Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
HETEROARYL DIOL ACIDS AS LEUKOTRIENE ANTAGONISTS
BACKGROUND OF THE INVENTION
The leukotrienes constitute a group of locally acting
hormones, produced in living systems from arachidonic acid. The major
leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4,
and LTE4. The biosynthesis of these leukotrienes begins with the action
of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide
known as Leukotriene A4 (LTA4), which is converted to the other
leukotrienes by subsequent enzymatic steps. Further details of the
biosynthesis as well as the metabolism of the leukotrienes are to be found
in the book Leukotrienes and LipoxXgenases, ed. J. Rokach, Elsevier,
Amsterdam (1989). The actions of the leukotrienes in living systems and
their contribution to various diseases states are also discussed in the book
by Rokach.
Recently a number of compounds of formula (a) in which A
represents optionally substituted heterocycle, and pharmaceutically
acceptable salts thereof, have been disclosed as leukotriene antagonists
and inhibitors of leukotriene biosynthesis.
CO2H
S QJOH
(a)
EP 480,717 discloses compounds of formula (a) in which A
represents optionally substituted quinoline; more specifically disclosed is
the compound in which A represents 7-chloro-2-quinolinyl. US Patent
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5,270,324 discloses two compounds of formula (a) in which A represents
6-fluoro- or 6,7-difluoro-2-quinolinyl. EP Published Application 604,114
discloses compounds in which A is halo-substituted thienopyridine,
particularly 2,3-dichlorothieno[3,2-b]pyridin-5-yl.
SUMMARY OF THE INVENTION
The present invention relates to unsaturated heteroaryl diol
acid compounds having activity as leukotriene antagonists, to methods for
their preparation, and to methods and pharmaceutical formulations for
using these compounds in mammals (especially humans).
Because of their activity as leukotriene antagonists, the
compounds of the present invention are useful as anti-asthmatic, anti-
allergic, anti-inflammatory, and cytoprotective agents. They are also
useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis,
endotoxemia, uveitis, and allograft rejection.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention are best realized by the
Formula I:
R2 S . (CR3R3)mCO2H
R~ (CH26
H R4
CH3
CH2R5
OH
I
wherein
A and the pyridine ring to which it is fused together represent quinolinyl
or thienopyridinyl;
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R 1 and R2 are independently hydrogen or halogen;
R3 is H, lower alkyl, CF3 or two R3 groups joined to the same
carbon form a 3- to 5-membered carbocyclic ring
one of R4 and R5 is H and the other is OH;
mis lto5;
m' is 1 or 2;
or a pharmaceutically acceptable salt thereof.
In one preferred embodiment, the bicyclic heterocylic
fragment
R2
R'A IN
is selected from quinoline and thieno[3,2-b]pyridine. More preferred are
substituted bicyclic heterocycles selected from 7-chloroquinolin-2-yl, 6,7-
difluoroquinolin-2-yl and 2,3-dichlorothieno [3,2-b]pyridin-5-yl.
In another preferred embodiment, (CR3R3)m represents
-CH2C(CH2CH2)CH2-.
Another preferred embodiment provides compounds of
formula I in which R4 is H and R5 is OH.
Yet another preferred embodiment provides compounds of
formula I in which R5 is H and R4 is OH.
In the application "lower alkyl" includes linear, branched
and cyclic structures of from 1 to 7 carbon atoms. Examples of lower
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-
butyl, pentyl, hexyl, heptyl, and the like.
Halogen includes F, Cl, Br, and I.
When a variable occurs more than once in a molecule, each
occurrence of that variable is defined independently of the others. For
example CR3R3 may be -CH2-, -CHCH3-, etc, and (CR3R3)3 may
represent -CH2C(CH2CH2)CH2-.
Abbreviations
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Ac = acetyl
DMAP = 4-(dimethylamino)pyridine
DMF = N,N-dimethylformamide
DMSO = dimethyl sulfoxide
EA (EtOAc)= ethyl acetate
Hex = hexane
NEt3 = triethylamine
Ms = methanesulfonyl = mesyl
NBS = N-bromosuccinimide
NSAID = non-steroidal anti-inflammatory drug
Ph = phenyl
PPTS = pyridinium para-toluenesulfonate
r.t. = room temperature
rac. = racemic
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
Tol = toluene
Alkyl group abbreviations
Me = methyl
Et = ethyl
n-Pr = normal propyl
i-Pr = isopropyl
n-Bu = normal butyl
i-Bu = isobutyl
s-Bu = secondary butyl
t-Bu = tertiary butyl
c-Pr = cyclopropyl
c-Bu = cyclobutyl
c-Pen = cyclopentyl
c-Hex = cyclohexyl
Optical Isomers - Diastereomers - Geometric Isomers
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Compounds described herein contain one or more
asymmetric centers and may thus give rise to diastereomers and optical
isomers. The present invention is meant to comprehend such possible
diastereomers as well as their racemic and resolved, enantiomerically
pure forms and pharmaceutically acceptable salts thereof.
Salts
The pharmaceutical compositions of the present invention
comprise a compound of Formula I as an active ingredient or a
pharmaceutically acceptable salt thereof, and may also contain a
pharmaceutically acceptable carrier and optionally other therapeutic
ingredients. The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases including
inorganic bases and organic bases, or acids including inorganic and
organic acids.
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,N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,
glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
Salts derived from pharmaceutically acceptable non-toxic
inorganic and organic acids include acetic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,
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hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
Particularly preferred are citric, hydrobromic, hydrochloric, maleic,
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.
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Utilities
The ability of the compounds of Formula I to antagonize the
actions of the leukotrienes makes them useful for preventing or reversing
the symptoms induced by the leukotrienes in a human subject. This
antagonism of the actions 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 disorders
including diseases such as asthma, chronic bronchitis, and related
obstructive airway diseases, 2) allergies and allergic reactions such as
allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like,
3)
inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5)
skin disorders such as atopic eczema, and the like, 6) cardiovascular
disorders such as angina, myocardial ischemia, hypertension, platelet
aggregation, and the like, 7) renal insufficiency arising from ischaemia
induced by immunological or chemical (cyclosporin) etiology, 8)
migraine or cluster headache, 9) ocular conditions such as uveitis, 10)
hepatitis resulting from chemical, immunological or infectious stimuli,
11) trauma or shock states such as burn injuries, endotoxemia, and the
like, 12) allograft rejection, 13) prevention of side effects associated with
therapeutic administration of cytokines such as Interleukin II and tumor
necrosis factor, 14) chronic lung diseases such as cystic fibrosis,
bronchitis and other small- and large-airway diseases, and 15)
cholecystitis.
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; diarrhea; cerebral spasm;
premature labor; spontaneous abortion; dysmenorrhea; ischemia; noxious
agent-induced damage or necrosis of hepatic, pancreatic, renal, or
myocardial tissue; liver parenchymal damage caused by hepatoxic agents
such as CC14 and D-galactosamine; ischemic renal failure; disease-
induced hepatic damage; bile salt induced pancreatic or gastric damage;
trauma- or stress-induced cell damage; and glycerol-induced renal failure.
The compounds also exhibit cytoprotective action.
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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.
