CA2222790A1 - Quinoline derivatives containing a diol as leukotriene antagonists - Google Patents
Quinoline derivatives containing a diol as leukotriene antagonists Download PDFInfo
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- CA2222790A1 CA2222790A1 CA002222790A CA2222790A CA2222790A1 CA 2222790 A1 CA2222790 A1 CA 2222790A1 CA 002222790 A CA002222790 A CA 002222790A CA 2222790 A CA2222790 A CA 2222790A CA 2222790 A1 CA2222790 A1 CA 2222790A1
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- propandiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Abstract
The present invention relates to hitherto unknown compounds of formula (I) in which R1 is hydrogen or halogen, preferably fluorine or chlorine, and m is 0, 1 or 2. The present compounds are of value in the human and veterinary practice as leukotriene antagonists.
Description
W O 97/19925 PCT~DK96/00467 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
WO 97/19925 PCT~DK96/00467 (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 . 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.
W O 97/19925 PCT~DK96/00467 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.
W O 97/1992~ PCTADK96/00467 ~ 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~ ~
o O a~ ~ O o O
X ~~r o E
~_ ~ ~C
W O 97/19925 PCT~DK96/00467 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 W O 97/1992S PCT~DK96/00467 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 W O 97/1992~ PCT~DK96/00467 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 CA 02222790 1997-ll-28 W O 97/19925 PCT~DK96/00467 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.
WO 97/19925 PCT~DK96/00467 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).
CA 02222790 1997-ll-28 W O 97/19925 PCT~DK96/00467 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
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
WO 97/19925 PCT~DK96/00467 (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 . 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.
W O 97/19925 PCT~DK96/00467 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.
W O 97/1992~ PCTADK96/00467 ~ 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~ ~
o O a~ ~ O o O
X ~~r o E
~_ ~ ~C
W O 97/19925 PCT~DK96/00467 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 W O 97/1992S PCT~DK96/00467 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 W O 97/1992~ PCT~DK96/00467 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 CA 02222790 1997-ll-28 W O 97/19925 PCT~DK96/00467 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.
WO 97/19925 PCT~DK96/00467 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).
CA 02222790 1997-ll-28 W O 97/19925 PCT~DK96/00467 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
, W O 97/19925 PC~ADK96/00467 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.
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
, W O 97/19925 PC~ADK96/00467 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.
Claims (10)
1. A compound of the formula I
I
in which R1 is hydrogen or halogen, preferably fluorine or chlorine, and m is 0, 1 or 2; and pharmaceutically acceptable, non-toxic salts thereof.
I
in which R1 is hydrogen or halogen, preferably fluorine or chlorine, and m is 0, 1 or 2; and pharmaceutically acceptable, non-toxic salts thereof.
2. A compound according to formula I of claim 1, in which R1 is preferably fluorine or chlorine.
3. A stereoisomer of a compound according to any one of claims 1-2, in pure form; or a mixture of such stereoisomers.
4. A salt according to claim 1 in which the salt is selected from the group consisting of salts formed with hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, and maleic acid.
5. A compound of claim 1 which is selected from the group consisting of:
(+)-2R,3R-E-3-N-[3-2-(6,7-difluoroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (+)-2R,3R-E-3-N-[3-2-(quinolin-2-yl)ethenyl]-phenylamino-3-phenyl--1,2-propandiol, (-)-2S,3S-E-3-N-[3-(2-quinolin-2-yl)ethenyl]-phenylamino-3-phenyl--1,2-propandiol, (+)-2R,3R-E-3-N-[3-2-(7-chloroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (-)-2S,3S-E-3-N-[3-2-(7-chloroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (+)-2R,3R-E-3-N-[3-2-(7-fluoroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (-)-2S,3S-E-3-N-[3-2-(7-fluoroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (-)-2S,3S-E-3-N-[3-2-(6,7-difluoroquinolin-2-yl)ethenyll-phenylamino--3-phenyl-1,2-propandiol, and their salts and pure enantiomeric forms.
(+)-2R,3R-E-3-N-[3-2-(6,7-difluoroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (+)-2R,3R-E-3-N-[3-2-(quinolin-2-yl)ethenyl]-phenylamino-3-phenyl--1,2-propandiol, (-)-2S,3S-E-3-N-[3-(2-quinolin-2-yl)ethenyl]-phenylamino-3-phenyl--1,2-propandiol, (+)-2R,3R-E-3-N-[3-2-(7-chloroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (-)-2S,3S-E-3-N-[3-2-(7-chloroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (+)-2R,3R-E-3-N-[3-2-(7-fluoroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (-)-2S,3S-E-3-N-[3-2-(7-fluoroquinolin-2-yl)ethenyl]-phenylamino--3-phenyl-1,2-propandiol, (-)-2S,3S-E-3-N-[3-2-(6,7-difluoroquinolin-2-yl)ethenyll-phenylamino--3-phenyl-1,2-propandiol, and their salts and pure enantiomeric forms.
6. A pharmaceutical preparation, containing a compound according to any one of claims 1 - 5 alone or together with the necessary auxiliary agents.
7. A method of treating patients in need of treatment characterized in administering to said patients an effective amount of one or more compounds according to any of claims 1 - 5, if necessary together or concomitantly with one or more other therapeutically active components.
8. A method according to claim 7 for the treatment and prophylaxis of a number of disease states including asthma, allergy, rheumatoid arthritis, spondyloarthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic inflammatory bowel disease, and other inflammatory conditions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syndrome, ischemic and reperfusion injury, migraine headache.
9. Method for producing a compound of formula I according to claim 1, in which a) an amine of the formula II
II
in which R1 m have the above meanings, is reacted with a compound of the formula III
III
in which X is capable of forming a "good leaving group"; or b) an amine of the formula II is reacted with a compound of the formula IV
IV
in which R2 and n have the above meanings.
II
in which R1 m have the above meanings, is reacted with a compound of the formula III
III
in which X is capable of forming a "good leaving group"; or b) an amine of the formula II is reacted with a compound of the formula IV
IV
in which R2 and n have the above meanings.
10. The use of a compound of claim 1 in the manufacture of a medicament for the treatment and prophylaxis of a number of disease states, including asthma, allergy, rheumatoid arthritis, spondyloarthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic inflammatory bowel disease, and other inflammatory conditions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syndrome, ischemic and reperfusion injury, migraine headache.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002222790A CA2222790A1 (en) | 1995-11-27 | 1996-11-13 | Quinoline derivatives containing a diol as leukotriene antagonists |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9524185.7 | 1995-11-27 | ||
| CA002222790A CA2222790A1 (en) | 1995-11-27 | 1996-11-13 | Quinoline derivatives containing a diol as leukotriene antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2222790A1 true CA2222790A1 (en) | 1997-06-05 |
Family
ID=4161814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002222790A Abandoned CA2222790A1 (en) | 1995-11-27 | 1996-11-13 | Quinoline derivatives containing a diol as leukotriene antagonists |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2222790A1 (en) |
-
1996
- 1996-11-13 CA CA002222790A patent/CA2222790A1/en not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |