ~
XXXVII C R4) P XXVII C R4) P O
4
R ) P / / ~ I ,/ ----> I / Me
Oz Me O XL
R
O
(R4)P / / CR4)P / r~
Oz ~ XLI
XLI V R
R CCzMs
C R4) ~ C R4) P / ~ Me
P / /
OH XLII
I R
CCHz)zNCCO)NHz
XL V
OH
I
CHz)zNCCO)NHz
C R4) \ ~ Me
P /
XLIII
R
2007786
15~DAM~ - 4~ -
METHOD 5
Intermediate $~ is treated with a suitable
strong base, such as LDA, in a suitable organic
solvent, such as THF and the resulting solution was
treated with a suitably substituted alkyl halide
(R-hal), such as 4-methylthiobenzyl chloride,
providing the intermediate ~. Intermediate 8~ is
treated as described in Method 4 for intermediate ~V
to provide intermediate LIB which in turn is treated
as described in Method 1 for intermediate vzlz to
provide a compound gLIII of the present invention.
Intermediate VII, described in Method 4,
is treated as described above for intermediate ~L to
provide the ester intermediate BLIV. Intermediate
gIIV is treated as described in Method 1 for
intermediate VIII to provide a compound ~V of the
present invention. R is -CH2-phenyl, as described
under definition e) of R2 and R3, or alkyl.
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.
2~~7786
15~DAM7 - 48 - 17977
EXAMPLE 1
(Z)-N-Hydroxy-N-methyl-5-fluoro-2-methyl-1-(4-
methvlthiobenz3~lidene)inden-3 vlacetamide
To a suspension of (Z)-5-fluoro-2-methyl-1-
(4-methylthiobenzylidene) inden-3-ylacetic acid (U. S.
Patent 3,647,858; U.S. Patent 3,654,349; J.O.C. Vol
42, 1914-1919 (1977) (130 mg, 0.38 mmol) in methylene
chloride (3 mL) at room temperature there was added
l0 oxalyl chloride <96.5 mg, 0.76 mmol) and one drop of
N, N-dimethylformamide (DMF). When gassing had
subsided another drop of DMF was added and stirring
was continued for 30 minutes. This solution was
added, at 0°C, to a mixture of N-methyl hydroxylamine
hydrochloride <125 mg, 1.5 mmol) and triethylamine
(253 mg, 2.5 mmol) in tetrahydrofuran (THF) (5 mL).
After 30 minutes at 0°C, the mixture was diluted with
water and ethyl acetate and acidified with 1N aqueous
HC1. The crude product from the organic extract was
2o crystallized from a mixture of ethyl acetate and
hexane to afford the title product as yellow-orange
crystals, mp: slow decomp. from 118°C.
30
2oo7~8s
15/DAM7 - 49 - 17977
EXAMPLE 2
(Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methylthio
benzylidene)inden-3 y1]eth3r N hydrox~racPiram~~p
step 1: (Z)-N-Acetoxy-{N-2-[5-fluoro-2-methyl-1-(4-
methylthiobenzylidene)inden-3-y1]-
~tl~vl~acetamide
To a suspension of (Z)-3-(2-hydroxamino-
ethyl)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)
indene from Example 3, Method A, Step 4 and Method B,
Step 4 (220 mg, 0.645 mmol) in methylene chloride (8
mL) there was added pyridine (253 mg, 3.2 mmol) and
acetyl chloride (151 mg, 1.93 mmol). The mixture was
stirred at room temperature for 1 hour. Then it was
diluted with methylene chloride, washed successively
with water, 1N aqueous HC1, water, saturated aqueous
NaHC03 and water. After drying over Na2S04, the
solvent was evaporated away and the crude title
compound used as such for the next step.
Step 2: (Z)-N-{2-[5-fluoro-2-methyl-1-<4-methylthio-
benzylidene)inden-3-y1]ethyl}-N-hydroxyacet-
~i.de
The crude diacetylated product from Step 1
was suspended in methanol (10 mL), potassium
carbonate (51 mg, 0.368 mmol) was added and the
mixture stirred at room temperature for 1 hour. The
methanol was evaporated and the residue partitioned
between ethyl acetate and water. The residue from
3o evaporation of the organic fraction was triturated
with ether and filtered to afford the title product
as a yellow solid, mp: 149-151°C, dec.
2oo~a8s
15/DAM7 - 50 - 17977
EXAMPLE 3
(Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)inden-3-3rlleth3~ -N-h3~drox~rurea
METHOD A
Step 1: Methyl (Z)-5-fluoro-2-methyl-1-(4-methyl
thiobenzvlidene)inden-3 ylacetatP
To a suspension of (Z)-5-fluoro-2-methyl-1-
l0 (4-methylthiobenzylidene)inden-3-ylacetic acid (51 g,
0.15 mol) in methanol <600 mL) at 0°C there was
slowly added thionyl chloride (26.8 g, 0.225 mol).
The mixture was then stirred at room temperature for
2 hours and filtered to afford the title compound as
a yellow solid, mp 73-75°C.
step 2: (Z)-5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)inden-3-5~lacetaldehvde
To a solution of the ester from Step 1 (3.39
g, 9.57 mmol) in toluene (75 mL) at -70°C, there was
slowly added diisobutyl aluminum hydride (1M) in
toluene <12 mL, 12 mmol) and the resulting mixture
stirred at -70°C for 45 minutes. Methanol (10 mL)
was added slowly at -70°C, then the mixture was
warmed to room temperature and water (100 mL) and 1N
aqueous HC1 (50 mL) were added. The mixture was
shaken and the organic layer collected; the aqueous
fraction was extracted with ether and the combined
organic fractions washed 3 times with water, dried
over MgS04 and evaporated down to a thick oil. The
crude title compound was used as such in the next
step.
