CA2060825A1 - Therapeutic agent - Google Patents
Therapeutic agentInfo
- Publication number
- CA2060825A1 CA2060825A1 CA002060825A CA2060825A CA2060825A1 CA 2060825 A1 CA2060825 A1 CA 2060825A1 CA 002060825 A CA002060825 A CA 002060825A CA 2060825 A CA2060825 A CA 2060825A CA 2060825 A1 CA2060825 A1 CA 2060825A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- ethyl
- biphenyl
- tetrazol
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
ABSTRACT
THERAPEUTIC AGENT
The invention concerns a novel pharmaceutical agent which comprises a new crystalline form of a substituted quinoline derivative (defined herein) which is a potent antagonist of angiotensin AII and of use in treating conditions such as hypertension, congestive heart disease or hyperaldosteronism. A process for the production of the novel crystalline form and pharmaceutical compositions containing it are also included.
THERAPEUTIC AGENT
The invention concerns a novel pharmaceutical agent which comprises a new crystalline form of a substituted quinoline derivative (defined herein) which is a potent antagonist of angiotensin AII and of use in treating conditions such as hypertension, congestive heart disease or hyperaldosteronism. A process for the production of the novel crystalline form and pharmaceutical compositions containing it are also included.
Description
P~IARHACE:UTICAL AGI~NT
Technical Field The present invention relates to a new pharmaceutical agent and, more particularly, to a new physical form of a substituted quinoline derivative with valuable pharmacological properties in antagonising wholly or in part one or more of the actions of the substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "AII" ) . The invention also concerns pharmaceutical compositions containing the new physical form and for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role. The invention also concerns a process for the manufacture of the new physical form and the use of the form in treating one of the afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.
Background to the Invention 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. Hitherto there have been a number of different approaches to pharmacological intervention in the renin-angiotensin-aldosterone system for therapeutic control of blood pressure and/or fluid/electrolyte balance, including, for example, inhibiting the actions of renin or ACE. However, there remains a continuing need for an alternative - 2 - ~ r~ '?5 approach because of the side-effects and/or idiosyncratic reactions associated with any particular therapeutic approach.
It is known in the chemical art that a compound may often exist in the solid state in one or more different and discrete physical forms which have different physical properties including melting point and solubility. This phenomenon is known as polymorphism. Some of these physical forms may be intrinsically more stable than others, for example, as a result of the different energies associated with the crystal lattices involved. It is desirable in the production of pharmaceutical formulations for medical use that the active ingredients are in a physical form which is both physically stable and can be prep~red to reproduclble quality standards substantially free of impurities and other physical forms. This latter requirement is especially important because different physical forms can have markedly different bioavailabilities.
Our European patent application, Publication Number 412,848 describes a series of quinoline derivatives which antagonise the pharmacological actions of the physiological agent known as angiotensin II. One such quinoline derivative which is especially preferred for its angiotensin II antagonist properties is 2-ethyl-4-l(2'-(lD-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]-quinoline hydrochloride (shown as chemical structure A hereinafter and referred to hereinafter as "compound A"). We have now discovered, and this a basis for our invention, that compound A may be isolated in a number of different forms, one of which, now referred to as the gamma form, is particularly useful for pharmaceutical use, for example, by virtue of its stability.
Disclosure of the Invention According to the invention there is provided the gamma crystalline form of the compound A, essentially anhydrous and substantally free of other physical forms and which form is characterised by having a melting point which is in the range about 185-192 degrees Celsius (C) and an X-ray powder diffraction pattern includiDg specific peaks at about 2~ = 8.6, 11.9, 12.4, 14.3, 15.5, 19.0, 19.3, 19.9, 20.3, 22.8, 23.1, 24.3, 25.7, 27.5, 28.7 and 29.4.
It is to be understood that references in this specification - 3 ~ r~3~
to the gamma crystalline form of the compound A, essentially anhydrous and substantially free of other physical forms (hereinafter referred to as the gamma form of compound A), refer to material containing less than 0.5% by weight of water and in which material at least 95~ by weight of the compound A is present in that single physical form.
