CA2047249A1 - Process - Google Patents
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- CA2047249A1 CA2047249A1 CA002047249A CA2047249A CA2047249A1 CA 2047249 A1 CA2047249 A1 CA 2047249A1 CA 002047249 A CA002047249 A CA 002047249A CA 2047249 A CA2047249 A CA 2047249A CA 2047249 A1 CA2047249 A1 CA 2047249A1
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- 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
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
ABSTRACT
PROCESS
The invention provides a novel process for the manufacture of quinoline derivatives of the formula III as defined hereinafter which are angiotensin II inhibitors. The process involves the removal of a trisubstituted tin moiety from a compound of the formula IV, in which R1, R2, R3, R4, R5, Ra, Rb and Q have the various meanings defined hereinafter. Certain of the intermediates are novel and are provided as a further feature of the invention.
PROCESS
The invention provides a novel process for the manufacture of quinoline derivatives of the formula III as defined hereinafter which are angiotensin II inhibitors. The process involves the removal of a trisubstituted tin moiety from a compound of the formula IV, in which R1, R2, R3, R4, R5, Ra, Rb and Q have the various meanings defined hereinafter. Certain of the intermediates are novel and are provided as a further feature of the invention.
Description
PROCESS
This invention concerns a novel process for the production of novel quinoline derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "AII"). The invention also concerns various quinoline derivatives which are valuable chemical intermediates, for example for use in the abovementioned process.
The angiotensins are key mediators of the renin-angiotensin-aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man. The angiotensin known as AII is produced by the action of angiotensin converting enzyme (ACE) from angiotensin I, itself produced by the action of the enzyme renin from the blood plasma protein angiotensinogen. AII is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure. In addition, the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms. AII
inhibitors are useful for the reduction or prevention of these effects produced by the action of AII. Although a number of AII inhibitors and processes for their preparation are known, for example certain substituted imidazoles described in European Patent Application, Publication No. tEPA) 253310 and EPA 324377, certain benzimidazoles described in U.S. Patent no. 4880804 and certain pyrroles, pyrazoles and triazoles described in EPA 323841, there remains a continuing need for alternative inhibitors and for effective synthetic procedures for their production such as those provided by this invention.
Certain quinoline derivatives which are structurally related to the novel quinoline derivatives obtainable by the process of the present invention are described in EPA 348155 as having leukotriene D4 antagonist activity.
r In our co-pending EPA 412848 there is described a series of quinoline derivatives of formula I ~set out hereinafter~ wherein R is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C~alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl substituent; R2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl; R3 and R4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (1-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(_-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (1-4C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, and substituted (1-4C)alkyl, the latter bearing an amino, hydroxy or (1-4C)alkoxy substituent; or R3 and R4 together form (1-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R5 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro; A is methylene; X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl group and moiety A; Z is lH-tetrazol-5-yl, -CO.NH.(lH-tetrazol-5-yl) or a group of the formula -CO.OR6 or -Co.N~.So2.R7 in which R6 is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R7 is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; but excluding methyl 2-[(3-methoxycarbonylquinolin-4-yloxy)-methyl]benzoate.
It will be appreciated that the compounds of formula I, depending on the nature of the substituents, may possess one or more 2~72~9 chiral centres and may be isolated in one or more racemic or optically active forms.
In addition, in the compounds of formula I generic terms such as "alkyl" include both straight and branched chain variants when the carbon numbers permit. However, when a particular radical such as "propyl" is given, it is specific to the straight chain variant, branched chain variants such as "isopropyl" being specifically named where intended. The same convention applies to other radicals.
A particular value for R or R when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; and when it is cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
A particular value for R1 when it is alkyl bearing one or more fluoro substitutents is, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing a hydroxy, cycloalkyl, (1-4C)alkoxy or phenyl substituent is, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl.
A particular value for R2 when it Is cycloalkyl-alkyl is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopentyl-ethyl; when it is phenylalkyl is, for example, benzyl, 1-phenylethyl or 2-phenylethyl; and when it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.
Appropriate values for R3, R4, R5, or Ra, or for an optional substituent which may be present when X is phenylene, as defined above, include by way of example:-for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for halogeno: fluoro, chloro, bromo and ;~ ~72~9 iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkylamino: methylamino, ethylamino and butylamino; for dialkylamino:
dimethylamino, diethylamino and dipropylamino; for dialkylamino-alkyl:
dimethylaminomethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl and 3-(diethylamino)propyl; for alkanoyl: formyl, acetyl and butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl;
for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkylthio: methylthio, ethylthio and butylthio;
for alkylsulphinyl: methylsulphinyl, ethylsulphinyl and butylsulphinyl; and for alkylsulphonyl: methylsulphonyl, ethylsulphonyl and butylsulphonyl; for alkyl bearing an amino, hydroxy or alkoxy substituent: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; and alkylenedioxy: methylenedioxy and ethylenedioxy.
A particular value for R6 when it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol is, for example, a residue derived from a (1-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the like.
A particular value for R7 when it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.
Particular values for optional substituents which may be present on one or more phenyl moieties include, by way of example, for halogeno: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.
A specific value for X which is of particular interest is, for example, p-phenylene.
A preferred value for R6 or R5 is, for example, hydrogen and for R1 is, for example, methyl, ethyl or propyl.
7 2 ~ ~
A preferred group of compounds described in our co-pending application comprises those compounds of the formula Ia (set out hereinafter) wherein R1, R2, R3, R4 and R5 have any of their meanings as defined above and zl is carboxy, lH-tetrazol-5-yl or benzenesulphonamido, the latter optionally containing one or two substituents independently selected from halogeno (such as fluoro, chloro or bromo), (1-4C)alkyl (such as methyl or ethyl), (1-4C)alkoxy (such as methoxy or ethoxy), cyano, nitro and trifluoromethyl;
together with the non-toxic salts thereof.
A preferred value for Z or zl is, for example, carboxy or lH-tetrazol-5-yl, which latter is especially preferred and, in particular, when it is attached ortho to the group X.