20077s6
15~DAM7 - 51 - 17977
Step 3: (Z)-5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)-3-(2-h3rdrox~m~nnpth,~)indene
A mixture of the acetaldehyde derivative
from Step 2 (3.3 g, 10.18 mmol), hydroxylamine
hydrochloride (1.42 g, 20.4 mmol), ethanol (25 mL)
and triethylamine (2.06 g, 20.4 mmol) was stirred at
room temperature for 30 minutes. The solvent was
evaporated away and the residue was partitioned
between ethyl acetate and water. The crude product
to from the organic phase was purified by column
chromatography on silica gel using a 1:2 mixture of
ethyl acetate: hexane as eluent. The title compound
was obtained as a yellow solid, mp: 146-150°C.
Step 4 (Z)-5-fluoro-3-(2-Hydroxaminoethyl)-2-methyl
1-( 4-methylthi obenz3rl i dene 1 ins Pne
To a suspension of the oxime from Step 3
(2.0 g, 5.9 mmol) in ethanol (35 mL) at 0°C there was
added pyridine-borane <1.1 g, 11.8 mmol) and 12N
aqueous HC1 (1.48 mL, 17.75 mmol). The mixture was
stirred at 0°C for 1 hour, then warmed to room
temperature. Most of the ethanol was evaporated, the
residue diluted with water and ethyl acetate (the
product as hydrochloride salt remains in the organic
phase) and basified with 1N aqueous NaOH. The
product obtained from the organic phase was
triturated with hexane and filtered to afford the
title compound as a yellow solid, mp: 126°C dec.
3o Analysis: Calc~d for C20H20FNOS: C, 70.35; H, 5.90;
N, 4.10; S, 9.39; F, 5.56. Found: C, 70.51; H,
6.27; N, 4.15; S, 9.40; F, 5.62.
~~~7~as
15/DAM7 - 52 - 17977
Step 5: <Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methyl-
thiobenzylidene)inden-3-yl]ethyl}-N-
h5~d r oxsru r a a
To a solution of the hydroxylamine
intermediate from Step 4 (1.62 g, 4.7 mmol) in THF
(15 mL) there was added 85% trimethylsilyl isocyanate
(954 mg, 7.25 mmol). The mixture was stirred at room
temperature for 30 minutes. Water (10 mL) was added
and stirring was continued for a further 10 minutes.
to Ethyl acetate was then added, the organic layer was
decanted, washed with brine, dried over MgS04 and
evaporated to dryness. The residue was triturated
with ether and filtered to afford the pure title
product as a yellow solid, mp: 149°C dec.
METHOD B
Step 1: <Z)-5-Fluoro-3-(2-hydroxyethyl)-2-methyl-1-
(4methvlthiobenzvlidene)~ndene
To a solution of (Z)-5-fluoro-2-methyl-1-(4-
2o methylthiobenzylidene)inden-3-ylacetic acid (1.70 g,
5 mmol) in THF (25 mL) at 0°C and under nitrogen
atmosphere, there was added a solution of borane (1M)
in THF (5.5 mL, 5.5 mmol) and the mixture stirred in
the cold for 30 minutes, then at room temperature for
2 hours. More borane was added (2.5 mL) and stirring
was continued f or 1 hour. Water was added slowly (20
mL), the THF was evaporated away and the residue
partitioned between water and ethyl acetate. The
crude product from the organic phase was purified by
chromatography on silica gel using a 1:2 mixture of
ethyl acetate-hexane as eluent to afford the desired
product (1.25 g) as a yellow oil which solidified on
2007786
15/DAM7 - 53 - 17977
standing. This was triturated with hexane and
filtered to yield the title compound as a yellow
solid, mp 101-103°C.
Step 2: (Z)-3-(2-Bromoethyl)-5-fluoro-2-methyl-1-(4-
~bh3ilthiobenzylidenP ) indene
To a solution of the alcohol from Step 1
(4.8 g, 14.7 mmol) and carbon tetrabromide (6.34 g,
19.1 mmol) in methylene chloride (100 mL) at 0°C
there was added, in portions, 1,2-bis(diphenyl-
phosphino)ethane (6.34 g, 17.3 mmol). The mixture
was stirred at 0°C for 1 hour, and the solvent was
evaporated. The residue was stirred in a mixture of
ethyl acetate and water (150 mL each) for 30
minutes. After filtration, the organic portion of
the filtrate was evaporated down and the crude
product purified by column chromatography on silica
gel using 10% ethyl acetate in hexane as eluent to
afford pure title compound as a yellow oil which
solidified on standing.
Step 3: (Z)-5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)-3-[2-((tetrahydropyran-2-y1)
h3idroxamino)eth3~.] indene
A mixture of the bromide derivative from
Step 2 (4.86 g, 12.5 mmol), 0-(tetrahydropyran-2-yl)
hydroxylamine <4.39 g, 37.5 mmol) and potassium
iodide (2.08 g, 12.5 mmol) in DMF (50 mL) was heated
at 80°C for 9 hours. After standing at room
3o temperature overnight, the mixture was diluted with
ether, washed four times with water, dried over MgS04
and evaporated to dryness. The crude product was
purified by column chromatography on silica gel using
2pp7~86
15/DAM7 - 54 - 17977
a 60:40 mixture of hexane-ethyl acetate as eluent
yielding pure title compound as a thick oil which was
used in the next step.
Step 4: (Z)-5-fluoro-3-(2-Hydroxaminoethyl)-2-
methvl-1-(4-methylthiobenzylidene inden
A mixture of the indene intermediate from
Step 3 (1 g, 2.35 mmol) and (1R)-(-)-10-
camphorsulf onic acid (546 mg, 2.35 mmol) in methanol
l0 (30 mL) was refluxed for 3 hours. The methanol was
evaporated, the residue dissolved in ethyl acetate
and the solution washed successively with water,
twice with saturated aqueous sodium bicarbonate, and
with water. After drying over Na2S04, the residue
obtained on evaporation of the solvent was triturated
with ether and filtered to obtain the title compound
as a yellow solid, mp: dec 126°C which was identical
to the product obtained in Method A, Step 4.
Conversion of this intermediate to the title
2o compound was performed following the procedure of
Method A, Step 5.
