Note: Descriptions are shown in the official language in which they were submitted.
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QUINOLINE DERIYATIVES CONTAINING A DIOL AS LEUKOTRIENE ANTM ONISTS
The present invention relates to hitherto unknown compounds useful
in the human and veterinary therapy, to pharmaceutically acceptable salts
thereof, to bioreversible derivatives thereof, to methods for producing said newcompounds, to pharmaceutical compositions containing the new compounds,
to dosage units of the compositions, and to methods of treating patients using
said compositions and dosage units.
Leukotrienes, which are formed via the 5-lipoxygenase pathway of
arachidonic acid metaboiism, are implicated in a variety of pathophysiolo~ic
functions, such as bronchoconstriction, plasma exudation, coronary artery
spasm, leukocyte chemotaxis and neutrophil degranulation 1 It is therefore
of considerable interest to develop compounds which antagonize the eflects of
leukotrienes.
International patent application No. PCT/DK93/00254 ~Publication
No. WO94/03431) describes a series of quinolyl substituted N-phenyl sub-
stituted isoserines with leukotriene antagonistic activity.
Now we have surprisingly found that novel diol containing com-
pounds according to general formula I are very potent antagonists, especially
in the presence of human serum albumin, and with superior bioavailability and
prolonged activity in vivo.
~he present compounds have the general formula I
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(R
y m
~,CH=CH ~H H OH
1 ~
R1 is hydrogen or halogen, preferabiy fluorine or chlorine, and m is
0, 1 or 2;
The compounds described herein contain more ce~ s of asymme-
try and may thus give rise to stereoisomers. The present invention is meant to
5 comprise all such possible stereoisomers as well as their racemic and stereo-
chemfcal mixtures.
The present salts of the compounds of formula I may be formed with
pharmaceutically acceptable inorganic or organic acids, such as hydrochloric,
hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid,
10 p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid,
propionic acid, citric acid, tartaric acid, and maleic acid.
5-Lipoxygenase inhibitors and leukotriene antagonists are of potential
interest in the therapy of asthma, allergy, rheumatoid arthritis, spondylo-
arthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders,15 such as psoriasis and atopic der",~lili~, chronic i"n~""~,alory bowel ~ise~se,
and other inflammatory conditions, vasospasm associated with angina
pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress
syndrome, ischemic and reperfusion injury, migraine he~d~che, etc. 2 The
idenliric~Lion of specific 5-lipoxygenase inhibitors and leukotriene antagonists
202
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. WO 97tl9925 PCT~DK96/00467
is thus a novel approach with very wide implications for the treatment of a
diversity of clinical disorders.
Leukotriene antagonists may be identified by observing the contrac-
tions elicited in preparations of guinea-pig ileum strips suspended in a physi-
oiogical buffer by addition of pure leukotriene D4 (LTD4) 3 . When the com-
pounds of the present invention were added to the ileum preparation before
addition of LTD4 a significant inhibition occurred of the specific LTD4- inducedcontraction. This inhibition occurred at concentrations as low as 0.1 - 1 nM.
On the other hand, contractions induced with histamine at 10 7 M were not
inhibited by these compounds even at micromolar concenL,~Iiolls.
It is of importance to investigate the receptor binding properties of
leukotriene antagonists in relation to their inhibition of smooth muscle
contraction. Receptor blnding studies may be performed with guinea-pig lung
membranes in a direct competition assay between a leukotriene antagonist
and [3H~LTD4 for binding to the LTD4 receptor 3,4. A plc50 value is deter-
mined as the negative iogarithm of the molar co"ce~ lion of antagonist
inhibiting [3H~LTD4 binding by 50%. The plc50 values for the compounds of
the present invention are equal to or higher than those for the reference
compound SR3040 5 (see ~able 1)
25 3 I. Ahnfelt-R0nne, D. Kirstein and C. K~rgaard-Nielsen, European J.
Pharmacol. 155 (1988) 117.
4 S. Mong, H.-L. Wu, M.O. Scott, M.A. Lewis, M.A. Clarke, B.M. Weich-
man, C.M. Kinzig, J.G. Ole~on and S.T. Crooke, J. rl,~r"~acol. Exp.
Ther. 234 (1985) 316.
30 5 International Patent Appl. No. PCT/DK93100254 ~Pu~l. No. WO
94/03431), Example 18.
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Table I Bindinq of r3H1LTDq to quinea-Pig lung membranes in the
absence or Presence of 0.1% human serum albumin (plC50,
mean +SD (n~ or individual values~
Compound Absence of albumin Presence of albumin
Example 7 8.8 + 0.1 (3) 9.1 t 0.1 (3)
Example 8 9.0 + 0.3 (3) 9.3 + 0.2 (3)
Example 5 8.4 + 0.1 (3) 8.6 + 0.1 (3)
Example 6 8.8 f 0.5 (3) 8.8 + 0.4 (3)
Example 3 8.3 - 8.2 8.4 - 8.6
Example 4 8.4 - 8.4 8.9 - 8.7
SR3040 5 8.9 + 0.3 (3) 8.8 + 0.1 (3)
The leukotriene antagonistic effect was tested in vivo on LTD4 -
15 induced bronchoconstriction in anaesthetized guinea-pigs 3. Intravenously thecompounds were administered 10 minutes, orally 24, 48 and 72 hours before
the bronchoconstriction. The ED50 values represent the dose inhibiting the
leukotriene induced bronchoconslli~;lion by 50%. The ED50 values were calcu
lated by regression analysis of 2 - 3 doses. The following Table ll shows the
20 results.
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~ o A C C C C
Cl Q
IL
:n
~ O a~ /~ ~ A C
Ll~
o O ~- ~ C~~ ao A
~'
O
E ~ c a~ ~ 0
o
~, g
o~ o o o~ o~ ~
111
o
O a~ ~ O o O
X ~~r o E
~_ ~ ~C
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The present invention also relates to a method for producing the
present compounds.
In one embodiment, an amine of the formula ll
~R ~
m
~,XN~,~CH CH--@_NH2
in which R1 m have the above meanings, is reacted with a compound of the
5 formula lll
H H
C--~CH20H
~ 1 1
~ X OH 111
in which X is capable of rO~ i"y a "good leaving group", X thus standing for
e.g. a halogen atom, such as chlorine, bromine or iodine, or an alkyl- or
arylsulphonyloxy group, but other leaving groups can be used as well, such as
an alkylsulphate group, a chlorosulphonyloxy group, an alkylsulphite group, a
10 mono- or dialkylphosphate group or a nitrate group, to form a compound of
the formula 1.
The reaction is performed in a suitable inert organic solvent, such as
dimethylfo"l,d",i~;3, but other solvents can be used as well. The reaction is
preferably performed at ambient temperature, but in some cases it is
15 convenient to cool the reaction mixture below room temperature, or to heat
the reaction mixture above room temperature, up to the boiling point of the
solvent used, depending on the nature of the reactants of the formulae ll and
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111 used. The crude reaction products of the formula I are collected by
filtration, or, after dilution with water, extracted from the reaction mixture with
a suitable solvent, such as diethyl ether, ethyl acetate, dichloromethane or
chloroform. The products are purified e.g. by recryst~lli7~tion or by ch~u,l,atog-
5 raphy.
In another embodiment, an amine of the formula 11 is reacted with a
compound of the formula IV
~I H
p~ CH20H
$~\o/
~R2)n
in which R2 and n have the above meanings.
The reaction is performed either in a 5l~it~1E inert organic so1vent,
such as methanol, ethanoi, dimethyiformamide or hexamethyl phosphoric
triamide, or in water, or in mixtures thereof. The reaction is pe,r~r,l,ed at a
temperature about or above room temperature, up to the boiiing point of the
solvent used. In some cases it can, however, be convenient to cool the reac-
tion mixture below room temperature, depending on the nature of the
compound of the formula IV used. The isol~tion and purification of the prod-
ucts can be performed as described above.