X-ray powder diffraction spectra may be determined in conventional manner, for example, using a Philips PW1130 X-ray generator with a broad focus copper tube and approximately 0.5 g of sample material mounted in a standard Philips pack holder over the scanning range of 4-40 2~ counting for 4 seconds per point at 0.02 intervals to produce a trace of spacings against intensity for this range. An X-ray diffraction spectrum of a typical sample of the gamma crystalline form of the compound A is shown in Figure 1 attached hereinafter. It will be understood that the 2~ values obtained in practice may vary slightly from one machine to another and so the values quoted hereinabove are not to be construed as absolute.
The melting characteristics of samples of the compound A
vary with their purity, degree of hydration and physical form and may be determined by conventional procedures well known in the art, for example, by differential scanning calorimetry. The melting point characteristics of a typical sample of the gamma form of compound A
are given for illustration in Example 3 hereinafter.
The compound A may be obtained by procedures well known in the chemical art for the production of chemically analogous compounds such as the procedures described in our aforementioned European patent application. Typical procedures are described in the accompanying Examples. Such known procedures tend to give material of different crystalline form and degree of hydration or solvation than the gamma form of compound A of the present invention. This can be inferred from the different physical properties of the forms. Thus, for example the melting characteristics, X-ray powder spectra and Fourier transform infra-red spectra are different to those of the gamma form of compound A of the invention. Many of the procedures for the production of compound A may give rise to one particular form (now referred to as the alpha form) which is inherently less thermodynamically stable than the gamma form of the invention. Thus, for example, a sample of compound A produced by the general procedure - 4 - ~ 5 described in Example 25 of the aforesaid European patent application is obtained as predominantly the alpha form having a melting point (with decomposition) of about 178-181C and with an X-ray powder diffraction pattern including strong specific peaks at about 2~ =
7.21, 10.17 and 11.40~. A typical X-ray powder diffraction pattern of the alpha form of the compound A is shown in Figure 2 hereinafter.
This can be contrasted with the different X-ray diffraction pattern for a typical sample of the gamma form of compound A of the present invention which is shown in Figure 1 hereinafter. The gamma form is intrinsically more stable and has a more compact crystal form than the alpha form of compound A and is consequently generally preferred for pharmaceutical purposes.
According to a further feature of the invention there is provided a process for the preparation of the gamma form of compound A
as defined above, which comprises heating at elevated temperature a source of compound A in one or more suitable polar organic solvents, optionally reducing the volume of the resultant solution by partial evaporation, optionally followed by adding a non-hydroxylic organic solvent or diluent and then cooling the mixture obtained to about O to 20 degrees Celsius (C).
The source of compound A may typically contain predominantly the form now known as the alpha form of compound A, for example as may be obtained by one of the procedures described hereinafter.
Suitable polar organic solvents include, for example, hydroxylic solvents, such as methanol, ethanol, propanol and 2-methoxyethanol, or a mixture thereof, especially a mixture of ethanol containing up to about 10% by volume of methanol.
Suitable non-hydroxylic solvents for use as specified in the above process include7 for example, ethyl acetate and butyl acetate.
The process preferably requires the heating to be carried out at elevated temperature, for example from about 40 to 130'7C, conveniently at or about the boiling point of the solvent or solvent mixture. It will be understood that it is necessary to carry out the process for sufficient time to permit complete conversion to the gamma from to occur. In general this will require several hours, preferably at least 1 to 12 hours, of heating.
One preferred process comprises dissolving the source of - 5 - ~ q~ 5 compound A by heating in a hydroxylic solvent (especially ethanol) at or near the boiling point of said solvent, adding another more polar and lower boiling hydroxylic solvent (especially methanol) and then removing the lower boiling point solvent by fractional distillation prior to addition of a suitable non-hydroxylic solvent (especially ethyl acetate).
Another preferred process comprises heating a source of compound A in a mixture of ethanol containing up to 10~ by volume of methanol (conveniently that mixture known in the UK as industrial methylated spirits) at or near the boiling point of said mixture for at least 2 hours, followed by cooling to about 0 to 20C.
It will be recognised that the process may be carried without complete solution of the source of compound A, that is with the material as a slurry in the polar organic solvent.
The procedure of the invention may optionally be preceded by a preliminary purification step. This step involves the conversion of the compound A into its free base form and subsequently into its sodium salt form which latter is purified by extraction into a suitable organic solvent mixture and then reconverted into the hydrochloride salt to give compound A.