EXAMPLE 4
(Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene ) inden-3-girl l ethyl -N-hydrox~r-N ~ -me hylurea
To a solution of (Z)-3-(2-hydroxamino-
ethyl)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-
indene from Example 3, Method A, Step 4 (34 mg, 0.1
mmol) in THF (0.5 mL), there was added methyl
3o isocyanate (11.4 mg, 0.2 mmol) and the mixture
stirred at room temperature for 1 hour. The solvent
was evaporated and the residue triturated with hexane
and filtered to afford the title product as a yellow-
orange solid, mp: dec 138°C.
2oo>>8s
15/DAM7 - 55 - 17977
EXAMPLE 5
(Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)inden-3-vllethvl'~-N-hvdroxv-N'-+-h"+~7 ",.o~
Following the procedure of Example 4, but
substituting t-butyl isocyanate for methyl
isocyanate, the title product was obtained in 75%
yield as a yellow solid, mp: dec 134°C.
EXAMPLE 6
l0 (Z)-N-[5-Fluoro-2-methyl-1-(4-methylthiobenzylidene)-
inden-3-ylme yes)-N~-hydroxv-N'-methyl urea
Step 1: (Z)-5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)inden-3-vlmethyl isoc3~n~tP
To a suspension of (Z)-5-fluoro-2-methyl-1-
(4-methylthiobenzylidene)inden-3-ylacetic acid (5.0
g, 14.7 mmol) in methylene chloride (50 mL) at room
temperature there was added oxalyl chloride (2.8 g,
22 mmol) and DMF (2 drops) and the mixture stirred
for 1 hour; the solution was evaporated and the crude
2o acid chloride flushed twice with carbon tetrachloride
<20 mL) then suspended in carbon tetrachloride (25
mL) and trimethylsilyl azide (2.53 g, 22 mmol) was
added. The mixture was stirred at room temperature
for 15 minutes, then gently heated on a steam bath as
nitrogen was evolved. The heating was continued
until gas evolution ceased, then the mixture was
evaporated to afford the crude title compound as an
oil which was used as such in the next step.
2007786
15/DAM7 - 56 - 17977
Step 2: (Z)-N-[5-Fluoro-2-methyl-1-(4-methylthio-
benzylidene)inden-3-ylmethyl]-N~-
hydroxy-N~-hv1 urea
To a suspension of N-methyl hydroxylamine
hydrochloride (9.82 g, 117.6 mrnol) in THF (150 mL) at
room temperature there was added triethylamine (16.3
mL, 117.6 mmol) and the mixture stirred for 10
minutes. There was added, over 15 minutes, a
solution of the isocyanate from Step 1 in THF (100
mL). After 2 hours of stirring at room temperature,
the THF was evaporated and the residue, on
trituration with water, afforded a yellow solid which
was filtered. This solid was stirred in ether (150
mL) and filtered again. This crude material was
chromatographed on silica gel eluting with 5% ethanol
in methylene chloride. The more polar component of
the mixture was stirred with methylene chloride (50
mL) for 2 hours and filtered and the solid crystal-
lized from ethyl acetate to afford the pure title
2o product as yellow crystals, mp 190-192°C dec.
Analysis: Calc~d f or C21H21FN202S: C, 65.60; H,
5.51; N, 7.29; S, 8.34; F, 4.94. Found: C, 65.88;
H, 5.43; N, 7.58; S, 8.27; F, 4.99.
EXAMPLE 7
(Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methylsulfinyl-
benzylidene)inden 3 ylleth3rl} N hvdroxv urea
Following the procedure of Example 3, Method
3o A, but substituting (Z)-5-fluoro-2-methyl-1-(4-
methylsulfinylbenzylidene)inden-3-ylacetic acid
(Sulindac) (U. S. Patent 3,647,858; U.S. Patent
3,654,349; J.O.C. Vol 42, 1914-1919 (1977)) for
2oo,~~ss
15~DAM7 - 57 - 17977
(Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)
inden-3-ylacetic acid as starting material, the title
compound was obtained as a yellow solid, mp: 132°C
dec.
EXAMPLE 8
(Z)-N-{2-[5-Fluoro-2-methyl-1-(4-methylsulfonyl-
benzvlidene)inden-3-Y1]ether -N-h dro ~ urea
Step 1: Methyl (Z)-5-fluoro-2-methyl-1-(4-methyl-
sulfon3ilbenz~rlidene)inden- -SilacetatP
To a solution of methyl (Z)-5-fluoro-2-
methyl-1-(4-methylsulfinyl benzylidene)inden-3-y1-
acetate from Example 7 (3.7 g, 10 mmol) in methylene
chloride (100 mL) there was added 85% m-chloroperoxy
benzoic acid (2.54 g, 12.5 mmol) and the mixture was
stirred at room temperature for 1 hour. There was
added more methylene chloride (100 mL) then calcium
hydroxide (5.5 g) and after 10 minutes, the
2o suspension was filtered. The residue obtained by
evaporation of the filtrate was stirred with ether
(100 mL) at room temperature for 5 hours, then
filtered to afford the title compound as a fluffy
yellow solid, mp 162-164°C.
~te_p 2 (Z)-5-Fluoro-3-(2-hydroxyethyl)-2-methyl-
1-(4-methyls~ 1.~ fonylbenz,~rl.idnriP~~ndene
To a solution of the ester from Step 1 (2.7
g, 7 mmol) in THF (20 mL) at 0°C there was added
3o diisobutyl aluminum hydride (1M) in toluene (17 mL,
17 mmol) and the mixture was stirred at 0°C for 1
hour, then quenched with methanol (10 mL). Ethyl
acetate and 1N aqueous HCl were added and after
~pp~'~86
15~DAM7 - 58 - 17977
collection of the organic phase the aqueous phase was
extracted once more with ethyl acetate. The combined
organic extracts, after washing with water three
times and drying over Na2S04, afforded on evaporation
a yellow residue which was triturated with ether to
afford the title compound as a yellow solid, mp:
102-104°C.