A particularly preferred combination of values in any of the above definitions is wherein the quinoline moiety together with the attached substituents R1, R2, R3 and R4, and Ra when present, has any of the following values:- 2-methylquinoline, 2-ethylquinoline, 2-ethyl-6-methoxyquinoline, 6,7-dimethoxy-2-ethylquinoline, 2-ethyl-5,6,7-trimethoxyquinoline, 2-ethyl-6-hydroxyquinoline, 2-ethyl-6-methylthioquinolire, 2-ethyl-7-hydroxymethylquinoline, 2-ethyl-6-(2-fluoroethoxy)quinoline, 2-ethyl-6-(2,2,2-trifluoroethoxy)-quinoline, 2-ethyl-6-carboxamidoquinoline, 2-ethyl-6-fluoroquinoline, 2-ethyl-6-isopropoxyquinoline or 6-aminomethyl-2-ethylquinoline; and in which the substituent O.A.X- is attached at the 4-position of the quinoline ring.
Compounds disclosed in our co-pending application which are particularly preferred are 2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-7-hydroxymethyl-4-1(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-6-(2-fluoroethoxy)-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-6-(2,2,2-trifluoroethoxy)-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline and 2-ethyl-6-isopropoxy-4-[(2'-(lH-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline together with their non-toxic salts.
Although all of the formula I compounds can form salts with suitable acids, it will be appreciated that those compounds of formula I wherein Z is other than an ester group or in which R3 or R4 is a carboxy group can form salts with acids as well as with bases.
Particularly suitable non-toxic salts for such compounds therefore also include, for example, salts with bases affording physiolagically acceptable cations, for example, alkali metal (such as sodium and-potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine or triethylamine, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with p-toluenesulphonic and methanesulphonic acids.
The compounds of the formula I are described in our co-pending application as obtainable by a variety of standard procedures of organic chemistry well known in the art for the production of structurally analogous compounds. We have now discovered a simple alternative procedure for the production of quinoline derivatives of formula I wherein X is optionally substituted p-phenylene and Z is tetrazolyl.
According to the invention there is provided a process for the manufacture of a compound of formula III, wherein R1, R2, R3, R4, R5 and Ra have any of the values defined hereinbefore and Rb is hydrogen or a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, which comprises removal of a trisubstituted tin moiety of the formula Sn(Q)3 from a compound of the formula IV wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings as defined hereinbefore and Q is a (1-6C)alkyl or phenyl group, the latter optionally substituted by an (1-4C)alkyl, tl-4C)alkoxy or halogeno group.
2~72 ~
A particular value for Q is, for example, (1-4C)alkyl such as methyl, ethyl, propyl or butyl, of which butyl is preferred.
A particular value for Rb, or for an optional substituent on Q when it is phenyl, when it is alkyl is, for example, methyl or ethyl; when it is halogeno is, for example, fluoro, chloro or bromo;
and when it is alkoxy is, for example, methoxy or ethoxy.
, The process is particularly suitable for the manufacture of compounds of the formula III wherein the tetrazolyl group is in a position ortho to the adjacent phenyl group.
The trisubstituted tin moiety Sn(Q)3 may be removed, for example, by acid or base hydrolysis. The reaction is conveniently carried out, for example, by treatment of the compound of formula IV
with mineral acid, such as aqueous hydrochloric acid, in the presence of a suitable solvent or diluent. A suitable solvent or diluent is, for example, a hydrocarbon such as toluene or xylene, an ether such as dioxan or tetrahydrofuran, or water, or mixtures thereof. The reaction is generally carried out at a temperature in the range, for example, 0-50C, and conveniently at or about ambient temperature.
Compounds of the formula IV as defined hereinbefore may be obtained, for example, by reaction of a nitrile of the formula V with an azide of the formula VI wherein R1, R2, R3, R4, R5, Ra, Rb and Q
have any of the meanings defined hereinbefore. The reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50-150~C, and preferably at 100-145C. Preferably an excess of the azide is used, especially 1.5 to 5 equivalents excess. The procedure is particularly suitable for obtaining compounds of the formula IV
wherein the tetrazolyl group bearing the trisubstituted tin moiety of formula Sn(0)3 is at a position ortho to the adjacent phenyl group.
Compounds of the formula V may be obtained, for example, by radical bromination of a nitrile of formula VII wherein R5 and Rb have any of the values defined hereinbefore to the corresponding bromomethyl derivative followed by alkylation of a quinolone of the formula VIII wherein R1, R2, R3, R' and Ra have any of the meanings defined hereinbefore. The bromination is carried out using procedures and reagents well known in the art, such as by reaction with N-bromosuccinimide in the presence of benzoyl peroxide or azo(bisisobutyronitrile) in a solvent such as chlorobenzene or carbon tetrachloride, and the alkylation is generally carried out in the presence of a base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydride such as sodium hydride and in a solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10-100C. Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous or non-aqueous solvent such as water and dichloromethane.
Compounds of the formula VII may be obtained, for example, by the procedure described in European Patent Application, Publication no. 0253310 A2. Alternatively, they may be obtained, for example, by reaction of a Grignard reagent, formed from an unsubstituted or substituted 4-bromotoluene in a solvent such as tetrahydrofuran, with a trialkyltin halide, such as tributyltin chloride, at a temperature of 0-25C, followed by reaction of the resulting (substituted)phenyltrialkyltin compound with a substituted or unsubstituted bromobenzonitrile in the presence of a palladium (0) catalyst, such as tetrakis(triphenylphosphine) palladium, and azo(bisisobutyronitrile). A further alternative to obtain compounds of the formula VII is by reaction of 4-methylphenylboronic acid with a suitably substituted bromobenzonitrile in the presence oE a palladium catalyst, such as palladium (II) chloride or tetrakis-(triphenylphosphine)palladium(0), and azo(bisisobutyronitrile). Yet another alternative to obtain formula VII compounds is by reaction of an unsubstituted or substituted 4-bromotoluene with an alkali metal ~V~7~ 9 _ 9 _ alkane, such as butyllithium, and zinc chloride followed by reaction with a suitably substituted bromobenzonitrile in the presence of tetrakis(triphenylphosphine)palladium.
Compounds of the formula VIII are known, for example as described in EPA 412848, or may be obtained using standard procedures of organic chemistry, such as those described in Org. Syn., Coll. Vol.