Dose Ranges
The magnitude of prophylactic or therapeutic dose of a
compound of Formula I will, of course, vary with the nature of the
severity of the condition to be treated and with the particular compound
of Formula I and its route of administration. It will also vary according to
the age, weight and response of the individual patient. In general, the
daily dose range for anti-asthmatic, anti-allergic or anti-inflammatory use
and generally, uses other than cytoprotection, lie within the range of from
about 0.00 1 mg to about 100 mg per kg body weight of a mammal,
preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1
mg per kg, in single or divided doses. On the other hand, it may be
necessary to use dosages outside these limits in some cases.
For use where a composition for intravenous administration
is employed, a suitable dosage range for anti-asthmatic, anti-
inflammatory, or anti-allergic use is from about 0.001 mg to about 25 mg
(preferably from 0.01 mg to about 1 mg) of a compound of Formula I per
kg of body weight per day and for cytoprotective use from about 0.1 mg
to about 100 mg (preferably from about 1 mg to about 100 mg and more
preferably from about 1 mg to about 10 mg) of a compound of Formula I
per kg of body weight per day.
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In the case where an oral composition is employed, a
suitable dosage range for anti-asthmatic, anti-inflammatory or anti-
allergic use is, e.g. from about 0.01 mg to about 100 mg of a compound
of Formula I per kg of body weight per day, preferably from about 0.1 mg
to about 10 mg per kg and for cytoprotective use from 0.1 mg to about
100 mg (preferably from about 1 mg to about 100 mg and more
preferably from about 10 mg to about 100 mg) of a compound of Formula
I per kg of body weight per day.
For the treatment of diseases of the eye, ophthalmic
preparations for ocular administration comprising 0.001-1% by weight
solutions or suspensions of the compounds of Formula I in an acceptable
ophthalmic formulation may be used.
The exact amount of a compound of the Formula I to be used
as a cytoprotective agent will depend on, inter alia, whether it is being
administered to heal damaged cells or to avoid future 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 an
NSAID that might otherwise cause 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
NSAID, (for example, in a combination dosage form).
Pharmaceutical Compositions
Any suitable route of administration may be employed for
providing a mammal, especially a human with an effective dosage of a
compound of the present invention. For example, oral, rectal, topical,
parenteral, ocular, pulmonary, nasal, and the like may be employed.
Dosage forms include tablets, troches, dispersions, suspensions, solutions,
capsules, creams, ointments, aerosols, and the like.
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The pharmaceutical compositions of the present invention
comprise a compound of Formula I as an active ingredient or a
pharmaceutically acceptable salt thereof, and may also contain a
pharmaceutically acceptable carrier and optionally other therapeutic
ingredients. The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral,
rectal, topical, parenteral (including subcutaneous, intramuscular, and
intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation),
or nasal administration, although the most suitable route in any given case
will depend on the nature and severity of the conditions being treated and
on the nature of the active ingredient. They may be conveniently
presented in unit dosage form and prepared by any of the methods well-
known in the art of pharmacy.
For administration by inhalation, the compounds of the
present invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or nebulisers. The compounds
may also be delivered as powders which may be formulated and the
powder composition may be inhaled with the aid of an insufflation
powder inhaler device. The preferred delivery system for inhalation is a
metered dose inhalation (MDI) aerosol, which may be formulated as a
suspension or solution of a compound of Formula I in suitable
propellants, such as fluorocarbons or hydrocarbons.
Suitable topical formulations of a compound of formula I
include transdermal devices, aerosols, creams, ointments, lotions, dusting
powders, and the like.
In practical use, the compounds of Formula I can be
combined as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of forms
depending on the form of preparation desired for administration, e.g., oral
or parenteral (including intravenous). In preparing the compositions for
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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 as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating agents and
the like in the case of oral solid preparations such as, for example,
powders, capsules and tablets, with the solid oral preparations being
preferred over the liquid preparations. Because of their ease of
administration, tablets and capsules represent the most advantageous oral
dosage unit form in which case solid pharmaceutical carriers are
obviously employed. If desired, tablets may be coated by standard
aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the
compounds of Formula I may also be administered by controlled release
means and/or delivery devices 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 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
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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 1 mg to about 500 mg
of the active ingredient and each cachet or capsule contains from about 1
to about 500 mg of the active ingredient.
The following are examples of representative pharmaceutical
dosage forms for the compounds of Formula I:
Injectable Suspension (I.M.) mg/mL
Compound of Formula I 10
Methylcellulose 5.0
Tween* 80 0.5
Benzyl alcohol 9.0
Benzalkonium chloride 1.0
Water for injection to a total volume of 1 mL
Tablet m /tg/ ablet
Compound of Formula I 25
Microcrystalline Cellulose 415
Povidone 14.0
Pregelatinized Starch 43.5
Magnesium Stearate 2.5
500
Capsule m /gcapsule
Compound of Formula I 25
Lactose Powder 573.5
Magnesium Stearate 1.5
600
Aerosol Per canister
* Trade-mark
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Compound of Formula I 24 mg
Lecithin, NF Liquid Concentrate 1.2 mg
Trichlorofluoromethane, NF 4.025 g
Dichlorodifluoromethane, NF 12.15 g
Combinations with Other Drugs
In addition to the compounds of Formula I, the
pharmaceutical compositions of the present invention can also contain
other active ingredients, such as cyclooxygenase inhibitors, non-steroidal
anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as
zomepirac diflunisal and the like. The weight ratio of the compound of
the Formula I to the second active ingredient may be varied and will
depend upon the effective dose of each ingredient. Generally, an
effective dose of each will be used. Thus, for example, when a
compound of the Formula I is combined with an NSAID the weight ratio
of the compound of the Formula I to the NSAID will generally range
from about 1000:1 to about 1:1000, 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.
NSAIDs can be characterized into five groups:
(1) propionic acid derivatives;
(2) acetic acid derivatives;
(3) fenamic acid derivatives;
(4) oxicams; and
(5) biphenylcarboxylic acid derivatives,
or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be used comprise:
alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen,
fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,
miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,
tiaprofenic acid, and tioxaprofen. Structurally related propionic acid
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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 pharmaceutically acceptable salt group, e.g.,
-CH(CH3)COO-Na+ or -CH2CH2COO-Na+), typically attached directly
or via a carbonyl function to a ring system, preferably to an aromatic ring
system.
The acetic acid derivatives which may be used comprise:
indomethacin, which is a preferred NSAID, acemetacin, alclofenac,
clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,
ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin,
and zomepirac. Structurally 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 pharma-
ceutically acceptable salt group, e.g. -CH2COO-Na+), typically attached
directly to a ring system, preferably to an aromatic or heteroaromatic ring
system.
The fenamic acid derivatives which may be used comprise:
flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and
tolfenamic acid. Structurally related fenamic acid derivatives having
similar analgesic and anti-inflammatory properties are also intended to be
encompassed by this group.
Thus, "fenamic acid derivatives" as defmed herein are non-
narcotic analgesics/non-steroidal anti-inflammatory drugs which contain
the basic structure:
&q NH O
COOH
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which can bear a variety of substituents and in which the free -COOH
group can be in the form of a pharmaceutically acceptable salt group, e.g.,
-COO-Na+.
The biphenylcarboxylic acid derivatives which can be used
comprise: diflunisal and flufenisal. Structurally related biphenyl-
carboxylic acid derivatives having similar analgesic and anti-
inflammatory properties are also intended to be encompassed by this
group.
Thus, "biphenylcarboxylic acid derivatives" as defined
herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs
which contain the basic structure:
O-OaCOOH
which can bear a variety of substituents and in which the free -COOH
group can be in the form of a pharmaceutically acceptable salt group, e.g.,
-COO-Na+.
The oxicams which can be used in the present invention
comprise: isoxicam, piroxicam, sudoxicam and tenoxican. Structurally
related oxicams having similar analgesic and anti-inflammatory
properties are also intended to be encompassed by this group.
Thus, "oxicams" as defined herein are non-narcotic
analgesics/non-steroidal anti-inflammatory drugs which have the general
formula:
OH 0
C-NH-R
S.N.CH3
(b)2
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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 HCl,
tiflamizole, timegadine, tolpadol, tryptamid, and ufenamate.
The following NSAIDs, designated by company code
number (see e.g., Pharmaprojects), may also be used:
480156S, AA861, AD1590, AFP802, AFP860, A177B, AP504, AU8001,
BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044,
GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897,
MY309, ON03144, PR823, PV102, PV108, R830, RS2131, SCR152,
SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901
(4-benzoyl-l- indancarboxylic acid), TVX2706, 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, diclofenac, fenbufen, fenoprofen, flurbiprofen,
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ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac,
and tolmetin.
Pharmaceutical compositions comprising the Formula I
compounds may also contain inhibitors of the biosynthesis of toe
leukotrienes such as are disclosed in EP 138,481 (Apri124,1985), 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 (Apri125, 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 second active ingredient,
prostaglandin antagonists such as those disclosed in EP 11,067 (May 28,
1980) or thromboxane antagonists such as those disclosed in U.S. Pat.
4,237,160. They may also contain histidine decarboxylase inhibitors such
as a-fluoromethyl-histidine, described in U.S. Pat. 4,325,961. The
compounds of the Formula I may also be advantageously combined with
an H1- or H2-receptor antagonist, 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-carboxychromon-5-yloxy)-2-hydroxypropane
and related compounds described in British Patent Specifications
1,144,905 and 1,144,906. Another useful pharmaceutical composition
comprises the Formula I compounds in combination with serotonin
* Trade-mark
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antagonists such as methysergide, the serotonin antagonists described in
Nature, 316, 126-131 (1985), and the like.
Other advantageous pharmaceutical compositions,.comprise
the Formula I compounds in combination with anti-cholinergics such as
ipratropium bromide, bronchodilators such as the beta agonist salbutamol,
metaproterenol, terbutaline, fenoterol and the like, and the anti-asthmatic
drugs theophylline, choline theophyllinate and enprofylline, the calcium
antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine,
felodipine, etc. and the corticosteroids, hydrocortisone,
methylprednisolone, betamethasone, dexamethasone, beclomethasone,
and the like.
Methods of S nty hesis
Compounds of the present invention can be prepared
according to the following methods.
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SCHEME 1
R2
A HO O OR
1 ~
R N / I \ (CH26 1
CH3MgBr, LiN[Si(CH3)3]2
R2
HO O
AI
R' N / I \
(CH2)m'
(CH30CH2OCH2)Sn(Bu)3/ 2
n-BuLi
R2
I HO HO CH2OCH2OCH3
A
R1 N / I \ (CH2)m'
3
1. MsCI
2. LiS(CR3R3)mCO2Li
3. PPTS/MeOH
R2 jCR3R) mCO2H
A S HO CH2OH
R1 N / I \ (CH2)' \
I /
Ia
In Scheme 1, R is lower alkyl. The ester 1 is converted to
the corresponding methyl ketone 2 using standard reagents such as
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methyl magnesium bromide and lithium hexamethyldisilazide. The
ketone 2 is then treated with (methoxymethoxymethyl)tributylstannane/n-
butyllithium to provide the mono-methoxymethyl (MOM) protected triol
3. Conversion of the secondary hydroxyl group of 3 to a leaving group
such as the methanesulfonate, followed by displacement with the
mercaptoalkanoic acid dianion provides MOM-protected Ia. The MOM
protecting group may be removed by pyridinium p-toluenesulfonate to
give a diastereomeric mixture of Ia which may then be separated using
chromatographic techniques such as using a chiral column. More
preferably, Ia or protected Ia is converted into an ester, for example the
methyl ester using diazomethane, followed by MOM deprotection, if
necessary; the diastereomeric mixture of the ester is then subject to
separation, and the separated diastereomers are then hydrolyzed to give
the desired acids Ia.
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SCHEME 2
R O OR
I HO
A
R N / I \ (CH2)m'
1
- 1. Ac20
2. NBS, [PhC(O)]2O2
R2
A CH3C(O)O Br O OR
R' N / I \ (CH2)m, I \
4
LiOH/TFA
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SCHEME 2 (cont'd)
R2 O
A HO O
R1 e
(C
H2)m'
1. CH3(CH2)3SO2CI 5
2. LiS(CR3R3)mCO2Li
R2 ~CR3R3)mC02H O
I S O
R1 A N (CH2)m'
6
CeCI3/CH3MgCI
R2 / (CR3R3)mC02H
I \ S OH
A
R1 N / I \ I \
HO
Ib
In Scheme 2, R is lower alkyl. The secondary hydroxyl
group of ester 1 is first protected, for example by acetylation, followed by
bromination at the available benzylic carbon using N-bromosuccinimide
and benzoyl peroxide to provide bromo ester 4. Hydrolysis of the ester in
the presence of a base such as lithium hydroxide provide the bicyclic
lactone 5, after acid treatment. Conversion of the secondary hydroxyl
group of 5 to a leaving group such as the butanesulfonate, followed by
displacement with the mercaptoalkanoic acid dianion provides thiolated
lactone 7. Cerium chloride and methylmagnesium bromide are used to
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provide the diol Ib as a diasteromeric mixture, which can then be
chromatographically separated into the individual diastereomers.
Compounds of formula I are metabolites of compounds of
formula Ic. Therefore, in addition to chemical synthesis, compounds of
formula I can also be isolated from plasma of individuals to whom a
compound of formula Ic has been administered, using methodologies that
are well known in the art.
R S" , (CR3R3)mCO2H
R XN ~ I \ (CH26
H H
CH3
CH3
OH
Ic
Assays for Determining Biological Activity
The leukotriene antagonist properties of the compounds of
the present invention are evaluated using the following assays:
1. [3H]LTD4 Receptor Binding Assay in DMSO-differentiated U937
Cells (a human monocytic cell line);
2. [3H]LTD4 Receptor Binding on Guinea Pig Lung Membranes;
3. [3H]LTD4 Receptor Binding on Human Lung Membranes;
4. In Vitro Guinea Pig Trachea; and
5. In Vivo Assays in Anesthetized Guinea Pigs.
The above assays are described by T.R. Jones et al., Can. J.
Physiol. Pharmacol. 1991, 69, 1847-1854.
Asthmatic Rat Assay
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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 is supplied by Sandoz Ltd., Basel.
The challenge and subsequent respiratory recordings are
carried out in a clear plastic box with internal dimensions 10x6x4 inches.
The top of the box is removable; in use, it is held firmly in place by four
clamps and an airtight seal is maintained by a soft rubber gasket.
Through the center of each end of the chamber a DeVilbiss nebulizer
(No. 40) is inserted via an airtight seal and each end of the box also has
an outlet. A Fleisch No. 0000 pneumotachograph is inserted into one end
of the box and coupled to a Grass volumetric pressure transducer (PT5-A)
which is then connected to a Buxco Electronics preamplifier (Buxco
Electronics Inc., Sharon, Conn.). The preamplifier is connected to a
Beckman Type R Dynograph and to a Buxco computer consisting of
waveform analyzer, Data Acquisition Logger with special software.
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 is placed into each nebulizer and the aerosol
is generated with air from a small Potter diaphragm pump operating at 10
psi and a flow of 8 liters/minute.
Rats are sensitized by injecting (subcutaneously) 1 mL of a
suspension containing 1 mg EA and 200 mg aluminum hydroxide in
saline. They are used between days 12 and 24 post sensitization. In order
to eliminate the serotonin component of the response, rats are pretreated
intravenously 5 minutes prior to aerosol challenge with 3.0 g/kg of
methysergide. Rats are then exposed to an aerosol of 3% EA in saline for
exactly 1 minute, then their respiratory profiles are recorded for a further
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30 minutes. The duration of continuous dyspnea is measured by the
Buxco computer.
Compounds are generally administered either orally 2-4
hours prior to challenge or intravenously 2 minutes prior to challenge.
They are either dissolved in saline or 1% methocel or suspended in 1%
methocel. The volume injected is 1 mL/kg (intravenously) or 10 mLJkg
(orally). Prior to oral treatment rats are starved overnight. The activity of
compounds is determined in terms of their ability to decrease the duration
of antigen-induced 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 (mg/kg) which would
inhibit the duration of symptoms by 50%.
Pulmonary Mechanics in Trained Conscious Squirrel Monkeys
The test procedure involves placing trained squirrel monkeys
in chairs in aerosol exposure chambers. For control purposes, pulmonary
mechanics measurements of respiratory parameters are recorded for a
period of about 30 minutes to establish each monkey's normal control
values for that day. For oral administration, compounds are dissolved or
suspended in a 1% methocel* solution (methylcellulose, 65HG, 400 cps)
and given in a volume of 1 mL/kg body weight. For aerosol
administration of compounds, a DeVilbiss ultrasonic nebulizer is utilized.
Pretreatment periods vary from 5 minutes to 4 hours before the monkeys
are challenged with aerosol doses of either leukotriene D4 (LTD4) or
A cari suum antigen; 1:25 dilution.
Following challenge, each minute of data is calculated by
computer as a percent change from control values for each respiratory
parameter including airway resistance (RL) and dynamic compliance
(Cdyn). The results for each test compound are subsequently obtained for
a minimum period of 60 minutes post challenge which are then compared
to previously obtained historical baseline control values for that monkey.
In addition, the overall values for 60 minutes post-challenge for each
monkey (historical baseline values and test values) are averaged
* Trade-mark
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separately and are used to calculate the overall percent inhibition of
LTD4 or Ascaris antigen response by the test compound. For statistical
analysis, paired t-test is used. (References: McFarlane, C.S. et al.,
Prostaglandins, 2$, 173-182 (1984) and McFarlane, C.S.
et al., Agents Actions, 22, 63-68 (1987).)
Prevention of Induced Bronchoconstriction in Allergic Sheep
A. Rationale: Certain allergic sheep with known sensitivity
to a specific antigen (Ascaris suum) respond to inhalation challenge with
acute and late bronchial responses. The time course of both the acute and
the late bronchial responses approximates the time course observed in
asthmatics and the pharmacological modification of both responses is
similar to that found in man. The effects of antigen in these sheep are
largely observed in the large airways and are conveniently monitored as
changes in lung resistance or specific lung resistance.
B. Methods: Animal Preparation: Adult sheep with a mean
weight of 35 kg (range, 18 to 50 kg) are used. All animals used meet two
criteria: a) they have a natural cutaneous reaction to 1:1,000 or 1:10,000
dilutions of Ascaris suum extract (Greer Diagnostics, Lenois, NC); and b)
they have previously responded to inhalation challenge with Ascaris
suum with both an acute bronchoconstriction and a late bronchial
obstruction (W.M. Abraham et al., Am. Rev. Resn. Dis., 128, 839-44
(1983)).
Measurement of Airway Mechanics: The unsedated sheep
are restrained in a cart in the prone position with their heads immobilized.
After topical anesthesia of the nasal passages with 2% lidocaine solution,
a balloon catheter is advanced through one nostril into the lower
esophagus. The animals are then intubated with a cuffed endotracheal
tube through the other nostril using a flexible fiberoptic bronchoscope as
a guide. Pleural pressure is estimated with the esophageal balloon
catheter (filled with one mL of air), which is positioned such that
inspiration produces a negative pressure deflection with clearly
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discernible cardiogenic oscillations. Lateral pressure in the trachea is
measured with a sidehole catheter (inner dimension, 2.5 mm) advanced
through and positioned distal to the tip of the nasotracheal tube.
Transpulmonary pressure, the difference between tracheal pressure and
pleural pressure, is measured with a differential pressure transducer
(DP45; Validyne Corp., Northridge, CA). For the measurement of
pulmonary resistance (RL), the maximal end of the nasotrachel tube is
connected to a pneumotachograph (Fleisch, Dyna Sciences, Blue Bell,
PA). The signals of flow and transpulmonary pressure are recorded on an
oscilloscope (Model DR- 12; Electronics for Medicine, White Plains, NY)
which is linked to a PDP-11 Digital computer (Digital Equipment Corp.,
Maynard, MA) for on-line calculation of RL from transpulmonary
pressure, respiratory volume obtained by integration and flow. Analysis
of 10-15 breaths is used for the determination of RL. Thoracic gas
volume (Vtg) is measured in a body plethysmograph, to obtain specific
pulmonary resistance (SRL = RL=Vtg).
Aerosol Delivery Systems: Aerosols of Ascaris suum
extract (1:20) are generated using a disposable medicalnebulizer
(Raindrop , Puritan Bennett), which produces an aerosol with a mass
median aerodynamic diameter of 6.2 M (geometric standard deviation,
2.1) as determined by an electric size analyzer (Model 3030; Thermal
Systems, St. Paul, MN). The output from the nebulizer is directed into a
plastic t-piece, one end of which is attached to the nasotracheal tube, the
other end of which is conected to the inspiratory part of a Harvard
respirator. The aerosol is delivered at a tidal volume of 500 mL of a rate
of 20 per minute. Thus, each sheep receives an equivalent dose of
antigen in both placebo and drug trials.
Experimental Protocol: Prior to antigen challenge baseline
measurements of SRI, are obtained, infusion of the test compound is
started 1 hr prior to challenge, the measurement of SRL repeated and then
the sheep undergoes inhalation challenge with Ascaris suum antigen.
Measurements of SRL are obtained immediately after antigen challenge
and at 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, and 8 hrs after antigen challange.
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Placebo and drug tests are separated by at least 14 days. In a further
study, sheep are given a bolus dose of the test compound followed by an
infusion of the test compound for 0.5-1 hr prior to Ascaris challenge and
for 8 hrs after Ascaris as described above.
Statistical Anal,vsis: A Kruskal-Wallis one way ANOVA
test is used to compare the acute immediate responses to antigen and the
peak late response in the controls and the drug treated animals.
The invention will now be illustrated by the following non-
limiting examples in which, unless stated otherwise:
(i) all operations were carried out at room or ambient
temperature, that is, at a temperature in the range 18-25 C;
(ii) evaporation of solvent was carried out using a rotary
evaporator under reduced pressure (600-4000 pascals:
4.5-30 mm Hg) with a bath temperature of up to 60 C;
(iii) the course of reactions was followed by thin layer
chromatography (TLC) and reaction times are given for
illustration only;
(iv) melting points are uncorrected and 'd' indicates
decomposition; the melting points given are those obtained
for the materials prepared as described; polymorphism may
result in isolation of materials with different melting points
in some preparations;
(v) the structure and purity of all fmal products were assured by
at least one of the following techniques: TLC, mass
spectrometry, nuclear magnetic resonance (NMR)
spectrometry, or microanalytical data;
(vi) yields are given for illustration only;
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(vii) when given, NMR data are in the form of delta (S) values for
major diagnostic protons, given in parts per million (ppm)
relative to tetramethylsilane (TMS) as internal standard,
determined at 300 MHz or 400 MHz using the indicated
solvent; conventional abbreviations used for signal shape
are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad;
etc.: in addition "Ar" signifies an aromatic signal;
(viii) chemical symbols have their usual meanings; the following
abbreviations have also been used: v (volume), w (weight),
b.p. (boiling point), m.p. (melting point), L (liter(s)), mL
(milliliters), g (gram(s)), mg (milligram(s)), mol (moles),
mmol (millimoles), eq. (equivalent(s)).
EXAMPLE 1
(R,R or S)-1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)-3-(2-
(1,2-dihydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane
acetic acid:
COOH
OH
I rN--
Step S OH
CI 1 : (S)1-(2-(3-(3-(2-(7-Chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-hydroxypropyl)phenyl)ethanone:
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To a solution of lithium bis(trimethylsilyl)amide (355 ml,
352 mmol, 1M in THF) at -150C was added dropwise methylmagnesium
chloride (59.3 ml, 178 mmol, 3 M in THF ). The reaction mixture was
warmed to 0oC and stirred for lh . The methylmagnesiate reagent was
then added over lh to a solution of methyl (S)-2-(3-(3-(2-(7-chloro-2-
quinolinyl)-(E)-ethenyl)phenyl)(1-hydroxypropyl))benzoate ( see US
Patent 5,270,324, 25.0 g, 54.6 mmol) in toluene (150 ml) at - 200C. The
reaction mixture was warmed to 0oC for 3h. The mixture was poured
into 2.4 M NH4C1 solution (H20 / HOAc 20 %, 2 L) and extracted with
EtOAc (2 x 500 ml). The combined EtOAc fractions were dried over
anhydrous MgSO4. Flash chromatography of the concentrated extract on
silica gel (Tol/EtOAc 20%) gave 19.0 g of the title compound. 1 H NMR
(400 MHz, acetone-d6) 8 2.04 (m, 2H), 2.56 (s, 3H), 2.89-2.96 (m, 1H),
3.00-3.07 (m, 1H), 4.40 (d, J=4.2 Hz, 1 H), 4.75 (m, 1 H), 7.28-7.60 (m,
8H), 7.75 (s, 2H), 7.83-8.00 (m, 4H), 8.33 (d, J=8.6 Hz, 1H).
Step 2 : (S )-1-(2-(3-(3-(2-(7-Chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)(1-hydroxypropyl))phenyl)-1-(methoxymethoxymethyl)
ethanol
To a solution of ((methoxymethoxy)methyl)tributylstannane
(22.3 g, 61.1 mmol) in THF (100 ml) at -78 oC was added n-butyllithium
(23.3 ml, 58.2 mmol ) over 10 min. A solution of the starting ketone
from step 1 (7.20 g, 16.3 mmol ) in THF (20 ml) at -78 OC was canulated
slowly. The mixture was stirred for lh at -780C. Aqueous NH4C1(25%)
was added directly into the reaction mixture and extracted with EtOAc.
Flash chromatography of the crude product on silica gel (Hex / AcOEt
40%) gave 2.70 g of the title compound as a diastereomeric mixture. 1 H
NMR (400 MHz, CDC13) 8 1.64 (m, 3H), 2.15 (m, 2H), 3.00-3.30 (m,
3H), 3.33 (s, 3H), 3.42-3.48 (m, 1H), 3.62 (d, J=10 Hz, 1H), 3.98 (d, J=10
Hz, 1 H), 3.73 (d, J=10 Hz, 1H), 4.05 (d, J=10 Hz, 1H), 4.69-4.70 (m,
3H), 7.15-7.43 (m, 7H), 7.49 (m, 1H), 7.60-7.71 (m, 5H), 8.05-8.09 (m,
2H).
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Step 3: (R,R or S)-1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-(2-(1-(methoxymethoxymethyl)ethanol)phenyl)
propyl)thio)methyl)cyclopropaneacetic acid:
(a) To a solution of the diol from step 2 (170 mg, 0.33
mmol) in 1 mL Tol / CH3CN 1:1 was added diisopropylethylamine (60.9
L, 0.34 mmol ). The reaction mixture was cooled to -48oC, then
methanesulfonyl chloride (25.8 L, 0.33 mmol) was added slowly. The
temperature was raised to -200C and maintained for lh. The cold
solution was poured into saturated aqueous NaHCO3 and extracted with
EtOAc. The combined extracts were dried over Na2SO4, concentrated
and used as such for the next step. 1H NMR (400 MHz, CDC13) S 1.55
(s, 3H), 2.20-2.32 (m, 1H), 2.38-2.49 (m, 1H), 2.76 (s, 3H), 2.94-3.11 (m,
1H), 3.12-3.20 (m, 2H), 3.30 (s, 3H), 3.59-3.64 (m, 1H), 3.89-3.96 (m,
1H), 4.66 (m, 2H), 5.67 (m, 1H), 7.10-7.49 (m, 8H), 7.61-7.74 (m, 5H),
8.09-8.15 (m, 2H).
(b) To 1-(mercaptomethyl)cyclopropaneacetic acid (48.6 mg,
0.33 mmol) in degassed THF (0.45 ml ) cooled at -15 oC was added
slowly a solution of n-butyllithium (265 L, 0.66 mmol, 2.5 M in Hex)
over 10 min. The heterogeneous mixture was warmed to -80C for 30
min. The crude mesylate from (a) in THF (0.5 ml) was added to the
mercapto acid suspension and stirred at -150C overnight. Aqueous
NH4C1(25%) was added and the mixture was extracted with EtOAc.
Flash chromatography (Hex / EtOAc 30% / AcOH 1%) gave 100 mg of
the title product. 1H NMR (400 MHz, CDC13) S 0.46-0.57 (m, 4H), 1.53
(s, 3H), 2.15-2.25 (m, 2H), 2.26-2.36 (m, 2H), 2.57-3.06 (m, 3H), 3.07-
3.14 (m, 1H), 3.29 (s, 3H), 3.60-3.64 (m, 1H), 3.93-4.02 (m, 2H), 4.66
(m, 2H), 7.10-7.80 (m, 13H), 8.03-8.11 (m, 2H).
Step 4: Methyl (R,R or S)-1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-(2-(1,2-dihydroxy-l-methylethyl)phenyl)propyl)thio)
methyl)cyclopropaneacetate:
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To a solution of the acid of step 3 (1.000 g, 1.55 mmol) in 10
mL of Et20 was added a standard solution of diazomethane until TLC
showed total consumption of starting material. The mixture was
evaporated to dryness and was then dissolved in 35 mL of tert-butanol.
PPTS (3.89 g, 15.5 mmol) was added and the mixture was refluxed for
12h. It was poured in 250 mL aqueous NH4OAc (25%) and extracted
with 100 mL Et20. The organic phase was washed with 100mL water,
dried over Na2SO4, filtered and concentrated. Flash chromatography
(Tol / EA 30%) afforded the title compounds (550 mg, 58%) along with
300 mg of the methyl ester intermediate. The two diastereoisomers were
separated by HPLC on a CHIRALPAK AD praparative column using
ethanol as the eluent. From 25 mg of the diastereomeric mixture was
obtained 11.8 mg of the title compound (RT = 44min). 1H NMR (400
MHz, acetone-d6) 8 0.38-0.53 (m, 4H), 1.51 (s, 3H), 2.23 (dd, J=16.3, 7.6
Hz, 2H), 2.39 (d, J=15.9 Hz, 1 H), 2.46 (d, J=15.9 Hz, 1H), 2.55 (s, 2H),
2.85-2.92 (m, 1H), 3.05-3.11 (m, 1H), 3.57 (s, 3H), 3.63 (d, J=10.8 Hz,
1H), 3.89 (d, J=10.8 Hz, 1H), 4.05 (t, J=7.4 Hz, 1H), 7.06-7.17 (m, 3H),
7.39-7.44 (m, 3H), 7.52-7.56 (m, 2H), 7.62-7.64 (m, 1H), 7.79 (s, 1H),
7.87-7.96 (m, 3H), 8.04 (s, 1H), 8.35 (d, J=8.6 Hz, 1H).
Step 5 (R,R/S)-1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-(2-(1,2-dihydroxy-l-methylethyl)phenyl)propyl)
thio)methyl)cyclopropaneacetic acid
To a solution of the compound from step 4(10.1 mg,
0.016mmol) in 0.25mL of ethanol was added 0.033mL of aqueous NaOH
(1N). The mixture was stirred at 60 C for 4h, then cooled and acidified
with 0.02 ml of AcOH. This was then diluted with 1 mL H20, and 2 mL
of EA. The organic extracts were dried over Na2SO4, filtered and
concentrated to afford the title compound (6.5 mg, 66%). NMR (400
MHz, acetone d6) 8 0.38-0.56 (m, 4H), 1.51 (s, 3H), 2.19-2.27 (m, 2H),
2.44 (s, 2H), 2.60 (s, 2H), 2.83-2.97 (m, 1H), 3.08-3.15 (m, 1H), 3.63 (d,
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10.8 Hz, 1H), 3.76 (d, J = 10.8 Hz, 1H), 4.08 (t, 7.35 Hz, 1H), 7.05-7.19
(m, 4H), 7.39-7.62 (m, 5H), 7.80-8.02 (m, 5H), 8.33 (d, 8.6 Hz, 1H).
EXAMPLE 2
(R,S or R)-1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)-3-(2-
(1,2-dihydroxy-l-methylethyl)phenyl)propyl)thio)methyl)
cyclopropaneacetic acid
Step 1 Methyl-(R,S or R)-1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-(2-(1,2-dihydroxy- 1 -methylethyl)phenyl)propyl)thio)
methyl)cyclopropaneacetate:
The column of step 4, Example 1 was further eluted to give
8.1 mg of the second diastereoisomer (RT = 51min). 1H NMR (400
MHz, acetone-d6) b 0.38-0.53 (m, 4H), 1.51 (s, 3H), 2.20-2.29 (m, 2H),
2.39 (d, J=15.8 Hz, 1H), 2.46 (d, J=15.8 Hz, 1H), 2.55 (s, 2H), 2.81-2.88
(m, 1H), 3.09-3.12 (m, 1H), 3.57 (s, 3H), 3.63 (d, J=10.8 Hz, 1H), 3.76 (s,
J=10.8 Hz, 1H), 4.05 (t, J=6.6 Hz, 1H), 7.06-7.16 (m, 3H), 7.39-7.43 (m,
3H), 7.53-7.57 (m, 2H), 7.62-7.64 (m, 1H), 7.80 (s, 1H), 7.88-7.97 (m,
3H), 8.05 (s, 1H), 8.35 (d, J=8.6 Hz, 1H).
Step 2
To a solution of the compound from step 1 (5.2 mg, 0.0084
mmol) in 0.15mL of ethanol was added 0.016mL of aqueous NaOH (1N).
The mixture was stirred at 60 C for 4h, then cooled and acidified with
0.01 ml of AcOH. This was then diluted with 1 mL H20, and 2 mL of
EA. The organic extracts were dried over Na2SO4, filtered and
concentrated to afford the title compound (3.5 mg, 70%). NMR (400
MHz,acetone d6) 8 0.39-0.55 (m, 4H), 1.51 (s, 3H), 2.16-2.30 (m, 2H),
2.44 (s, 2H), 2.60 (s, 2H), 2.80-2.88 (m, 1H), 3.10-3.17 (m, 1H), 3.63 (d,
10.8 Hz, 1H), 3.76 (d, 10.8 Hz, 1H), 4.08 (t, 7.8 Hz, 7.0 Hz, 1H), 7.04-
7.19 (m, 4m), 7.39-7.60 (m, 5H), 7.80-8.02 (m, 5H), 8.33 (d, 8.6 Hz, 1H).
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EXAMPLE 3
(R,R or S) and (R, S or R) -1-((((3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-(2-(1,2-dihydroxy-l-methylethyl)phenyl)propyl)thio)
methyl)cyclopropaneacetic acid:
The title compounds are prepared following the procedures
of Examples 1 and 2, and substituting methyl (S)-2-(3-(3-(2-(6,7-
difluoro-2-quinolinyl)-(E)-ethenyl)phenyl)(1-hydroxypropyl))benzoate
(see US Patent 5,270,324) for methyl (S)-2-(3-(3-(2-(7-chloro-2-
quinolinyl)-(E)-ethenyl)phenyl)(1-hydroxypropyl))benzoate in Step 1.
EXAMPLE 4
(R,R or S) and (R,S or R)-1-((((3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-
yl)-(E)-ethenyl)phenyl)-3-(2-(1,2-dihydroxy-1-
methylethyl)phenyl)propyl) thio)methyl)cyclopropaneacetic acid:
The title compounds are prepared following the procedures
of Examples 1 and 2, and substituting methyl (S)-2-(3-(3-(2-(2,3-
dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)(1-
hydroxypropyl))benzoate (see EP 604,114) for methyl (S)-2-(3-(3-(2-(7-
chloro-2-quinolinyl)-(E)-ethenyl)phenyl)(1-hydroxypropyl))benzoate in
Step 1.