Step 3 (Z)-N-{-2-[5-Fluoro-2-methyl-1-(4-methyl-
sulfonylbenzylidene)inden-3-yl]ethyl}-N-
hvdrQxZr urea
Following the procedure of Example 3, Method
B, Steps 2-5, but substituting the alcohol inter-
mediate from Step 2 for (Z)-5-fluoro-3-(2-hydroxy-
ethyl)-2-methyl-1-(4-methylthiobenzylidene)indene as
starting material, the title compound was obtained as
a yellow solid, mp: 187°C.
EXAMPLE 9
(Z)-N-[5-Fluoro-2-methyl-1-(4-methylthiobenzylidene)
inden-3-3rlmeth3,r~]-N-h d~~ urea
step 1 (Z)-3-Aminomethyl-5-fluoro-2-methyl-1-(4-
~thylthioben~r idene)indemP
To a solution of (Z)-5-fluoro-2-methyl-1-
(4-methylthiobenzylidene)inden-3-ylmethyl isocyanate
from Example 6, Step 1 in acetic acid (80 mL) there
was added 12N aqueous HCl (20 mL); the mixture, which
became a suspension, was heated on a steam bath for
15 minutes, then diluted with cold water (150 mL) and
filtered. The solid was washed with water and ether
to afford the amine hydrochloride (5.1 g) as a yellow
solid. The free amine, which is unstable on
2oo~~ss
15~DAM7 - 59 - 17977
standing, was liberated just prior to use by
neutralization with aqueous 2.5N NaOH and extraction
with ethyl acetate to afford the title compound as a
dark oil.
Step 2 (Z)-5-Fluoro-3-formyl-2-methyl-1-(4-methyl-
thiobenzylidene)indene
To a suspension of freshly liberated amine
from Step 1 (11.5 g, 37 mmol) in ether (220 mL) at
0°C there was added a solution of t-butyl
hypochlorite (4.0 g) in ether (10 mL); the mixture
was stirred at 0°C for 5 minutes as a yellow solid
formed. The mixture was then allowed to warm up to
room temperature and there was slowly added a
solution of potassium tert-butoxide (15 g, 133 mmol)
in ethanol (200 mL). The mixture was boiled on a
steam bath for 10 minutes and then cooled down.
There was added 1N aqueous HC1 (200 mL) and after
stirring for 20 minutes, the mixture was extracted
2o with ether to afford the crude aldehyde which was
purified by column chromatography on silica gel,
eluting with a 1:5 mixture of ethyl acetate: hexane.
The pure title compound was obtained as an oil.
Step 3 (Z)-5-Fluoro-3-hydroxymethyl-2-methyl-1-(4-
methvlthiobenz3rlidene indene
To a solution of the aldehyde from Step 2
(1.0 g, 3.2 mmol) in ethanol (50 mL) and THF (20 mL)
there was added cerous chloride (0.79 g, 3.2 mmol)
3o and sodium borohydride (0.13 g, 3.5 mmol). The
mixture was stirred at room temperature f or 30
minutes, there was added acetone <3 mL) and after 5
minutes the mixture was diluted with brine (100 mL)
2oa7786
15~DAM7 - 60 - 17977
and extracted with ether (100 mL). The crude
material was purified by column chromatography on
silica gel, eluting with a 1:5 mixture of ethyl
acetate-hexane to afford the title compound as a
thick yellow oil.
Step 4 (Z)-N-[5-Fluoro-2-methyl-1-(4-methylthio-
benzylidene)inden-3-ylmethyl]-N-hydroxy
l0 Following the procedure of Example 3, Method
B, Steps 2-5, but substituting the alcohol inter-
mediate from Step 3 for (Z)-5-fluoro-3-(2- hydroxy-
ethyl)-2-methyl-1-(4-methylthiobenzylidene)-indene as
starting material, the title compound was obtained as
yellow needles, mp: 173-176°C dec. after crystalli-
zation from ethyl acetate-hexane.
EXAMPLE 10
(Z)-N-fl-[5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
~~ne)inden-3~i1]ethyl'-N-hydrox3r urea
Step 1 (Z)-5-Fluoro-3-(1-hydroxyethyl)-2-methyl-1-
(4-methylthiobenzylidene)indene
To a solution of aldehyde from Example 9,
Step 2 (1.5 g, 4.8 mmol) in THF (25 mL) at 0°C there
was added methyl lithium (1.4 M) in ether (3.8 mL,
5.3 mmol) and the mixture stirred at 0°C for 45
minutes; it was then quenched with saturated aqueous
ammonium chloride and extracted with ether to afford
crude material which was chromatographed on silica
gel to provide the title compound as a reddish syrup.
2007786
15~DAM7 - 61 - 17977
Step 2 (Z)-5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)-3-[1-((tetrahydropyran-2-y1)-hydrox-
amino)ethvllindene
To a solution of the alcohol from Step 1
(0.25 g, 0.75 mmol) and 0-(tetrahydropyran-2-yl)-
hydroxylamine (0.1 g, 0.85 mmol) in methylene
chloride (5 mL) at 0°C there was slowly added
trifluoroacetic acid (0.25 mL, 3.2 mmol) and the
mixture was stirred at 0°C for 2.5 hours. After
l0 quenching with brine the mixture was extracted with
ether to afford the crude title compound which was
used as such in the next step.
Step 3 (Z)-5-Fluoro-3-(1-hydroxaminoethyl)-2-methyl-
1-(4-methylthiobenzylidene)indenP
The amine intermediate from Step 2 was
heated to 50°C in methanol (20 mL) containing
(1R)-(-)-10-camphorsulfonic acid (200 mg) for 18
hours. After quenching with brine the mixture was
2o extracted with ether (100 mL). The crude material
was chromatographed on silica gel eluting with a 1:5
mixture of ethyl acetate-hexane to collect the least
polar of the two main components of the mixture.
This afforded the title compound as a yellow filmy
residue which was taken into the next step.