By virtue of its specific physical characteristics, the gamma form of compound A is particularly suitable for incorporation into pharmaceutical compositions and especially into conventional solid state pharmaceutical compositions suitable for oral administration, such as tablets, capsules and powders, which compositions may be formulated in a conventional manner.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises the gamma form of compound A as defined hereinbefore together with a pharmaceutically acceptable diluent or carrier.
As stated above, the compound A will have beneficial pharmacolcgical effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of the vasoconstrictor and fluid retaining properties of the renin-angiotensin-aldosterone system is desirable, at least in part by antagonism of one or more of the physiological actions of AII. The compound A will thus be useful in the treatment of diseases or medical - 6 - 2~ 5 conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
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 in 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 test 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 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, the compound A shows 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 _ 7 _ 2~ ~.~ 5 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, the compound A shows 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 compound A shows 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.
The compound A shows 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.
The compound A will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight tand preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and .he route and form of administration depending on size, age and sex of the person being treated and on the - 8 - X ~ ~.S
particular disease or medical condition being treated according to principles well known in the medical arts.
In addition to their aforesaid use in therapeutic mediclne in humans, the compounds A is also useful in the veterinary treatment of similar conditions affecting commercially valuable warm-blooded animals, such as dogs, cats, horses and cattie. In general for such treatment, the compound A will generally be administered in an analogous amount and manner to those described above for administration to humans.
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 guidance and are not necessarily the maximum attainable by diligent process development;
(iv) lH NMR spectra were normally determined at 200 MHz in C~Cl3 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, multiplet; t, triplet; br, broad;
d,doublet; and (v) products had satisfactory microanalyses.
CHEHICAL STRUCTURE OF COMPOUND A
N ~'~
~=
_ 9 ~ C ~ ~5 Example 1 lThis Example descibes an existing procedure for the preparation of a source of compound A-l A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline in toluene (15 ml), prepared ln 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) Ithe 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 mll, was added slowly over 1 hour to a solution of sodium nitrite (2.5 g) in water (10 ml) containing lZ% 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 THP (5 ml) and dried to give: 2-ethyl-4-l(2~ 1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline hydrochloride; 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.P,3(t,1H), 8.08(t,1H), 8.18(d,1H), 8.32(d,1H).
The starting 4'-[(2-ethylquinolin-4-yloxy)methyl~biphenyl-2-carbonitrile was obtained as follows:
A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a similar method to that described in Org. Syn., Coll. Vol. III, p.374 and p.593 from aniline and methyl propionylacetate), 4'-bromomethylbiphenyl-2-carbonitrile (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 15-25"C 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 -10- 2r~ 5 ether to give 4'-[(2-ethylquinolin-4-yloxy)methyll-biphenyl-2-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,lH), 8.25(d, lH).
The starting 4'-bromomethylbiphenyl-2-carbonitrile was itself obtained as follows:-(i) 2M Sodium carbonate solution (200 ml) was added to a stirred mixture 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 20C
and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture uas 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 which was used without further purification.
(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.~ g) (A) as a solid; NMR
(CDCl3): 4.55(s,2H), 7.4-7.85(m, 8H).
Example Z
[This Example describes the purification of material obtained by an an~logo~s procedure to that described in Example 1.]
2-Ethyl-4-[(2'-(lH-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-~v~ ~5 methoxy]quinoline hydrochloride (50.0 g~, obtained for example asdescribed in Example 1, was slurried in a mixture of methyl t-butyl ether (125 ml), butanol (175 ml) and 10~ w/v aqueous sodium chloride solution (150 ml) at 10-12C. A mixture of 10~ w/v aqueous sodium chloride solution (50 ml), water (25ml) and 48% w/w aqueous sodium hydroxide solution (20 g) was prepared and added to the slurry, maintaining the temperature at 10-12C. After mixing, the layers were separated and the organic phase was added to a mixture of methyl t-butyl ether (200 ml), butanol (30 ml) and concentrated hydrochloric acid (23.5 g) at 10C. The reaction mixture was stirred at 10C for one hour and the purifed 2-ethyl-4-1~2'-(lH-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxylquinoline hydrochloride isolated by filtration.