The present compounds are intended for use in pharmaceutical
compositions which are useful in the l,eal-nent of the above mentioned dis-
eases.
The amount required of a compound of formula I (hereinafter
referred to as the active ingredient) for therapeutic effect will, of course, vary
both with the particular compound, the route of administration and the mam-
mal under treatment. A suitable dose of a compound of formula I for systemic
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treatment is 0.1 to 20 mg per kilogram bodyweight, the most preferred dosage
being 0.2 to 10 mg/kg of ",allllllai bodyweight, ad"~i"islered one or more
times daiiy.
In spray formulations, a suitable anti-a~ r.,dlic dose of a co",pound
5 of formula (I) is 1 ,ug to 5 mg of compound per kilogram bodyweight, the most
preferred dosage being 1 ,ug to 1 mg/kg of mammal bodyweight, for example
from 1 ,ug to 0.5 mg/kg.
While it is possible for an active ingredient to be ad~"i"i:jL~red alone
as the raw chel"ical, it is preferable to present it as a pharmaceutical formula-
10 tion. Conveniently, the active ingredient comprises from 0.1% to 100% byweight of the formulation. Conveniently, dosage units of a formulation contain
between 0.07 mg and 1 9 of the active ingredient. For topical administration,
the active ingredient preferably comprises from 1% to 2% by weight of the
formulation but the active ingredient may comprise as much as 10% w/w.
15 Formulations suitable for nasal or buccal administration may comprise 0.1 to
20% w/w, for example about 2% wlw of active ingredient.
By the term "dosage unit" is meant a unitary, i.e. a singie dose which
is capable of being administered to a patient, and which may be readily
handled and packed, remaining as a physically and chemically stable unit
20 dose comprising either the active material as such or a mixture of it with solid
or liquid pharmacelltic~i diluents or carriers.
The formulations, both for veterinary and for human medical use, of
the present invention comprise an active ingredient in association with a phar-
maceutically acce,ul~ble carrier therefor and optionally other therapeutic in-
25 gredient(s). The carrier(s) must be "acceplable" in the sense of being compat-
ible with the other ingredients of the formulations and not .lel~t~,rious to therecipient thereof.
The formulations include those in a form suita~le for oral, ophthal-
mic, rectal, parenteral (including subcutaneous, intraml~sc(ll~r and intra-
30 venous), transdermal, intra-articular, topical, nasal, or buccal administration.
The formulations may conveniently be presented in dosage unit form
and may be prepared by any of the methods well known in the art of
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pharmacy. All methods include the step of bringing the active in~redient into
association with the carrier which constitutes one or more accessory
ingredients. In general, the formulations are prepared by uniformly and inti-
,, mately bringing the active ingredient into associdlion with a liquid carrier or a
finely divided solid carrier or both, and then, if necess~ry, shaping the product
into the desired formulation.
Formulations of the present invention suitable for oral administration
may be in the form of .JiscreLe units as capsules, sachets, tablets or lozenges,each containing a predetermined amount of the active ingredient; in the form
of a powder or granules; in the form of a solution or a suspension in an aque-
ous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a
water-in-oil emulsion. The active ingredient may also be adn,i"is~ered in the
form of a bolus, elec~ ry or paste.
Formulations for rectal administration may be in the form of a sup-
pository incorporating the active ingredient and a carrier, or in the forrn of an
enema.
Formulations suitable for parenteral administration conveniently
comprise a sterile oily or aqueous preparation of the active ingredient which ispreferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular or ophthalmic adminisl,~Lion
may be in the form of a sterile aqueous prt~ r;~lion of the active ingredient
which may be in microcrystalline form, for exampie, in the form of an aqueous
microcrystalline suspension. Liposomal formulations or biodegradable polymer
systems may also be used to present the active ingredient for both intra-
-articular and ophthalmic admini~ lion.
Formulations suitable for topical or opl)ll,al~"ic administration include
liquid or semi-liquid preparations, such as oil-in-water or water-in-oil
emulsions, ointments or pastes; or solutions or suspensions, such as drops.
Formulations suitable for administration to the nose or buccal cavity
include powder, self-propelling and spray formulations, such as aerosols and
atomizers.
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Other formuiations suitable for nasal admi"isL~lion include a fine
powder which is administered in the manner in which snuff is taken, i.e. by
rapid inhalation through the nasal p~s.s~ge from a container of the powder
heid close up to the nose.
In addition to the aforementioned ingredients, the formulations of this
invention may include one or more additional ingredients.
The compositions may further co"ldi" other ther~pelltic~lly active
compounds usually appiied in the treatment of the above mentioned pathologi-
cal conditions, for instance glucoco,licoi-ls, anti-hislami"es, platelet activating
~actor (PAF) antagonists, anticholinergic agents, methyl xal,Llli"es"B-adre-
nergic agents, salicylates, indomethacin, flufenamate, naproxen, tlmegadine,
gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc
salts, and salicylazosulfapyridin (.S~ opyrin).
The invention will now be further described in the foliowing
1 5 Examples:
l~xample 1
(+~-2R,3R-E-3-N-~3-2-(quinolin-2-vl)ethenYll-Phenvlamino-3-phenvl-1 .2-proPan-
A mixture of E-3-[2-(quinolin-2-yl)ethenyl]aniline (0.~ g, 2 mmol)
(confer EP O 206 751 A Merck Frosst Canada Inc) and (2R,3R-t+)-3-phenyl-
glycidol (Aldrich) (0.3 g, 2 mmol) in ethanol (10 ml) is refluxed for 8 days.
After cooling, the resulting precipitate is colle~,led by filtration, and washedwith ethanol and ether. The title compound is obtained with a melting point of
164-166~C and [a]D20 = +60.9~ (c=1,Q, CH30H).
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ExamPIeS 2 - 8
By following the procedure of Example 1 and using the appropriate
starting materials, compounds of Table lll are obtained.
( l)m =1~'HO/ \ H OH
Table lll
15 Ex. No. (R1)mMelting pointCon~guration ~a]D
2 H 164-66 2S,3S-58.0~ c=1, MeOH
3 7-CI 185-86 2R,3R +59.5~ c=1, MeOH
4 7-CI 189-91 2S,3S-58.3O c=1, MeOH
7-F 172-74 2R,3R +57.5~ c=1, MeOH
6 7-F 173-75 2S,3S-58.1~ c=1, MeOH
7 6-F,7-F 162-64 2R,3R +64.2~ c=1, MeOH
8 6-F,7-F 162-64 2S,3S-63.0~ c=1, MeOH
,
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ExamPie 9
Tablet
(+)-2R,3R-E-3-N-[3-2-(6,7-difluoroquinotin-2-
-yl)ethenyl]-phenylamino-3-phenyl-1,2-propandiol
(active substance) 100 mg
I ~ctose 75 mg
Starch 12 mg
Methyl cellulose 2 mg
Sodium carboxymethyl cell~lQse (CMC-Na3 10 mg
Magnesium stearate 1 mg
The active substance, lactose and starch are mixed to a homogene-
ous state in a suitable mixer and moistened with a 5 per cent aqueous sol-
ution of methylcellulose 15 cps. The mixing is continued until granules are
formed. If necess~ry, the wet granulation is passed through a suitable screen
and dried to a water cG.,Ler,l of less than 1% in a suitable dryer, e.g. fluid bed
or drying oven. The dried granulaton is passed through a 1 mm screen and
mixed to a homogeneous state with CMC-Na. Magnesium stearale is added,
and the mixing is continued for a short period of time.
Tablets with a weight of 200 mg are produced from the granulation
by means of a suitable tabletting machine.