III, p.374 and p.593.
In a modified procedure for carrying out the process of the invention, and which is provided as a further feature of the invention, a compound of the formula IV as defined above is generated ln situ from a compound of the formula V as defined above by reaction with an azide of the formula VI as defined above. The trisubstituted tin moiety Sn~Q)3 present may then be removed without isolation of the compound of the formula IV, for example, by addition of aqueous mineral acid to the reaction mixture. A mixture of sodium nitrite and hydrochloric acid may be used to acidify the reaction mixture, thereby conveniently destroying any excess azide present.
The azides of formula VI are either commercially available or may be prepared by standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.
Whereafter, when a non-toxic salt of a compound of formula II is required, it may be obtained, for example, by reaction with the appropriate base affording a physiologically acceptable cation, or with the appropriate acid affording a physiologically acceptable anion, or by any other conventional salt formation procedure.
Further, when an optically active form of a compound of formula I is required, one of the aforesaid processes may be carried out using an optically active starting material. Alternatively, the racemic form of a compound of formula I may be resolved, for example by reaction with an optically active form of a suitable organic base, for example, ephedrine, N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or 1-phenylethylamine, followed by conventional separation i 2 i~ ~
of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (1-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid.
Certain of the intermediates defined herein are novel, for example the compounds of the formula IV and V and in particular those compounds of formula IV and V wherein the substituted tetrazolyl group and the cyano group respectively are in a position ortho to the adjacent phenyl group, and are provided as a further feature of the invention.
The antagonism of one or more of the physiological actions of AII and, in particular, the antagonism of the interaction of AII
with the receptors which mediate its effects on a target tissue, may be assessed using one or more of the following, routine laboratory procedures:
Test A: This ln vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled AII and a cell surface membrane fraction prepared from a suitable angiotensin target tissue. In this test, the source of cell surface membranes is the guinea pig adrenal gland which is well known to respond to AII. Interaction of the radiolabelled AII with its receptors (assessed as radiolabel bound to the particulate membrane fraction following removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) is antagonized by compounds which also bind to the membrane receptor sites and the degree of antagonism (observed in the test as displacement of membrane-bound radioactivity) is determined readily by comparing the receptor-bound radioactivity in the presence of the ~est compound at the specified test concentration with a control value determined in the absence of the test compound. Using this procedure compounds showing at least 50% displacement of radiolabelled AII binding at a t~ 3 concentration of 10 4 M are retested at lower concentrations to determine their potency. For determination of the IC50 (concentration for 50~ displacement of radiolabelled AII binding), concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC50, which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.
In general, compounds of formula III as defined above show significant inhibition in Test A at a concentration of 50 micromolar or much less.
Test B: This in vitro test involves the measurement of the antagonistic effects of the test compound against AII-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37C. In order to ensure that the effect of the compound is specific to antagonism of AII, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.
In general, compounds of formula III as defined above show significant inhibition in Test B at a final concentration of 50 micromolar or much less.
Test C: This in vivo test involves using terminally-anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure The AII
antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin II-induced pressor responses. To ensure that the effect is specific, the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.
The compounds of formula III generally show specific AII-antagonist properties in Test C at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
Test D: This in vivo test involves the stimulation of endogenous AII
biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.
In general compounds of formula III will show AII-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
- By way of illustration of the angiotensin II inhibitory properties of compounds of formula III, 2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride gave the following results in tests A, B and C described above:-In test A: an average IC50 of 1.7x10 8M;
In test B an average PA2 of 8.95;
In test C: ED50 of 0 5 mg/kg (i.v. administration).
The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:-(i) concentrations and evaporations were carried out by rotary evaporation in vacuo;
(ii) operations were carried out at room temperature, that is in the range 18-26C;
~iii) yields. where given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;
(iv) 1H NMR spectra were normally determined at 270 MHz in CDCl3 using tetramethylsilane (TMS) as an internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multplet; t, triplet; br, broad; d, doublet; and (v) the term "1_-tetrazol-5-yl" stands for "1-H-1,2,3,4-tetrazol-5-yl".
2~li2~
~xample 1 A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy~quinoline in toluene (15 ml), prepared in situ by refluxing for 90 hours a mixture of 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (0.9 g) and a solution of tributyltin azide in toluene (15 ml) [the latter prepared by reaction of tributyltin chloride (3.3 g) and sodium azide (1.13 g) in water (22.5 ml) at ambient temperature for 4 hours, followed by extraction with toluene and azeotropic removal of water from the extract to leave a volume of 15 ml], was added slowly over 1 hour to a solution of sodium nitrite (2.5 g) in water (10 ml) containing 12% w/v hydrochloric acid (10 ml), maintaining the temperature of the mixture below 5C. A solution of sulphamic acid (1.43g) in water (lOml) was then added, maintaining the temperature below 5C, and the mixture stirred for 1 hour. The resultant suspended semi-solid was collected by filtration and washed with water (3 x 10 ml), followed by toluene (10 ml). The semi-solid was then added to tetrahydrofuran (THF) (40 ml), which caused the product to dissolve and then crystallise as a white solid. After cooling for one hour the solid was collected by filtration, washed with THF (5 ml) and dried to give 2-ethyl-4-l(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]-quinoline hydrochloride in 53~ yield; m.p. 179-180C (dec.); NMR
(d6-DMSO): 1.46(t,3H), 3.18(q,2H), 5.68(s,2H), 7.22(d,2H), 7.5-7.8(m,7H), 7.83(t,1H), 8.08(t,1H), 8.18(d,1H), 8.32(d,1H).
xample 2 A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a similar method to that described in ~rg. Syn., Coll. Vol. III, p.374 and p.593 from aniline and ethyl propionylacetate), 4'-bromomethylbiphenyl-2-carbonitrile (A) (3.1 g) and solid potassium carbonate (1.81 g) in N-methylpyrrolidone (40 ml) were stirred for 36 hours under nitrogen. The mixture was then added dropwise to water (100 ml) at 15-25C and stirred for 30 minutes. The suspended solid was collected by filtration, washed with water, and dried at 60C
under vacuum. The solid was recrystallised from tert-butyl methyl ether to give 4'-[(2-ethylquinolin-4-yloxy3methyll-biphenyl-2-i 2`~ {3 carbonitrile as a solid (1.9 g), m.p. 151-153C; NMR(CDCl3): 1.4(t, 3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,1H), 7.4-7.6(m, 3H), 7.6-7.8(m, 6H), 8.0(d,1H), 8.25(d, lH).
The starting material A was obtained as follows:-(i) 2M Sodium carbonate solution (200 ml) was added to a stirredmixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5C. The temperature rose to approximately 20~C
and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110-120C) to give 4'-methylbiphenyl-2-carbonitrile in 80% yield, m.p. 44-46C; NMR
(d6-DMS0): 2.40 (s,3H), 7.30(d,2H), 7.35-7.55(m,4H), 7.60-7.65(m,lH), 7.75(d,lH).
(ii) A mixture of 4'-methylbiphenyl-2-carbonitrile (3.86 g), N-bromosuccinimide (3.92 g) and azo(bisisobutyronitrile) (0.15 g) in chlorobenzene (75 ml) was heated at 70C for 3 hours. Further N-bromosuccinimide (0.3 g) and azo(bisisobutyronitrile) (0.05 g) was added and the mixture was heated for another 15 minutes. Heating was stopped and the mixture stirred for 16 hours at ambient temperature.
Water (50 ml) was added and the mixture stirred for 30 minutes and filtered. The organic phase was separated, washed with water (50 ml) and dried (MgS04). The solvent was removed by evaporation and the resultant solid recrystallised from cyclohexane to give 4'-bromomethylbiphenyl-2-carbonitrile ~3.9 g) (A) as a solid; NMR
(CDCl3): 4.55(s,2H), 7.4-7.85(m, 8H).
, ~ ~ L;'~ 1 2 ~ ~
Che~; ~\_ tOr ~ R
R't ~ A--X
R
R R~
R R~ ~
1~3 q~ R2 L
--A X ~ 1 ~2 "~
R
~ ~s - l6 ~ l3 ~ 'i f). '1 ~
C~lCG~
Rb RS
R Ro~ , o ~,~C~ _ Rl ~Q~3 . S,~ . ~3 C~ V
Q~ 1~
R , 1~ r~-~ O
Q
This invention concerns a novel process for the production of novel quinoline derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "AII"). The invention also concerns various quinoline derivatives which are valuable chemical intermediates, for example for use in the abovementioned process.
The angiotensins are key mediators of the renin-angiotensin-aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man. The angiotensin known as AII is produced by the action of angiotensin converting enzyme (ACE) from angiotensin I, itself produced by the action of the enzyme renin from the blood plasma protein angiotensinogen. AII is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure. In addition, the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms. AII
inhibitors are useful for the reduction or prevention of these effects produced by the action of AII. Although a number of AII inhibitors and processes for their preparation are known, for example certain substituted imidazoles described in European Patent Application, Publication No. tEPA) 253310 and EPA 324377, certain benzimidazoles described in U.S. Patent no. 4880804 and certain pyrroles, pyrazoles and triazoles described in EPA 323841, there remains a continuing need for alternative inhibitors and for effective synthetic procedures for their production such as those provided by this invention.
Certain quinoline derivatives which are structurally related to the novel quinoline derivatives obtainable by the process of the present invention are described in EPA 348155 as having leukotriene D4 antagonist activity.
r In our co-pending EPA 412848 there is described a series of quinoline derivatives of formula I ~set out hereinafter~ wherein R is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C~alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl substituent; R2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl; R3 and R4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (1-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(_-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (1-4C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, and substituted (1-4C)alkyl, the latter bearing an amino, hydroxy or (1-4C)alkoxy substituent; or R3 and R4 together form (1-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R5 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro; A is methylene; X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl group and moiety A; Z is lH-tetrazol-5-yl, -CO.NH.(lH-tetrazol-5-yl) or a group of the formula -CO.OR6 or -Co.N~.So2.R7 in which R6 is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R7 is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; but excluding methyl 2-[(3-methoxycarbonylquinolin-4-yloxy)-methyl]benzoate.
It will be appreciated that the compounds of formula I, depending on the nature of the substituents, may possess one or more 2~72~9 chiral centres and may be isolated in one or more racemic or optically active forms.
In addition, in the compounds of formula I generic terms such as "alkyl" include both straight and branched chain variants when the carbon numbers permit. However, when a particular radical such as "propyl" is given, it is specific to the straight chain variant, branched chain variants such as "isopropyl" being specifically named where intended. The same convention applies to other radicals.
A particular value for R or R when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; and when it is cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
A particular value for R1 when it is alkyl bearing one or more fluoro substitutents is, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing a hydroxy, cycloalkyl, (1-4C)alkoxy or phenyl substituent is, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl.
A particular value for R2 when it Is cycloalkyl-alkyl is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopentyl-ethyl; when it is phenylalkyl is, for example, benzyl, 1-phenylethyl or 2-phenylethyl; and when it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.
Appropriate values for R3, R4, R5, or Ra, or for an optional substituent which may be present when X is phenylene, as defined above, include by way of example:-for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for halogeno: fluoro, chloro, bromo and ;~ ~72~9 iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkylamino: methylamino, ethylamino and butylamino; for dialkylamino:
dimethylamino, diethylamino and dipropylamino; for dialkylamino-alkyl:
dimethylaminomethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl and 3-(diethylamino)propyl; for alkanoyl: formyl, acetyl and butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl;
for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkylthio: methylthio, ethylthio and butylthio;
for alkylsulphinyl: methylsulphinyl, ethylsulphinyl and butylsulphinyl; and for alkylsulphonyl: methylsulphonyl, ethylsulphonyl and butylsulphonyl; for alkyl bearing an amino, hydroxy or alkoxy substituent: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; and alkylenedioxy: methylenedioxy and ethylenedioxy.
A particular value for R6 when it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol is, for example, a residue derived from a (1-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the like.
A particular value for R7 when it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.
Particular values for optional substituents which may be present on one or more phenyl moieties include, by way of example, for halogeno: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.
A specific value for X which is of particular interest is, for example, p-phenylene.
A preferred value for R6 or R5 is, for example, hydrogen and for R1 is, for example, methyl, ethyl or propyl.
7 2 ~ ~
A preferred group of compounds described in our co-pending application comprises those compounds of the formula Ia (set out hereinafter) wherein R1, R2, R3, R4 and R5 have any of their meanings as defined above and zl is carboxy, lH-tetrazol-5-yl or benzenesulphonamido, the latter optionally containing one or two substituents independently selected from halogeno (such as fluoro, chloro or bromo), (1-4C)alkyl (such as methyl or ethyl), (1-4C)alkoxy (such as methoxy or ethoxy), cyano, nitro and trifluoromethyl;
together with the non-toxic salts thereof.
A preferred value for Z or zl is, for example, carboxy or lH-tetrazol-5-yl, which latter is especially preferred and, in particular, when it is attached ortho to the group X.
A particularly preferred combination of values in any of the above definitions is wherein the quinoline moiety together with the attached substituents R1, R2, R3 and R4, and Ra when present, has any of the following values:- 2-methylquinoline, 2-ethylquinoline, 2-ethyl-6-methoxyquinoline, 6,7-dimethoxy-2-ethylquinoline, 2-ethyl-5,6,7-trimethoxyquinoline, 2-ethyl-6-hydroxyquinoline, 2-ethyl-6-methylthioquinolire, 2-ethyl-7-hydroxymethylquinoline, 2-ethyl-6-(2-fluoroethoxy)quinoline, 2-ethyl-6-(2,2,2-trifluoroethoxy)-quinoline, 2-ethyl-6-carboxamidoquinoline, 2-ethyl-6-fluoroquinoline, 2-ethyl-6-isopropoxyquinoline or 6-aminomethyl-2-ethylquinoline; and in which the substituent O.A.X- is attached at the 4-position of the quinoline ring.
Compounds disclosed in our co-pending application which are particularly preferred are 2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-7-hydroxymethyl-4-1(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-6-(2-fluoroethoxy)-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-6-(2,2,2-trifluoroethoxy)-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline and 2-ethyl-6-isopropoxy-4-[(2'-(lH-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline together with their non-toxic salts.
Although all of the formula I compounds can form salts with suitable acids, it will be appreciated that those compounds of formula I wherein Z is other than an ester group or in which R3 or R4 is a carboxy group can form salts with acids as well as with bases.
Particularly suitable non-toxic salts for such compounds therefore also include, for example, salts with bases affording physiolagically acceptable cations, for example, alkali metal (such as sodium and-potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine or triethylamine, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with p-toluenesulphonic and methanesulphonic acids.
The compounds of the formula I are described in our co-pending application as obtainable by a variety of standard procedures of organic chemistry well known in the art for the production of structurally analogous compounds. We have now discovered a simple alternative procedure for the production of quinoline derivatives of formula I wherein X is optionally substituted p-phenylene and Z is tetrazolyl.
According to the invention there is provided a process for the manufacture of a compound of formula III, wherein R1, R2, R3, R4, R5 and Ra have any of the values defined hereinbefore and Rb is hydrogen or a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, which comprises removal of a trisubstituted tin moiety of the formula Sn(Q)3 from a compound of the formula IV wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings as defined hereinbefore and Q is a (1-6C)alkyl or phenyl group, the latter optionally substituted by an (1-4C)alkyl, tl-4C)alkoxy or halogeno group.
2~72 ~
A particular value for Q is, for example, (1-4C)alkyl such as methyl, ethyl, propyl or butyl, of which butyl is preferred.
A particular value for Rb, or for an optional substituent on Q when it is phenyl, when it is alkyl is, for example, methyl or ethyl; when it is halogeno is, for example, fluoro, chloro or bromo;
and when it is alkoxy is, for example, methoxy or ethoxy.
, The process is particularly suitable for the manufacture of compounds of the formula III wherein the tetrazolyl group is in a position ortho to the adjacent phenyl group.
The trisubstituted tin moiety Sn(Q)3 may be removed, for example, by acid or base hydrolysis. The reaction is conveniently carried out, for example, by treatment of the compound of formula IV
with mineral acid, such as aqueous hydrochloric acid, in the presence of a suitable solvent or diluent. A suitable solvent or diluent is, for example, a hydrocarbon such as toluene or xylene, an ether such as dioxan or tetrahydrofuran, or water, or mixtures thereof. The reaction is generally carried out at a temperature in the range, for example, 0-50C, and conveniently at or about ambient temperature.
Compounds of the formula IV as defined hereinbefore may be obtained, for example, by reaction of a nitrile of the formula V with an azide of the formula VI wherein R1, R2, R3, R4, R5, Ra, Rb and Q
have any of the meanings defined hereinbefore. The reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50-150~C, and preferably at 100-145C. Preferably an excess of the azide is used, especially 1.5 to 5 equivalents excess. The procedure is particularly suitable for obtaining compounds of the formula IV
wherein the tetrazolyl group bearing the trisubstituted tin moiety of formula Sn(0)3 is at a position ortho to the adjacent phenyl group.
Compounds of the formula V may be obtained, for example, by radical bromination of a nitrile of formula VII wherein R5 and Rb have any of the values defined hereinbefore to the corresponding bromomethyl derivative followed by alkylation of a quinolone of the formula VIII wherein R1, R2, R3, R' and Ra have any of the meanings defined hereinbefore. The bromination is carried out using procedures and reagents well known in the art, such as by reaction with N-bromosuccinimide in the presence of benzoyl peroxide or azo(bisisobutyronitrile) in a solvent such as chlorobenzene or carbon tetrachloride, and the alkylation is generally carried out in the presence of a base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydride such as sodium hydride and in a solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10-100C. Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous or non-aqueous solvent such as water and dichloromethane.
Compounds of the formula VII may be obtained, for example, by the procedure described in European Patent Application, Publication no. 0253310 A2. Alternatively, they may be obtained, for example, by reaction of a Grignard reagent, formed from an unsubstituted or substituted 4-bromotoluene in a solvent such as tetrahydrofuran, with a trialkyltin halide, such as tributyltin chloride, at a temperature of 0-25C, followed by reaction of the resulting (substituted)phenyltrialkyltin compound with a substituted or unsubstituted bromobenzonitrile in the presence of a palladium (0) catalyst, such as tetrakis(triphenylphosphine) palladium, and azo(bisisobutyronitrile). A further alternative to obtain compounds of the formula VII is by reaction of 4-methylphenylboronic acid with a suitably substituted bromobenzonitrile in the presence oE a palladium catalyst, such as palladium (II) chloride or tetrakis-(triphenylphosphine)palladium(0), and azo(bisisobutyronitrile). Yet another alternative to obtain formula VII compounds is by reaction of an unsubstituted or substituted 4-bromotoluene with an alkali metal ~V~7~ 9 _ 9 _ alkane, such as butyllithium, and zinc chloride followed by reaction with a suitably substituted bromobenzonitrile in the presence of tetrakis(triphenylphosphine)palladium.
Compounds of the formula VIII are known, for example as described in EPA 412848, or may be obtained using standard procedures of organic chemistry, such as those described in Org. Syn., Coll. Vol.
III, p.374 and p.593.
In a modified procedure for carrying out the process of the invention, and which is provided as a further feature of the invention, a compound of the formula IV as defined above is generated ln situ from a compound of the formula V as defined above by reaction with an azide of the formula VI as defined above. The trisubstituted tin moiety Sn~Q)3 present may then be removed without isolation of the compound of the formula IV, for example, by addition of aqueous mineral acid to the reaction mixture. A mixture of sodium nitrite and hydrochloric acid may be used to acidify the reaction mixture, thereby conveniently destroying any excess azide present.
The azides of formula VI are either commercially available or may be prepared by standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.
Whereafter, when a non-toxic salt of a compound of formula II is required, it may be obtained, for example, by reaction with the appropriate base affording a physiologically acceptable cation, or with the appropriate acid affording a physiologically acceptable anion, or by any other conventional salt formation procedure.
Further, when an optically active form of a compound of formula I is required, one of the aforesaid processes may be carried out using an optically active starting material. Alternatively, the racemic form of a compound of formula I may be resolved, for example by reaction with an optically active form of a suitable organic base, for example, ephedrine, N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or 1-phenylethylamine, followed by conventional separation i 2 i~ ~
of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (1-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid.
Certain of the intermediates defined herein are novel, for example the compounds of the formula IV and V and in particular those compounds of formula IV and V wherein the substituted tetrazolyl group and the cyano group respectively are in a position ortho to the adjacent phenyl group, and are provided as a further feature of the invention.
The antagonism of one or more of the physiological actions of AII and, in particular, the antagonism of the interaction of AII
with the receptors which mediate its effects on a target tissue, may be assessed using one or more of the following, routine laboratory procedures:
Test A: This ln vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled AII and a cell surface membrane fraction prepared from a suitable angiotensin target tissue. In this test, the source of cell surface membranes is the guinea pig adrenal gland which is well known to respond to AII. Interaction of the radiolabelled AII with its receptors (assessed as radiolabel bound to the particulate membrane fraction following removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) is antagonized by compounds which also bind to the membrane receptor sites and the degree of antagonism (observed in the test as displacement of membrane-bound radioactivity) is determined readily by comparing the receptor-bound radioactivity in the presence of the ~est compound at the specified test concentration with a control value determined in the absence of the test compound. Using this procedure compounds showing at least 50% displacement of radiolabelled AII binding at a t~ 3 concentration of 10 4 M are retested at lower concentrations to determine their potency. For determination of the IC50 (concentration for 50~ displacement of radiolabelled AII binding), concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC50, which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.
In general, compounds of formula III as defined above show significant inhibition in Test A at a concentration of 50 micromolar or much less.
Test B: This in vitro test involves the measurement of the antagonistic effects of the test compound against AII-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37C. In order to ensure that the effect of the compound is specific to antagonism of AII, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.
In general, compounds of formula III as defined above show significant inhibition in Test B at a final concentration of 50 micromolar or much less.
Test C: This in vivo test involves using terminally-anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure The AII
antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin II-induced pressor responses. To ensure that the effect is specific, the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.
The compounds of formula III generally show specific AII-antagonist properties in Test C at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
Test D: This in vivo test involves the stimulation of endogenous AII
biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.
In general compounds of formula III will show AII-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
- By way of illustration of the angiotensin II inhibitory properties of compounds of formula III, 2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride gave the following results in tests A, B and C described above:-In test A: an average IC50 of 1.7x10 8M;
In test B an average PA2 of 8.95;
In test C: ED50 of 0 5 mg/kg (i.v. administration).
The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:-(i) concentrations and evaporations were carried out by rotary evaporation in vacuo;
(ii) operations were carried out at room temperature, that is in the range 18-26C;
~iii) yields. where given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;
(iv) 1H NMR spectra were normally determined at 270 MHz in CDCl3 using tetramethylsilane (TMS) as an internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multplet; t, triplet; br, broad; d, doublet; and (v) the term "1_-tetrazol-5-yl" stands for "1-H-1,2,3,4-tetrazol-5-yl".
2~li2~
~xample 1 A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy~quinoline in toluene (15 ml), prepared in situ by refluxing for 90 hours a mixture of 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (0.9 g) and a solution of tributyltin azide in toluene (15 ml) [the latter prepared by reaction of tributyltin chloride (3.3 g) and sodium azide (1.13 g) in water (22.5 ml) at ambient temperature for 4 hours, followed by extraction with toluene and azeotropic removal of water from the extract to leave a volume of 15 ml], was added slowly over 1 hour to a solution of sodium nitrite (2.5 g) in water (10 ml) containing 12% w/v hydrochloric acid (10 ml), maintaining the temperature of the mixture below 5C. A solution of sulphamic acid (1.43g) in water (lOml) was then added, maintaining the temperature below 5C, and the mixture stirred for 1 hour. The resultant suspended semi-solid was collected by filtration and washed with water (3 x 10 ml), followed by toluene (10 ml). The semi-solid was then added to tetrahydrofuran (THF) (40 ml), which caused the product to dissolve and then crystallise as a white solid. After cooling for one hour the solid was collected by filtration, washed with THF (5 ml) and dried to give 2-ethyl-4-l(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]-quinoline hydrochloride in 53~ yield; m.p. 179-180C (dec.); NMR
(d6-DMSO): 1.46(t,3H), 3.18(q,2H), 5.68(s,2H), 7.22(d,2H), 7.5-7.8(m,7H), 7.83(t,1H), 8.08(t,1H), 8.18(d,1H), 8.32(d,1H).
xample 2 A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a similar method to that described in ~rg. Syn., Coll. Vol. III, p.374 and p.593 from aniline and ethyl propionylacetate), 4'-bromomethylbiphenyl-2-carbonitrile (A) (3.1 g) and solid potassium carbonate (1.81 g) in N-methylpyrrolidone (40 ml) were stirred for 36 hours under nitrogen. The mixture was then added dropwise to water (100 ml) at 15-25C and stirred for 30 minutes. The suspended solid was collected by filtration, washed with water, and dried at 60C
under vacuum. The solid was recrystallised from tert-butyl methyl ether to give 4'-[(2-ethylquinolin-4-yloxy3methyll-biphenyl-2-i 2`~ {3 carbonitrile as a solid (1.9 g), m.p. 151-153C; NMR(CDCl3): 1.4(t, 3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,1H), 7.4-7.6(m, 3H), 7.6-7.8(m, 6H), 8.0(d,1H), 8.25(d, lH).
The starting material A was obtained as follows:-(i) 2M Sodium carbonate solution (200 ml) was added to a stirredmixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5C. The temperature rose to approximately 20~C
and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110-120C) to give 4'-methylbiphenyl-2-carbonitrile in 80% yield, m.p. 44-46C; NMR
(d6-DMS0): 2.40 (s,3H), 7.30(d,2H), 7.35-7.55(m,4H), 7.60-7.65(m,lH), 7.75(d,lH).
(ii) A mixture of 4'-methylbiphenyl-2-carbonitrile (3.86 g), N-bromosuccinimide (3.92 g) and azo(bisisobutyronitrile) (0.15 g) in chlorobenzene (75 ml) was heated at 70C for 3 hours. Further N-bromosuccinimide (0.3 g) and azo(bisisobutyronitrile) (0.05 g) was added and the mixture was heated for another 15 minutes. Heating was stopped and the mixture stirred for 16 hours at ambient temperature.
Water (50 ml) was added and the mixture stirred for 30 minutes and filtered. The organic phase was separated, washed with water (50 ml) and dried (MgS04). The solvent was removed by evaporation and the resultant solid recrystallised from cyclohexane to give 4'-bromomethylbiphenyl-2-carbonitrile ~3.9 g) (A) as a solid; NMR
(CDCl3): 4.55(s,2H), 7.4-7.85(m, 8H).
, ~ ~ L;'~ 1 2 ~ ~
Che~; ~\_ tOr ~ R
R't ~ A--X
R
R R~
R R~ ~
1~3 q~ R2 L
--A X ~ 1 ~2 "~
R
~ ~s - l6 ~ l3 ~ 'i f). '1 ~
C~lCG~
Rb RS
R Ro~ , o ~,~C~ _ Rl ~Q~3 . S,~ . ~3 C~ V
Q~ 1~
R , 1~ r~-~ O
Q
Claims (10)
1. A process for the manufacture of a compound of the formula III
III
wherein R1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl substituent; R2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl; R3 and R4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (1-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (1-4C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, and substituted (1-4C)alkyl, the latter bearing an amino, hydroxy or (1-4C)alkoxy substituent; or R3 and R4 together form (1-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R5 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro; Rb is hydrogen or a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; which comprises removal of a trisubstituted tin moiety of the formula Sn(Q)3 from a compound of the formula IV
IV
wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings as defined hereinbefore and Q is a (1-6C)alkyl or phenyl group, the latter optionally substituted by an (1-4C)alkyl, (1-4C)alkoxy or halogeno group.
III
wherein R1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl substituent; R2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl; R3 and R4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (1-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (1-4C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, and substituted (1-4C)alkyl, the latter bearing an amino, hydroxy or (1-4C)alkoxy substituent; or R3 and R4 together form (1-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R5 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro; Rb is hydrogen or a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; which comprises removal of a trisubstituted tin moiety of the formula Sn(Q)3 from a compound of the formula IV
IV
wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings as defined hereinbefore and Q is a (1-6C)alkyl or phenyl group, the latter optionally substituted by an (1-4C)alkyl, (1-4C)alkoxy or halogeno group.
2. A process as claimed in claim 1 wherein, in the starting material of formula IV, R1 is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl, or 2-phenylethyl; R2 is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, cyano, nitro, phenyl, benzyl, 1-phenylethyl or 2-phenylethyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, fluoro, chloro, bromo, iodo, hydroxy, trifluoromethyl, cyano, nitro, amino, formamido, acetamido, propanamido, methylamino, ethylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dimethylaminomethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl,
3-(diethylamino)propyl, formyl, acetyl, butyryl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylthio, ethylthio, butylthio,methylsulphinyl, ethylsulphinyl, butylsulphinyl, methylsulphonyl, ethylsulphonyl, butylsulphonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; or R3 and R4 together form methylenedioxy or ethylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R5 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano and nitro; Rb is hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano and nitro; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, cyano and trifluoromethyl.
3. A process as claimed in claim 1 or 2 wherein, in the starting material of formula IV, R1 is methyl and R4 is hydrogen or is ethyl and R4 is hydrogen, 7-hydroxymethyl, 6-(2-fluoroethoxy), 6-(2,2,2-trifluoroethoxy) or 6-isopropoxy; R2, R3, R5, Ra and Rb are each hydrogen; and the tetrazolyl group bearing the Sn(Q)3 moiety is in a position ortho to the adjacent phenyl group.
3. A process as claimed in claim 1 or 2 wherein, in the starting material of formula IV, R1 is methyl and R4 is hydrogen or is ethyl and R4 is hydrogen, 7-hydroxymethyl, 6-(2-fluoroethoxy), 6-(2,2,2-trifluoroethoxy) or 6-isopropoxy; R2, R3, R5, Ra and Rb are each hydrogen; and the tetrazolyl group bearing the Sn(Q)3 moiety is in a position ortho to the adjacent phenyl group.
4. A process as claimed in claim 3 wherein, in the starting material of formula IV, R1 is ethyl and R4 is hydrogen.
5. A process as claimed in any preceding claim wherein removal of the trisubstituted tin moiety of the formula Sn(Q)3 is carried out by acid hydrolysis.
6. A process as claimed in any preceding claim wherein, in the starting material of formula IV, Q is (1-4C)alkyl.
7. A process as claimed in any preceding claim wherein the starting material of formula IV is generated in situ from a compound of the formula V
V
wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings defined in any one of claims 1 to 4.
V
wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings defined in any one of claims 1 to 4.
8. A compound of the formula III as defined in claim 1 whenever prepared by any one of the processes of claims 1 to 7 or an obvious chemical equivalent thereof.
9. A compound of the formula IV wherein R1, R2, R3, R4, R5, Ra Rb and Q have any of the meanings defined in any one of claims 1 to 4 or claim 6.
10. A compound of the formula V wherein R1, R2, R3, R4, R5, Ra and Rb have any of the meanings defined in any one of claims 1 to 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909017479A GB9017479D0 (en) | 1990-08-09 | 1990-08-09 | Process |
| GB9017479.8 | 1990-08-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2047249A1 true CA2047249A1 (en) | 1992-02-10 |
Family
ID=10680406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002047249A Abandoned CA2047249A1 (en) | 1990-08-09 | 1991-07-17 | Process |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0495948A1 (en) |
| JP (1) | JPH05501728A (en) |
| KR (1) | KR920702357A (en) |
| CN (1) | CN1058965A (en) |
| AU (1) | AU8309091A (en) |
| CA (1) | CA2047249A1 (en) |
| CS (1) | CS88692A3 (en) |
| FI (1) | FI921319A7 (en) |
| GB (2) | GB9017479D0 (en) |
| HU (1) | HUT60490A (en) |
| IE (1) | IE912406A1 (en) |
| IL (1) | IL98833A0 (en) |
| PT (1) | PT98607A (en) |
| WO (1) | WO1992002508A1 (en) |
| ZA (1) | ZA915567B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5246944A (en) * | 1991-08-13 | 1993-09-21 | Merck & Co., Inc. | Quinoline angiotensin ii antagonists incorporating a substituted benzyl element |
| US5484955A (en) * | 1992-07-06 | 1996-01-16 | Takeda Chemical Industries, Ltd. | Tri-higher alkyl tin azide and its use |
| US6608048B2 (en) | 2000-03-28 | 2003-08-19 | Wyeth Holdings | Tricyclic protein kinase inhibitors |
| CA2688161C (en) | 2007-06-04 | 2020-10-20 | Kunwar Shailubhai | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| EP2810951B1 (en) | 2008-06-04 | 2017-03-15 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| ES2624828T3 (en) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| JP2016514670A (en) | 2013-03-15 | 2016-05-23 | シナジー ファーマシューティカルズ インコーポレイテッド | Guanylate cyclase receptor agonists in combination with other drugs |
| US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
| SI3004138T1 (en) | 2013-06-05 | 2024-07-31 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| SG11201601218PA (en) | 2013-09-16 | 2016-04-28 | Astrazeneca Ab | Therapeutic polymeric nanoparticles and methods of making and using same |
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| US4820843A (en) * | 1987-05-22 | 1989-04-11 | E. I. Du Pont De Nemours And Company | Tetrazole intermediates to antihypertensive compounds |
| US4920132A (en) * | 1987-11-03 | 1990-04-24 | Rorer Pharmaceutical Corp. | Quinoline derivatives and use thereof as antagonists of leukotriene D4 |
| IE902909A1 (en) * | 1989-08-11 | 1991-02-27 | Ici Plc | Nitrogen compounds |
-
1990
- 1990-08-09 GB GB909017479A patent/GB9017479D0/en active Pending
-
1991
- 1991-07-09 IE IE240691A patent/IE912406A1/en unknown
- 1991-07-15 IL IL98833A patent/IL98833A0/en unknown
- 1991-07-16 ZA ZA915567A patent/ZA915567B/en unknown
- 1991-07-16 GB GB919115250A patent/GB9115250D0/en active Pending
- 1991-07-17 CA CA002047249A patent/CA2047249A1/en not_active Abandoned
- 1991-07-24 CN CN91105053A patent/CN1058965A/en active Pending
- 1991-07-30 JP JP3513216A patent/JPH05501728A/en active Pending
- 1991-07-30 KR KR1019920700813A patent/KR920702357A/en not_active Withdrawn
- 1991-07-30 EP EP91914106A patent/EP0495948A1/en not_active Withdrawn
- 1991-07-30 HU HU92933A patent/HUT60490A/en unknown
- 1991-07-30 AU AU83090/91A patent/AU8309091A/en not_active Abandoned
- 1991-07-30 WO PCT/GB1991/001287 patent/WO1992002508A1/en not_active Application Discontinuation
- 1991-07-30 FI FI921319A patent/FI921319A7/en not_active Application Discontinuation
- 1991-08-08 PT PT98607A patent/PT98607A/en not_active Application Discontinuation
-
1992
- 1992-03-24 CS CS92886A patent/CS88692A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL98833A0 (en) | 1992-07-15 |
| FI921319L (en) | 1992-03-26 |
| ZA915567B (en) | 1992-07-29 |
| JPH05501728A (en) | 1993-04-02 |
| PT98607A (en) | 1992-06-30 |
| WO1992002508A1 (en) | 1992-02-20 |
| GB9115250D0 (en) | 1991-08-28 |
| GB9017479D0 (en) | 1990-09-26 |
| CN1058965A (en) | 1992-02-26 |
| FI921319A0 (en) | 1992-03-26 |
| HUT60490A (en) | 1992-09-28 |
| EP0495948A1 (en) | 1992-07-29 |
| AU8309091A (en) | 1992-03-02 |
| IE912406A1 (en) | 1992-02-12 |
| KR920702357A (en) | 1992-09-03 |
| FI921319A7 (en) | 1992-03-26 |
| CS88692A3 (en) | 1992-10-14 |
| HU9200933D0 (en) | 1992-05-28 |
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