The solid was washed with methyl t-butyl ether (2 x 100 ml), then slurried in water (500 ml), collected by filtration and washed with water (150 ml). It was dried in vacuo at 30 for 16 hours to give partially hydrated material (46.0g), m.p. 147-50C.
~xample 3 IThis Example describes a typical preparation of the ga~a form of compound Al A sample (5.0 g) of 2-ethyl-4-[(2'-(lH-1,2,3,4-tetrazol--5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride (obtained from Example 2) was heated to reflux in absolute ethanol (50 ml) and methanol (40 ml) was added at reflux to achieve solution (about 1 hour). The reaction solution was distilled (about 30 minutes) to remove 50 ml of distillate and then cooled to ambient temperature.
After stirring for 16 hours, ethyl acetate (50ml) was added and the mixture stirred at 0-5C for 1 hour. The solid material was collected by filtration and washed with ethyl acetate (Sml) and dried ln vacuo at 25C for 64 hours to give the gamma crystalline form of 2-ethyl-4-[(2'-(lEI-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxyl-quinoline hydrochloride, as a compact crystalline solid (4.42g), in essentially anhydrous state, with m.p. 189-191C and X-ray diffraction as shown in Figure 1 attached hereto. Using differential scanning calorimetry, this material showed an initial change at 188.8C and a final change at 192.5C.
This procedure may also be modified by heating a slurry of ;~t s~ 5 2-ethyl-4-[(2'-(lH-1,2,3,4-tetrazol--5-yl)biphenyl-4-yl)methoxy]-quinoline hydrochloride in a mixture of industrial methylated spirit (about 5% methanol, 95% ethanol) under reflux for at least two hours, cooling the slurry to ambient temperature, separating the solid by filtration, to give the gamma crystalline form of compound A in essentially anhydrous state and with essentially the same physical properties as those given above.
Example 4 [This Xxample describes a procedure for the preparation of a source of compound A which is predominantly the alpha form.l A mixture of 2-ethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (930 mg) and a mixture of ethanol (lOml), methanol (5ml) and concentrated hydrochloric acid (2 ml) was allowed to stand for 2 hours. Volatile material was removed by evaporation. The residue was mixed with ethanol (20ml) and volatile material removed by evaporation. This porocedure was repeated twice. The resultant residue was triturated with ether (2 x 30 ml). The ether was decanted off. The solid residue was dissolved in a mixture of ethyl acetate (40ml) and ethanol (60ml).
The volume of solution was then quickly reduced by about 50% by partial evaporaticn and then cooled to ambient temperature to give predominantly the alpha form of 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxylquinoline hydrochloride (160 mg), as a light crystalline solid, m.p. 179-182C (decomposition). Further crystalline material (240 mg) of m.p. 177-179C (decomposition) was obtained by concentrating the mother liquor in vacuo (to about 10 ml in volume) and then cooling it to about 0-5C. Both samples of crystalline solid were subsequently shown to be the alpha form by X-ray diffraction spectroscopy. [A typical X-ray diffraction pattern for a sample of the alpha form obtained by this procedure is shown in Figure 2 hereinafter.]
The starting 2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline may be obtained as a solid, m.p.
173-174DC (decomposition); N~R: 1.4(t,3H), 2.96(q,2H), 5.16(s,2H), 6.73(s,1H), 6.9-6.94(m,6H), 7.18-7.32(m,13H), 7.33-7.55(m,4H), 13 ~ ;~ ~ S
7.67(dt,1H), 7.99(m,2H), 8.11(d,1H); microanalysis, found: C,81.1;
H,5-4; N,10-9%; C44H35N50 requires C,81-4; ~,5.4; N~10-8%~ by alkylating at ambient temperature a solution of the sodium salt of 2-ethyl-4-quinolone (prepared by the method described in Org. Syn., 1955, Coll. Vol. III, p.374 and p.593) in _,_-dimethylformamide (DMF) with a solution in DMF of 5-12-(4'-bromomethylbiphenylyl)l-2-triphenylmethyl-2H-tetrazole (obtained as described in European Patent 0291969).
Example 5 [This Example describes a conventional tablet formulation of the gamma form of compound A (as defined hereinbefore) suitable for medical or veterinary administration to warm-blooded animals including humans.
Material mg/tablet Gamma form of Compound A 5 Croscarmellose sodium 2 Microcrystalline cellulose 16 Lactose 76 Hagnesium stearate 19-Jan-1992
Technical Field The present invention relates to a new pharmaceutical agent and, more particularly, to a new physical form of a substituted quinoline derivative with valuable pharmacological properties in antagonising wholly or in part one or more of the actions of the substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "AII" ) . The invention also concerns pharmaceutical compositions containing the new physical form and for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role. The invention also concerns a process for the manufacture of the new physical form and the use of the form in treating one of the afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.
Background to the Invention 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. Hitherto there have been a number of different approaches to pharmacological intervention in the renin-angiotensin-aldosterone system for therapeutic control of blood pressure and/or fluid/electrolyte balance, including, for example, inhibiting the actions of renin or ACE. However, there remains a continuing need for an alternative - 2 - ~ r~ '?5 approach because of the side-effects and/or idiosyncratic reactions associated with any particular therapeutic approach.
It is known in the chemical art that a compound may often exist in the solid state in one or more different and discrete physical forms which have different physical properties including melting point and solubility. This phenomenon is known as polymorphism. Some of these physical forms may be intrinsically more stable than others, for example, as a result of the different energies associated with the crystal lattices involved. It is desirable in the production of pharmaceutical formulations for medical use that the active ingredients are in a physical form which is both physically stable and can be prep~red to reproduclble quality standards substantially free of impurities and other physical forms. This latter requirement is especially important because different physical forms can have markedly different bioavailabilities.
Our European patent application, Publication Number 412,848 describes a series of quinoline derivatives which antagonise the pharmacological actions of the physiological agent known as angiotensin II. One such quinoline derivative which is especially preferred for its angiotensin II antagonist properties is 2-ethyl-4-l(2'-(lD-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]-quinoline hydrochloride (shown as chemical structure A hereinafter and referred to hereinafter as "compound A"). We have now discovered, and this a basis for our invention, that compound A may be isolated in a number of different forms, one of which, now referred to as the gamma form, is particularly useful for pharmaceutical use, for example, by virtue of its stability.
Disclosure of the Invention According to the invention there is provided the gamma crystalline form of the compound A, essentially anhydrous and substantally free of other physical forms and which form is characterised by having a melting point which is in the range about 185-192 degrees Celsius (C) and an X-ray powder diffraction pattern includiDg specific peaks at about 2~ = 8.6, 11.9, 12.4, 14.3, 15.5, 19.0, 19.3, 19.9, 20.3, 22.8, 23.1, 24.3, 25.7, 27.5, 28.7 and 29.4.
It is to be understood that references in this specification - 3 ~ r~3~
to the gamma crystalline form of the compound A, essentially anhydrous and substantially free of other physical forms (hereinafter referred to as the gamma form of compound A), refer to material containing less than 0.5% by weight of water and in which material at least 95~ by weight of the compound A is present in that single physical form.
X-ray powder diffraction spectra may be determined in conventional manner, for example, using a Philips PW1130 X-ray generator with a broad focus copper tube and approximately 0.5 g of sample material mounted in a standard Philips pack holder over the scanning range of 4-40 2~ counting for 4 seconds per point at 0.02 intervals to produce a trace of spacings against intensity for this range. An X-ray diffraction spectrum of a typical sample of the gamma crystalline form of the compound A is shown in Figure 1 attached hereinafter. It will be understood that the 2~ values obtained in practice may vary slightly from one machine to another and so the values quoted hereinabove are not to be construed as absolute.
The melting characteristics of samples of the compound A
vary with their purity, degree of hydration and physical form and may be determined by conventional procedures well known in the art, for example, by differential scanning calorimetry. The melting point characteristics of a typical sample of the gamma form of compound A
are given for illustration in Example 3 hereinafter.
The compound A may be obtained by procedures well known in the chemical art for the production of chemically analogous compounds such as the procedures described in our aforementioned European patent application. Typical procedures are described in the accompanying Examples. Such known procedures tend to give material of different crystalline form and degree of hydration or solvation than the gamma form of compound A of the present invention. This can be inferred from the different physical properties of the forms. Thus, for example the melting characteristics, X-ray powder spectra and Fourier transform infra-red spectra are different to those of the gamma form of compound A of the invention. Many of the procedures for the production of compound A may give rise to one particular form (now referred to as the alpha form) which is inherently less thermodynamically stable than the gamma form of the invention. Thus, for example, a sample of compound A produced by the general procedure - 4 - ~ 5 described in Example 25 of the aforesaid European patent application is obtained as predominantly the alpha form having a melting point (with decomposition) of about 178-181C and with an X-ray powder diffraction pattern including strong specific peaks at about 2~ =
7.21, 10.17 and 11.40~. A typical X-ray powder diffraction pattern of the alpha form of the compound A is shown in Figure 2 hereinafter.
This can be contrasted with the different X-ray diffraction pattern for a typical sample of the gamma form of compound A of the present invention which is shown in Figure 1 hereinafter. The gamma form is intrinsically more stable and has a more compact crystal form than the alpha form of compound A and is consequently generally preferred for pharmaceutical purposes.
According to a further feature of the invention there is provided a process for the preparation of the gamma form of compound A
as defined above, which comprises heating at elevated temperature a source of compound A in one or more suitable polar organic solvents, optionally reducing the volume of the resultant solution by partial evaporation, optionally followed by adding a non-hydroxylic organic solvent or diluent and then cooling the mixture obtained to about O to 20 degrees Celsius (C).
The source of compound A may typically contain predominantly the form now known as the alpha form of compound A, for example as may be obtained by one of the procedures described hereinafter.
Suitable polar organic solvents include, for example, hydroxylic solvents, such as methanol, ethanol, propanol and 2-methoxyethanol, or a mixture thereof, especially a mixture of ethanol containing up to about 10% by volume of methanol.
Suitable non-hydroxylic solvents for use as specified in the above process include7 for example, ethyl acetate and butyl acetate.
The process preferably requires the heating to be carried out at elevated temperature, for example from about 40 to 130'7C, conveniently at or about the boiling point of the solvent or solvent mixture. It will be understood that it is necessary to carry out the process for sufficient time to permit complete conversion to the gamma from to occur. In general this will require several hours, preferably at least 1 to 12 hours, of heating.
One preferred process comprises dissolving the source of - 5 - ~ q~ 5 compound A by heating in a hydroxylic solvent (especially ethanol) at or near the boiling point of said solvent, adding another more polar and lower boiling hydroxylic solvent (especially methanol) and then removing the lower boiling point solvent by fractional distillation prior to addition of a suitable non-hydroxylic solvent (especially ethyl acetate).
Another preferred process comprises heating a source of compound A in a mixture of ethanol containing up to 10~ by volume of methanol (conveniently that mixture known in the UK as industrial methylated spirits) at or near the boiling point of said mixture for at least 2 hours, followed by cooling to about 0 to 20C.
It will be recognised that the process may be carried without complete solution of the source of compound A, that is with the material as a slurry in the polar organic solvent.
The procedure of the invention may optionally be preceded by a preliminary purification step. This step involves the conversion of the compound A into its free base form and subsequently into its sodium salt form which latter is purified by extraction into a suitable organic solvent mixture and then reconverted into the hydrochloride salt to give compound A.
By virtue of its specific physical characteristics, the gamma form of compound A is particularly suitable for incorporation into pharmaceutical compositions and especially into conventional solid state pharmaceutical compositions suitable for oral administration, such as tablets, capsules and powders, which compositions may be formulated in a conventional manner.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises the gamma form of compound A as defined hereinbefore together with a pharmaceutically acceptable diluent or carrier.
As stated above, the compound A will have beneficial pharmacolcgical effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of the vasoconstrictor and fluid retaining properties of the renin-angiotensin-aldosterone system is desirable, at least in part by antagonism of one or more of the physiological actions of AII. The compound A will thus be useful in the treatment of diseases or medical - 6 - 2~ 5 conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
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 in 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 test 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 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, the compound A shows 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 _ 7 _ 2~ ~.~ 5 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, the compound A shows 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 compound A shows 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.
The compound A shows 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.
The compound A will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight tand preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and .he route and form of administration depending on size, age and sex of the person being treated and on the - 8 - X ~ ~.S
particular disease or medical condition being treated according to principles well known in the medical arts.
In addition to their aforesaid use in therapeutic mediclne in humans, the compounds A is also useful in the veterinary treatment of similar conditions affecting commercially valuable warm-blooded animals, such as dogs, cats, horses and cattie. In general for such treatment, the compound A will generally be administered in an analogous amount and manner to those described above for administration to humans.