Step 4 (Z)-N-fl-[5-Fluoro-2-methyl-1-(4-methyl-
thiobenzylidene)inden-3-y1]ethyl}-N-
h3t roxy urea
3o Following the procedure of Example 3, Method
A, Step 5, but substituting the indene intermediate
from Step 3 for (Z)-5-fluoro-3-(2-hydroxaminoethyl)-
2-methyl-1-(4-methylthiobenzylidene)indene as
2oa~~8s
15/DAM7 - 62 - 17977
starting material, the title compound was obtained
(49 mg) as a yellow solid, mp: 150-152°C.
EXAMPLE 11
(Z)-N-~3-[5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene) inden-3-v1]'prop~l~-N-h3rdroxvurea
Step 1 (Z)-5-Fluoro-3-(2-iodoethyl)-2-methyl-1-(4-
methvlthiobenz3~lidene)indene
To a solution of (Z)-5-fluoro-3-(2-hydroxy-
to ethyl)-2-methyl-1-(4-methylthio benzylidene)indene
from Example 3, Method B, Step 1, (9.0 g, 27.6 mmol)
and tetrabutylammonium iodide (20.4 g, 55 mmol) in
pyridine (4.9 mL, 61 mmol) and methylene chloride
(180 mL), cooled to -78°C, there was slowly added
trifluoromethane sulfonic anhydride (8 mL, 47.6
mmol). The mixture was stirred at -78°C for 15
minutes, then at room temperature for one hour. It
was then diluted with methylene chloride (200 mL) and
washed successively with 10~° aqueous sodium
thiosulfate, 1N aqueous HCI, saturated sodium
bicarbonate, and brine. The crude residue from
evaporation of the organic phase was chromatographed
on a column of silica gel eluting with a 1:10 mixture
of ether-hexane to afford the title compound as a
thick yellow oil.
Step 2 (Z)-3-(2-cyanoethyl)-5-Fluoro-2-methyl-1-
~4-methylthiobenzv~idene)indenP
A mixture of the iodide from Step 1 (3.7 g,
8.5 mmol) and potassium cyanide (5.5 g, 85 mmol) in
DMF (40 mL) was stirred at room temperature for 45
minutes. There was added water (50 mL) and brine
(100 mL) and the mixture was extracted with 1:1 ethyl
20~7~86
15/DAM7 - 63 - 17977
acetate-hexane (4 x 100 mL); the combined extracts
were washed with water (2 x 50 mL) and brine (1 x 50
mL), dried and evaporated. The crude residue was
chromatographed on silica gel eluting with a 1:2
mixture of ether-ethyl acetate to afford the title
compound as a yellow oil.
Step 3 (Z)-5-Fluoro-3-(2-formylethyl)-2-methyl-1-
(4-methvlthioben~y~.idene)indene
l0 To a solution of the nitrile from Step 2
(415 mg, 1.24 mmol) in toluene (4.5 mL) at -78°C
there was added diisobutyl aluminum hydride <1M) in
toluene (1.9 mL, 1.9 mmol) and the mixture was
stirred at -78°C for 2 hours; methanol (2 mL) was
added and the mixture allowed to warm to room
temperature. After partition between ether and
water, the residue from evaporation of the organic
fraction was chromatographed on silica gel eluting
with a 1:2 mixture of ether: hexane to afford the pure
title compound as an oil which solidified on standing.
Step 4 (Z)-N-{3-[5-Fluoro-2-methyl-1-(4-methyl-
thio-3.nzylidene)inden-3-yl]propyl~-N-
hvdroxv urea
Following the procedure of Example 3, Method
A, Steps 3-5, but substituting the aldehyde from Step
3 for (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzyl-
idene)inden-3-ylacetaldehyde as starting material,
the pure title compound was obtained after
chromatography on silica gel, eluting with a 1:30
mixture of methanol:methylene chloride, as a yellow
solid, mp: 145-147°C.
~oo~~8s
15/DAM7 - 64 - 17977
EXAMPLE 12
(Z)-N-{4-[5-Fluoro-2-methyl-1-(4-methylthiobenzyl-
idene) inden-3-yl]but~~ -N-hydroxv urea
Step 1 Dimethyl (Z)-5-fluoro-2-methyl-1-
(4-methylthiobenzylidene)inden-3-y1
malonate
To a suspension of 60% sodium hydride
dispersion in oil (550 mg, 13.8 mmol) in DMF (25 mL)
1o at 0°C there was added dimethyl malonate (1.6 mL,
13.8 mmol) and the mixture was stirred at 0°C for 1
hour affording a suspension. To this was added a
solution of (Z)-5-fluoro-3-<2-iodoethyl)-2-methyl-1-
(4-methylthiobenzylidene)indene, from Example 11,
Step 1, (2.0 g, 4.6 mmol) in DMF (15 mL) and the
mixture stirred at 0°C as gradually a solution
resulted; the mixture was then stirred at room
temperature for 6 hours. There was added water and
brine and the mixture was extracted 3 times with
2o ether. Combined extracts were washed twice with
brine, dried and after evaporation the residue was
chromatographed on silica gel eluting with a 1:2
mixture of ether-hexane to afford the title compound
as an oil.
Step 2 Methyl (Z)-4-[5-fluoro-2-methyl-1-(4-methyl-
thiobenzvlidene)inden-3-vilbvtan~ata
A mixture of the diester from Step 1 (1.5 g,
3.4 mmol), lithium chloride (0.29g, 6.8 mmol), water
(61 ML, 3.4 mmol) and dimethyl sulfoxide (10 mL) was
refluxed for 30 minutes. After having been cooled to
room temperature, the mixture was diluted with water
(50 mL) and brine (50 mL), then extracted with a 1:1
~,~p7~786
15/DAM7 - 65 - 17977
mixture of ether:ethyl acetate <3 x 50 mL). The
combined extracts were washed twice with water, dried
and evaporated to a residue which was purified by
chromatography on silica gel eluting with a 1:2
mixture of ether-hexane to afford the title compound
as an oil.
Step 3 <Z)-N-f4-[5-Fluoro-2-methyl-1-(4-methyl-
thiobenzylidene)inden-3-y1]butyl}-N-
to hydroxy urea
Following the procedure of Example 3, Method
A, Steps 2-5, but substituting the ester of Step 2
for methyl (Z)-5-fluoro-2-methyl-1-(4-
methylthiobenzylidene)inden-3-ylacetate as starting
material, the N-hydroxy urea derivative was
obtained. After chromatography on silica gel,
eluting with a 1:20 mixture of methanol:methylene
chloride, followed by trituration with ether and
filtration, the pure title compound was obtained as a
2o yellow solid, mp: 154-157°C.
'gXAMPLE 13
(E)-N-{2-[1-(4-Methylthiobenzylidene)inden-3-y1]
ethvl~-N-hydroxy urea
Step 1 Methvl inden-3~~lacetatP
Following the procedure of Example 19, Step
2, but substituting 1-indanone for 2-methyl-
3-(4-methylthiobenzyl)-1-indanone, there was obtained
the title compound as an oil.
~te~ 2 Methyl (E)-1-(4-methylthiobenzylidene)-
inden-3-ylacetatP
To a solution of methyl inden-3-ylacetate (2
200~78fi
15/DAM7 - 66 - 17977
g, 10.6 mmol) in dry THF (20 mL) at -70°C was added
dropwise a solution of LDA in THF (25.7 mL, 0.87 M,
2.1 eq.). The resulting orange solution was stirred
30 minutes at -70°C and then 4-methylthiobenzaldehyde
(1.6 mL, 11.7 mmol, 1.1 eq.) was added dropwise. The
cooling bath was removed and the reaction mixture was
left to warm up to room temperature while a
precipitate appeared. The reaction mixture Was then
quenched with a saturated aqueous solution of
ammonium chloride and extracted twice with ethyl
acetate. The organic phase was washed twice with 1N
aqueous HC1, then with brine and dried over MgS04 and
evaporated to dryness. The residue was dissolved in
methanol (5 mL) and a solution of benzyltrimethyl-
ammonium hydroxide in methanol (Triton*B, 1.4 M) (6
mL) was added at room temperature. After 10 minutes
the reaction mixture was added to 1N aqueous HC1 and
extracted with ethyl acetate. The organic layer was
treated with ethereal diazomethane, dried over MgS04
2o and evaporated to dryness. The residue was
chromatographed on silica gel eluting with a 95:5
mixture of hexane-ethyl acetate to afford the title
compound, as an oil.
p.m.r (250 MHz, CDC13): 8 2.5 (s, 3H, SMe), 3.65 (s,
2H, CH2C0), 3.75 (s, 3H, C02Me), 6.95 (s, 1H), 7.25 -
7.35 (m, 5H), 7.4 (s, 1H), 7.55 (d, 2H), 7.7 ppm (dd,
1H).
3o The E-configuration of the product was
established via Nuclear Overhauser effect (NOE)
experiments.
* Trade:~ark
B
200~~86
15/DAM7 - 67 - 17977
Step 3 (E)-N-{2-[1-(4-Methylthiobenzylidene)-
inden-3-vllethyl~-N-h.~~droxv urea
Following the procedure of Example 3, Method
A, Steps 2-5, but substituting the ester of Step 2
for methyl (Z)-5-fluoro-2-methyl-1-(4-methylthio-
benzylidene)inden-3-ylacetate as starting material,
the title product was obtained in 17% overall yield,
mp: 175-176°C.
EXAMPLE 14
(E)-N-f2-[1-(2-Furylmethine)inden-3-yl]ethyl~-
N-hvdroxv urea
Following the procedure of Example 13, Steps
2 and 3, but substituting 2-furaldehyde for
4-methylthiobenzaldehyde as starting material, the
title product was obtained in 22% overall yield, m.p.
140-141°c.
2 o EXAMPLE 1~
(E)-N-(2-[1-(2-Thienylmethine)inden-3-y1]ethyl)-N-
hvdroxv urea
Following the procedure of Example 13, Steps
2 and 3 but substituting 2-thiophene carboxaldehyde
for 4-methylthiobenzaldehyde as starting material,
the title product was obtained in 18% overall yield,
mp: 145°C.
Analysis: Calc~d for C17H1602N2S: C, 65.37; H,
5.17; S, 10.24; N, 8.97. Found: C, 65.25; H, 5.30;
S, 10.11; N, 8.85.
200786
15~DAM7 - 68 - 17977
EXAMPLE 16
(Z)-N-{2-[3-Methyl-1-(4-methylthiobenzylidene)inden-
2-y1]lethyl~h~ d~ roxy urea
Step 1 1-Methvl-3-oxo-2-indenvl~dene acetic acid
A mixture of 3-methylindan-1-one (J.C.S.
Chem. Comm. 1973, 636) (2.0 g, 13.7 mmol),
glyoxylicacid hydrate (12.6g, 137 mmol), dioxane (96
mL) and sulfuric acid (8.2 mL) was stirred at 95°C
for 45 minutes. Water (100 mL) was added, and the
l0 dioxane evaporated. The residual aqueous suspension
was diluted with water and filtered to afford the
title compound as a yellow solid.
Step 2 Methyl 1-methyl-3-oxo-2-indenXlidene acetate
To a solution of the acid from Step 1 (1.25
g, 6.2 mmol) in methanol (20 mL) there was slowly
added thionyl chloride (1.1 g, 9.3 mmol) and the
mixture stirred at room temperature for 22 hours. On
concentration to a small volume, a solid crystallized
out and was filtered to afford the title ester as
light yellow crystals, mp: 96-97°C.
~teu~ Methyl (Z)-3-methyl-1-(4-methylthiobenzyl-
idene)inden-2-ylacetate
To a solution of the ester from Step 2 (560
mg, 2.6 mmol) in ether (5 mL) at 0°C was added a
solution in ether of 4-methylthiobenzylmagnesium
chloride (0.21 M, 13.6 mL, 1.1 eq). After complete
addition, acetic acid (0.2 mL) was added followed by
an aqueous solution of ammonium chloride. The
reaction mixture was extracted with ethyl acetate and
the organic layer was washed with brine, dried over
MgS04 and evaporated to dryness. The crude material
2pp7786
15/DAM7 - 69 - 17977
was stirred for 2 h at 50-60°C with a mixture of
acetic acid: water: 12N HCI, 10:1:3 (8 mL). Water
was added and the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with
brine, dried over MgS04 and evaporated. The crude
product was chromatographed on silica gel eluting
with a 1:9 mixture of ethyl acetate: hexane to afford
the title compound as an oil.
p.m.r (250 MHz, CDC13): 8 2.2 (s, 3H, vinylic CH3),
2.55 (s, 3H, SMe), 3.6 (s, 2H, CH2C0), 3.7 (s, 3H,
C02CH3), 6.8-7.7 ppm (m, 9H).
~te~ 4 (Z)-2-(2-Hydroxyethyl)-3-methyl-1-(4-methyl-
thiobenzylidene)indene
To a solution of the ester from Step 3 (270
mg, 0.83 mmol) in dry THF (5 mL) at 0°C was added a
solution of diisobutyl aluminum hydride (1M) in
toluene (2.1 mL, 2.1 mmol, 3.5 eq). After 1 hour,
2o the reaction mixture was added dropwise to a solution
of 1N aqueous HC1 and extracted with ethyl acetate.
The organic phase was washed with brine, dried over
MgS04 and evaporated to dryness. The crude product
was chromatographed on silica gel eluting with a 1:3
mixture of ethyl acetate-hexane to afford pure title
compound as a yellow oil.
p.m.r (250 MHz, CDC13); 8 2.2 (s, 3H, vinylic CH3),
2.55 (s, 3H, SMe), 2.9 (t, 2H, J = 7Hz, CH2), 3.8 (t,
2H, J = 7Hz, CH2), 6.95 (m, 1H), 7.1 (s, 1H), 7.2-7.3
(m, 4H), 7.45 ppm (d, 3H).
._ zoo~~8s
15~DAM7 - 70 - 17977
Step 5 (Z)-3-Methyl-1-(4-methylthiobenzylidene)-
inden-2-3rlacetalde~vde
A solution of the primary alcohol from Step
4 (1 g, 3.25 mmol) in dichloromethane (10 mL) was
added dropwise to a mixture of chromium trioxide (3.3
g, 32 mmol, 10 eq.) in dichloromethane (50 mL) at 0°C
containing pyridine (5.1 mL, 63 mmol, 20 eq.). After
1.5 hour, ether was added to precipitate the chromium
salts and the heterogenous mixture was filtered
through silica gel and washed with ether. After
evaporation to dryness, the residue was purified by
chromatography on silica gel eluting with a 15:85
mixture of ethyl acetate-hexane to yield the title
compound as a yellow oil.
p.m.r. (250 MHz, CDC13): 8 2.2 (s, 3H, vinylic CH3,
2.5 (s, 3H, SCH3), 3.6 (d, 2H, J = 2.5 Hz, CH2C0),
7.0 (m), 7.3 (m), 7.45 (dd, J = 11, 7.5 Hz), 7.8 (d,
J = 9 Hz), 9.7 ppm (t, 1H, CHO).
Step 6 (Z)-N-{2-[3-Methyl-1-(4-methylthiobenzylid-
~r~P,~)-inden-2-vllethv'l~-N-hvdroxv urea
Following the procedure of Example 3, Method
A, Steps 3-5, but substituting the aldehyde of Step 5
for (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylid-
ene)inden-3-ylacetaldehyde as starting material, the
title compound was obtained, mp: 120-122°C.
2oo~~8s
15/DAM7 - 71 - 17977
EX~I~LE 17
(Z)-N-{2-[3-Methyl-1-(4-methylsulfinylbenzylidene)-
inden-2-ylleth3~l~-N-hydroxy urea
Step 1 (Z)-2-(2-hydroxaminoethyl)-3-methyl-1-(4-
methylsulfinylbenzylidene)indene
To a solution of the hydroxylamine from
Example 16, Step 6 (130 mg, 0.40 mmol) in
dichloromethane (5 mL) at 0°C was added in one
portion 85% m-chloroperoxy benzoic acid (90 mg, 0.44
io ~nol, 1.1 eq.). After 45 minutes the reaction
mixture was diluted with dichloromethane and washed
successively with 1N aqueous sodium hydroxide, water,
brine, dried over MgS04 and evaporated to dryness.
The residue was chromatographed on silica gel eluting
with a 30:1 mixture of dichloromethane:methanol to
yield the title compound as a yellow oil.
Step 2 (Z)-N-{2-[3-Methyl-1-(4-methylsulfinyl-
benzylidene)inden-2-y1]ethyl}-N-hydroxy
Following the procedure of Example 3, Method
A, Step 5, but substituting the hydroxylamine of Step
1 for (Z)-5-fluoro-3-(2-hydroxaminoethyl)-2-
methyl-1-(4-methylthiobenzylidene)indene as starting
material, the N-hydroxy urea derivative was
obtained. After chromatography on silica gel eluting
with a 5:95 mixture of methanol:methylene chloride,
the pure title compound was obtained in 91% yield,
mp: 166-169°C.