EXAMPLE 5
1-((((3-(2-(7-Chloro-2-quinolinyl)-(E)-ethenyl)phenyl)- (1R,3S)-3-(2-(1-
hydroxy-l-methylethyl)phenyl)-3-hydroxypropyl)thio)methyl)
cyclopropaneacetic acid
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HO2C
S OH
CI ~ N
HO
Step 1 Methyl-(S)-2-(3-(3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-acetoxypropyl)benzoate :
Methyl-(S)-2-(3-(3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-3-hydroxypropyl)benzoate-H20 (25.10 g, 52.7 mmol)
was dried by codistillation with 2 x 250 mL of toluene. To the residue
suspended in 100 mL of CH202 was added Ac20 (8.50 mL, 116 mmol)
then NEt3 (8.80 mL, 63.5 mmol). DMAP (321 mg, 2.63 mmol) was
added and the reaction mixture became homogeneous within 30 sec. The
fmal mixture was stirred 15 min then poured into 200 mL of saturated
aqueous NaHCO3, extracted with (2 x 100 mL) CH202. The combined
organic extracts were washed with 100 mL of 25% aqueous NH40,
dried over Na2SO4, filtered, concentrated and dried in vacuo at 600C for
lh to give 26.40 g (100%) of the desired material. It was used without
further purification. An analytical sample was obtained by flash
chromatography (Tol / EA 5%).: 1H NMR (400 MHz, acetone-d6) S 2.11
(s, 3H), 2.12-2.30 (m, 2H), 2.96-3.09 (m, 2H), 3.83 (s, 3H), 5.87 (dd,
J=7.92, 5.48 Hz, 1 H), 7.27 (dd, J=7.49, 1.30 Hz, 1 H), 7.29 (d, J=7.31 Hz,
1H), 7.35-7.47 (m, 5H), 7.62 (dt, J=7.38, 1.59, 1.56 Hz, 1H), 7.73 (d,
J=1.53 Hz, 1H), 7.74 (d, J=8.59 Hz, 1H), 7.83-7.88 (m, 3H), 7.99 (d,
J=2.17 Hz, 1H), 8.21 (d, 1H); 13C NMR (100 MHz, acetone-d6) 8 21.13,
31.14, 38.77, 52.15, 75.95, 121.00, 126.23, 126.61, 126.90, 127.38,
127.40, 127.62, 128.59, 129.57, 129.71, 130.11, 130.49, 131.33, 131.78,
132.76, 135.45, 135.52, 136.95, 137.48, 142.49, 143.75, 149.39, 157.65,
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168.19, 170.31; IR (neat) 3000, 1740, 1600 cm-1; [a] D20 -19.2
(c=0.0154, CHC13); Analysis calc'd for C30H26C1N04: C, 72.07; H,
5.24; N, 2.80; found: C, 71.48; H, 5.29; N, 2.84.
Step 2 Methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)-(E)-
ethenyl)phenyl)-(1 R/S, 3S)-3- acetoxy-l-bromopropyl)benzoate :
To a solution of the compound from Step 1 (26.30 g, 52.6
mmol) in 1.30 L of CC14 was added N-bromosuccinimide (9.93 g, 55.8
mmol) followed by benzoyl peroxide (923 mg, 3.81 mmol). The mixture
was refluxed for 3h, cooled to r.t. then poured into 200 mL of saturated
aqueous NaHCO3. The organic layer was separated, the aqueous phase
was washed with (2 x 100 mL) CH2C12. The combined organic extracts
were dried over Na2SO4, filtered and concentrated. Flash
chromatography (Tol / Et20 5%) afforded a mixture 21.00 g (69%) of the
desired diastereoisomers (1:1) along with 4.12 g (16%) of starting
material. This mixture was used without further purification. An
analytical sample of the 1:1 mixture of diastereoisomers was obtained by
repeated flash chromatography (Tol / Et20 5%).: 1H NMR (400 MHz,
acetone-d6) 8 2.06 (s, 3H), 2.08 (s, 3H), 2.78-2.87 (m, 3H), 2.96-3.04 (m,
1H), 3.78 (s, 3H), 3.90 (s, 3H), 5.72 (dd, J=8.30, 5.70 Hz, 1H), 6.08 (dd,
J=8.14, 5.24 Hz, 1 H), 6.30 (t, J=7.76, 7.51 Hz, 1 H), 6.43 (dd, J=8.31,
6.06 Hz, 1H), 7.32-7.47 (m, lOH), 7.51-7.66 (m, 4H), 7.70-7.73 (m, 4H),
7.82-7.93 (m, 8H), 8.00 (s, 1H), 8.00 (s, 1H), 8.18-8.21 (m, 2H); 13C
NMR (100 MHz, acetone-d6) S 20.9, 21.0, 45.9, 46.4, 46.7, 47.4, 52.5,
52.6, 74.4, 74.4, 120.9, 121.0, 126.1, 126.3, 126.6, 127.4, 127.4, 127.7,
127.8, 128.5, 128.9, 129.0, 129.1, 129.4, 129.7, 129.7, 129.8, 129.9,
130.0, 130.1, 130.2, 131.0, 131.0, 133.3, 133.5, 135.2, 135.2, 135.5,
136.9, 137.6, 141.0, 141.6, 142.6, 143.2, 149.3, 157.5, 167.6, 170.0,
171.1. Analysis calc'd for C30H25C1BrNO4: C, 62.25; H, 4.35; N, 2.42;
found: C, 62.26; H, 4.58; N, 2.42.
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Step 3 3-(2-(3-(2-(7-Chloro-2-quinolinyl)-(E)-ethenyl)phenyl)-(S)-
2-hydroxyethyl)-(R/S)-3H-isobenzofuran-1-one :
To a solution of 23.38 g of the compound from step 2 in 280
mL THF and 140 mL MeOH was added 140 mL (140 mmol) of a 1 N
LiOH aqueous solution. The mixture was stirred at r.t. for 24h. The
solution was neutralized using 11.0 mL (143 mol) of TFA and stirring for
2h. The volatiles were evaporated and the residue was poured in
saturated aqueous NaHCO3 (1.OL). The aqueous phase was extracted
with 3x500 mL of EA. The combined organic fractions were washed
with brine (200 mL), dried over Na2SO4, filtered and concentrated.
Flash chromatography (Tol / EA 20% then Tol / EA / AcOH 1:1:0.01 )
afforded the desired lactones (9.69 g ; 64%): 1H NMR (400 MHz,
acetone-d6) 81.89-1.96 (m, 1H), 2.33-2.52 (m, 3H), 4.65 (d, J=4.08 Hz,
1H), 4.90 (d, J=3.37 Hz, 1H), 5.13-5.17 (m, 2H), 5.51 (dd, J=8.11, 5.31
Hz, 1H), 5.95 (dd, J=10.43, 2.47 Hz, 1H), 7.37-7.52 (m, 8H), 7.56-7.65
(m, 4H), 7.67-7.77 (m, 4H), 7.79-7.93 (m, lOH), 7.98-8.00 (m, 2H), 8.28-
8.31 (m, 2H); 13C NMR (100 MHz, acetone-d6) 8 45.0, 45.9, 70.4, 71.3,
79.1, 79.6, 121.0, 123.1, 123.5, 125.3, 125.8, 125.8, 126.0, 126.6, 126.7,
126.7, 127.0, 127.1, 127.3, 127.4, 127.6, 128.4, 128.5, 129.2, 129.3,
129.6, 129.7, 129.8, 129.8, 130.2, 134.7, 134.8, 135.6, 135.8, 137.1,
137.3, 137.4, 146.1, 147.1, 149.4, 151.1, 151.4, 157.8, 170.3, 170.5.