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 guidance and are not necessarily the maximum attainable by diligent process development;
(iv) lH NMR spectra were normally determined at 200 MHz in C~Cl3 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, multiplet; t, triplet; br, broad;
d,doublet; and (v) products had satisfactory microanalyses.
CHEHICAL STRUCTURE OF COMPOUND A
N ~'~
~=
_ 9 ~ C ~ ~5 Example 1 lThis Example descibes an existing procedure for the preparation of a source of compound A-l A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline in toluene (15 ml), prepared ln 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) Ithe 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 mll, was added slowly over 1 hour to a solution of sodium nitrite (2.5 g) in water (10 ml) containing lZ% 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 THP (5 ml) and dried to give: 2-ethyl-4-l(2~ 1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline hydrochloride; 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.P,3(t,1H), 8.08(t,1H), 8.18(d,1H), 8.32(d,1H).
The starting 4'-[(2-ethylquinolin-4-yloxy)methyl~biphenyl-2-carbonitrile was obtained as follows:
A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a similar method to that described in Org. Syn., Coll. Vol. III, p.374 and p.593 from aniline and methyl propionylacetate), 4'-bromomethylbiphenyl-2-carbonitrile (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 15-25"C 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 -10- 2r~ 5 ether to give 4'-[(2-ethylquinolin-4-yloxy)methyll-biphenyl-2-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,lH), 8.25(d, lH).
The starting 4'-bromomethylbiphenyl-2-carbonitrile was itself obtained as follows:-(i) 2M Sodium carbonate solution (200 ml) was added to a stirred mixture 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 20C
and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture uas 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 which was used without further purification.
(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.~ g) (A) as a solid; NMR
(CDCl3): 4.55(s,2H), 7.4-7.85(m, 8H).
Example Z
[This Example describes the purification of material obtained by an an~logo~s procedure to that described in Example 1.]
2-Ethyl-4-[(2'-(lH-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-~v~ ~5 methoxy]quinoline hydrochloride (50.0 g~, obtained for example asdescribed in Example 1, was slurried in a mixture of methyl t-butyl ether (125 ml), butanol (175 ml) and 10~ w/v aqueous sodium chloride solution (150 ml) at 10-12C. A mixture of 10~ w/v aqueous sodium chloride solution (50 ml), water (25ml) and 48% w/w aqueous sodium hydroxide solution (20 g) was prepared and added to the slurry, maintaining the temperature at 10-12C. After mixing, the layers were separated and the organic phase was added to a mixture of methyl t-butyl ether (200 ml), butanol (30 ml) and concentrated hydrochloric acid (23.5 g) at 10C. The reaction mixture was stirred at 10C for one hour and the purifed 2-ethyl-4-1~2'-(lH-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxylquinoline hydrochloride isolated by filtration.
The solid was washed with methyl t-butyl ether (2 x 100 ml), then slurried in water (500 ml), collected by filtration and washed with water (150 ml). It was dried in vacuo at 30 for 16 hours to give partially hydrated material (46.0g), m.p. 147-50C.
~xample 3 IThis Example describes a typical preparation of the ga~a form of compound Al A sample (5.0 g) of 2-ethyl-4-[(2'-(lH-1,2,3,4-tetrazol--5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride (obtained from Example 2) was heated to reflux in absolute ethanol (50 ml) and methanol (40 ml) was added at reflux to achieve solution (about 1 hour). The reaction solution was distilled (about 30 minutes) to remove 50 ml of distillate and then cooled to ambient temperature.
After stirring for 16 hours, ethyl acetate (50ml) was added and the mixture stirred at 0-5C for 1 hour. The solid material was collected by filtration and washed with ethyl acetate (Sml) and dried ln vacuo at 25C for 64 hours to give the gamma crystalline form of 2-ethyl-4-[(2'-(lEI-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxyl-quinoline hydrochloride, as a compact crystalline solid (4.42g), in essentially anhydrous state, with m.p. 189-191C and X-ray diffraction as shown in Figure 1 attached hereto. Using differential scanning calorimetry, this material showed an initial change at 188.8C and a final change at 192.5C.