200786
15/DAM7 - 72 - 17977
EXAMPLE 18
(Z)-N-{2-[3-Methyl-1-(4-methylsulfonylbenzylidene)-
inden-2-yl~'ethyll-N-h~idroxv urea
Step 1 Methyl (Z)-3-methyl-1-(4-methylsulf onyl-
benzylidene)inden-2-vlacetate
To a solution of methyl (Z)-3-methyl-1-(4-methyl-
thiobenzylidene) indene-2-yl acetate from Example 16,
Step 3, (1 g, 3.1 mmol) in dichloromethane (30 mL) at
0°C was added in one portion 85% m-chloroperoxy
l0 benzoic acid (1.6 g, 7.7 mmol, 2.5 eq.). The
reaction mixture was stirred at 0°C for 30 minutes,
then diluted with dichloromethane and washed
successively with an aqueous solution of 1N sodium
hydroxide, brine, dried over MgS04 and evaporated to
dryness. The crude product was purified by flash
chromatography eluting with a 65:35 mixture of
hexane-ethyl acetate to afford the title compound .
p.m.r (250 MHz, CDC13): S 2.2 (s, 3H, vinylic CH3),
3.15 (s, 3H, S02CH3), 3.6 (s, 2H, CH2C0), 3.7 (s, 3H,
C02CH3), 6.95 (m, 1H), 7.1 (s, 1H), 7.15-7.3 <m, 3H),
7.75 (d, 2H, J = 7.5 Hz), 8.8 ppm (d, 2H, J = 7.5 Hz).
Step 2 (Z)-N-{2-[3-Methyl-1-(4-methylsulfonyl-
benzylidene)inden-2-yl]ethyl}-N-hydroxy
Following the procedure of Example 3, Method
A, Steps 2-5, but substituting the ester from Step 1
for (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)
3o inden-3-ylacetate as starting material, the title
compound was obtained in 27% overall yield, mp:
140-142°C.
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15/DAM7 - 73 - 17977
EXAMPLE 19
N-{2-[2-Methyl-1-(4-methylthiobenzyl)inden-3-yl]-
P t hx1 -~ N-h3r d_ r ox<r a r a a
Step 1 2-Meth3rl-3-(4-methylthiobenzyl)-1-indanon~
To a cooled solution (-70°C) of LDA (1 M) in
THF (37 mL) was added dropwise a solution of
2-methyl-1-indanone (J.A.C.S. Vol. 98, 8119-8124
(1976)) (2.5 g> 17 mmol) in THF (20 mL). The
resulting dark red solution was stirred at room
temperature for 3 hours, then cooled to -20°C and a
solution of 4-methylthiobenzyl chloride (3.1 g, 18
mmol) in THF (15 mL) was added slowly. The addition
completed, the reaction mixture was stirred at -20°C
for 30 minutes before being quenched with 3N aqueous
HCl (50 mL) and brine (50 mL). The product was
extracted with ether, dried over MgS04 and evaporated
to dryness. The oily residue was chromatographed on
silica gel eluting with a 1:5 mixture of ethyl
acetate-hexane to afford the pure title compound as
an oil.
S~e~ 2 Methyl 2-methyl-3-(4-methylthiobenzyl)-
ir~aen-1-5r.~acezaze
To a solution of the indanone derivative
from Step 1 (885 mg, 3.14 mmol) in ether (20 mL) were
added successively zinc (840 mg, 12.8 mmol), methyl
bromoacetate (0.5 mL, 5 mmol) and iodine <200 mg).
The reaction mixture was refluxed for 3 hours, then
cooled to 0°C and 6N aqueous HC1 was added dropwise
until the zinc complex was completely decomposed.
The organic layer was decanted, washed with brine,
dried over Na2S04 and evaporated to dryness. The
oily residue was dissolved in formic acid and
15~DAM7 - 74 - 17977
evaporated to dryness to complete the dehydration of
the intermediate methyl [1-hydroxy-2-methyl-
3-<4-methylthiobenzyl)indan-1-yl]acetate. The
resulting oily residue was chromatographed on silica
gel eluting with a 1:19 mixture of ethyl
acetate-hexane to afford pure title compound as an
oil.
Steg 3 N-{2-[2-Methyl-1-(4-methylthiobenzyl)-
io inden-3-yllethXl -N-h3~dr~~ urea
Following the procedure of Example 3, Method
A, Steps 2-5, but substituting the ester from Step 2
for methyl (Z)-5-fluoro-2-methyl-1- (4-methylthio-
benzylidene)inden-3-ylacetate as starting material,
15 the title compound was obtained in 44% overall yield,
mp: 163-164°C.
Analysis: Calc'd for C21H24N2~2S~ C, 68.45; H,
6.56; N, 7.60; S, 8.70. Found: C, 68.22; H, 6.85;
2o N, 7.30; S, 8.55.
EXAMPLE 20
N-I~2-(1-Eth3rlinden-3-3r1)ethyll-N-hard-_rox<r urea
Step 1 Meth~rl l,l-eth5rlinden-3-v1)acetate
To a solution of methyl inden-3-ylacetate
from Example 13, Step 1 (1 g, 5.32 mmol) in THF (10
mL) at -70°C was added dropwise a solution of LDA
(12.2 mL, 0.87 M, 2 eq.) in THF. The resulting
3o orange solution was stirred for 30 minutes at -70°C
and then ethyl iodide (0.47 mL, 5.85 mmol) was added
dropwise. The cooling bath was removed and the
reaction mixture was left to warm to room temperature
20~D~~86
15~DAM7 - 75 - 17977
while a precipitate appeared. The reaction mixture
was then quenched with a saturated aqueous solution
of ammonium chloride and extracted with ethyl
acetate. The organic layer was washed with 1N HC1,
then with brine, dried over MgS04 and evaporated to
dryness. The oily residue was chromatographed on
silica gel eluting with a 1:19 mixture of ethyl
acetate-hexane to afford pure title compound as an
oil.
Step 2 N 12-C1-eth5rlinden-3-vl)eth3il]-N-hydroxy urea
Following the procedure of Example 3, Method
A, Steps 2-5, but substituting the ester of Step 1
for methyl (Z)-5-fluoro-2-methyl-1-(4-methyl
15 thiobenzylidene)inden-3-ylacetate as starting
material, the title compound was obtained in 66%
overall yield, mp: 81-83°C.
Analysis: Calc~d for C14H18N202; C, 68.25; H, 7.37;
20 N, 11.38. Found: C, 68.29; H, 7.50; N, 11.09.
30