Step 4 1-(((1-(3-(2-(7-Chloro-2-quinolinyl)-(E)-ethenyl)phenyl)-
(R)-2-((R/S)-3-oxo-1, 3-dihydroisobenzofuran-1-yl)ethyl)thio)methyl)
cyclopropaneacetic acid:
To a solution of the compound from Step 3 (4.60 g, 10.4
mmol) in 28 mL of CH2C12 at -200C was added NEt3 (2.16 mL, 15.5
mmol) then butanesulfonyl chloride (1.61 mL, 12.4 mmol). The mixture
was stirred at 0oC for lh then poured in 20 mL of saturated aqueous
NaHCO3. The aqueous phase was extracted with 3x25 mL of EA. The
combined organic fractions were washed with brine (25 mL), dried over
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Na2SO4, filtered and concentrated to affored the desired busylate. It was
dissolved in 5 mL of dry THF. To a degassed solution of 1-
mercaptomethyl-l-cyclopropaneacetic acid (3.02 g, 20.7 mmol) in 20 mL
of dry THF at -200C was added dropwise n-BuLi (2.48 M, 16.7 mL, 41.4
mmol). The mixture was stirred at OOC for 15 min then cooled back to
-200C. The solution of the busylate was added and the final mixture was
stirred at 40C for 16h. The solution was exposed to air at 0OC for lh,
then it was poured in 200 mL water and 4.0 mL AcOH. The aqueous
phase was extracted with 3x200 mL of EA. The combined organic
fractions were washed with brine (200 mL), dried over Na2SO4, filtered
and concentrated to afford after flash chromatography (Tol / EA 10% ;
Tol / EA 10% / AcOH 1%) the title compound (2.68 mg, 45%).: 1H
NMR (400 MHz, acetone-d6) S 0.40-0.55 (m, 8H), 2.20-2.29 (m, 2H),
2.48-2.51 (m, 4H), 2.61-2.80 (m, 6H), 4.29-4.39 (m, 2H), 5.24 (dd, 1H),
5.93 (dd, 1H), 7.34-7.42 (m, 3H), 7.44-7.61 (m, 10H), 7.67-7.78 (m, 6H),
7.81-8.05 (m, 11H), 8.31-8.38 (m, 2H).
Step 5
A suspension of cerium chloride (1.49 g, 6.00 mmol) was
heated for lOh in 15 mL of THF. Methylmagnesium chloride (7.80 mL,
23.5 mmol) was then added to the suspension at 0OC and 40 min later, the
bath was heated to 400C. A solution of the lactone from step 4 (2.68 g,
4.70 mmol) in 15 mL of THF was added dropwise and the reaction
mixture was poured in 25% NH4OAc (60 mL) containing a few drops of
AcOH. The aqueous phase was extracted with EA (2x100 mL) and the
combined organic phases dried over Na2SO4. A first chromatography on
silica gel (Tol / EA 40%) removed the less polar triols. Then 1% HOAc
was added to the eluent to afford both diol-acids. The mixture of
diastereoisomers was separated on BondapakTM C 18 preparative HPLC
column (MeOH / H20 25% / AcOH 0.1%) to give 783 mg (RT : 9.12
min.) of the title compound. 1H NMR (400 MHz, acetone-d6) S 0.16-
0.60 (m, 4H), 1.67 (s, 6H), 2.08-2.13 (m, 2H), 2.27-2.33 (m, 1H), 2.46 (d,
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J=12.7 Hz, 1 H), 2.59 (d, J=14.3 Hz, 1 H), 2.79 (d, J=12.7 Hz, 1 H), 4.51
(dd, J=11.5, 2.7 Hz, 1H), 6.18 (d, J=9.3 Hz, 1H), 7.06-7.13 (m, 2H), 7.25-
7.54 (m, 7H), 7.69-7.85 (m, 4H), 7.95 (s, 1H), 8.19 (d, J=8.6 Hz, 1H);
HRMS (FAB+) calc'd for C35H35C1NO4SNa2 (M+Na): 646.17707,
found 646.17688.
EXAMPLE 6
1-((((3-(2-(7-Chloro-2-quinolinyl)-(E)-ethenyl)phenyl)- (1R,3R)-3-(2-(1-
hydroxy-l-methylethyl)phenyl)-3-hydroxypropyl)thio)methyl)
cyclopropaneacetic acid
The HPLC column from Example 5 step 5 was further eluted
to give 572 mg (RT: 11.36 min ) the title compound. 1H NMR (400
MHz, acetone-d6) b 0.28-0.52 (m, 4H), 1.30 (s, 3H), 1.34 (s, 3H), 2.14-
2.17 (m, 1H), 2.33 (s, 2H), 2.55-2.66 (m, 1H), 2.69 (m, 2H), 4.45-4.48
(dd, J=10.5, 4.03 Hz, 1H), 5.46 (d, J=8.6 Hz, 1H), 7.04-7.16 (m, 2H),
7.28-7.59 (m, 7H), 7.73-7.84 (m, 4H), 7.95 (s, 1H), 8.19 (d, J=8.6 Hz,
1H); HRMS (FAB+) calc'd for C35H35C1NO4SNa2 (M+Na):
646.17707, found 646.17688.
EXAMPLE 7
1-((((3-(2-(6,7-Difluoro-2-quinolinyl)-(E)-ethenyl)phenyl)-(1R,3R)- and
(1 R,3 S)-3-(2-(1-hydroxy-l-methylethyl)phenyl)-3-hydroxypropyl)thio)
methyl)cyclopropaneacetic acid
The title compounds are prepared following the general
procedures of Examples 5 and 6, and substituting methyl (S)-2-(3-(3-(2-
(6,7-difluoro-2-quinolinyl)-(E)-ethenyl)phenyl)(1-
hydroxypropyl))benzoate for methyl (S)-2-(3-(3-(2-(7-chloro-2-
quinolinyl)-(E)-ethenyl)phenyl)(1-hydroxypropyl))benzoate in Step 1.
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EXAMPLE 8
1-((((3-(2-(2,3-Dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-
(1R,3R)- and (1R,3S)-3-(2-(1-hydroxy-l-methylethyl)phenyl)-3-
hydroxypropyl)thio) methyl) cyclopropaneacetic acid
The title compounds are prepared following the general
procedures of Examples 5 and 6, and substituting methyl (S)-2-(3-(3-(2-
(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)(1-
hydroxypropyl))benzoate for methyl (S)-2-(3-(3-(2-(7-chloro-2-
quinolinyl)-(E)-ethenyl)phenyl)(1-hydroxypropyl))benzoate in Step 1.