This procedure may also be modified by heating a slurry of ;~t s~ 5 2-ethyl-4-[(2'-(lH-1,2,3,4-tetrazol--5-yl)biphenyl-4-yl)methoxy]-quinoline hydrochloride in a mixture of industrial methylated spirit (about 5% methanol, 95% ethanol) under reflux for at least two hours, cooling the slurry to ambient temperature, separating the solid by filtration, to give the gamma crystalline form of compound A in essentially anhydrous state and with essentially the same physical properties as those given above.
Example 4 [This Xxample describes a procedure for the preparation of a source of compound A which is predominantly the alpha form.l A mixture of 2-ethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (930 mg) and a mixture of ethanol (lOml), methanol (5ml) and concentrated hydrochloric acid (2 ml) was allowed to stand for 2 hours. Volatile material was removed by evaporation. The residue was mixed with ethanol (20ml) and volatile material removed by evaporation. This porocedure was repeated twice. The resultant residue was triturated with ether (2 x 30 ml). The ether was decanted off. The solid residue was dissolved in a mixture of ethyl acetate (40ml) and ethanol (60ml).
The volume of solution was then quickly reduced by about 50% by partial evaporaticn and then cooled to ambient temperature to give predominantly the alpha form of 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxylquinoline hydrochloride (160 mg), as a light crystalline solid, m.p. 179-182C (decomposition). Further crystalline material (240 mg) of m.p. 177-179C (decomposition) was obtained by concentrating the mother liquor in vacuo (to about 10 ml in volume) and then cooling it to about 0-5C. Both samples of crystalline solid were subsequently shown to be the alpha form by X-ray diffraction spectroscopy. [A typical X-ray diffraction pattern for a sample of the alpha form obtained by this procedure is shown in Figure 2 hereinafter.]
The starting 2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline may be obtained as a solid, m.p.
173-174DC (decomposition); N~R: 1.4(t,3H), 2.96(q,2H), 5.16(s,2H), 6.73(s,1H), 6.9-6.94(m,6H), 7.18-7.32(m,13H), 7.33-7.55(m,4H), 13 ~ ;~ ~ S
7.67(dt,1H), 7.99(m,2H), 8.11(d,1H); microanalysis, found: C,81.1;
H,5-4; N,10-9%; C44H35N50 requires C,81-4; ~,5.4; N~10-8%~ by alkylating at ambient temperature a solution of the sodium salt of 2-ethyl-4-quinolone (prepared by the method described in Org. Syn., 1955, Coll. Vol. III, p.374 and p.593) in _,_-dimethylformamide (DMF) with a solution in DMF of 5-12-(4'-bromomethylbiphenylyl)l-2-triphenylmethyl-2H-tetrazole (obtained as described in European Patent 0291969).
Example 5 [This Example describes a conventional tablet formulation of the gamma form of compound A (as defined hereinbefore) suitable for medical or veterinary administration to warm-blooded animals including humans.
Material mg/tablet Gamma form of Compound A 5 Croscarmellose sodium 2 Microcrystalline cellulose 16 Lactose 76 Hagnesium stearate 19-Jan-1992
Claims (13)
1. The compound: 2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline hydrochloride, as the gamma crystalline form, essentially anhydrous and substantally free of other physical forms and which form is characterised by having a melting point which is in the range about 185-192 degrees Celsius (°C) and an X-ray powder diffraction pattern including specific peaks at about 2 = 8.6, 11.9, 12.4, 14.3, 15.5, 19.0, 19.3, 19.9, 20.3, 22.8, 23.1, 24.3, 25.7, 27.5, 28.7 and 29.4°.
2. A crystalline form of the compound: 2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride, essentially anhydrous and substantially free of other crystalline forms, and having an X-ray powder diffraction pattern substantially as depicted in Figure 1 hereinbefore.
3. A process for the manufacture of a crystalline form of the compound: 2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline hydrochloride, as defined in claim 1 or 2 hereof, which comprises heating at elevated temperature a source of said compound in one or more suitable polar organic solvents, optionally reducing the volume of the resultant solution by partial evaporation, optionally followed by adding a non-hydroxylic organic solvent or diluent and then cooling the mixture obtained to about 0 to 20 degrees Celsius (°C).
4. A process as claimed in claim 3 in which the polar solvent is selected from methanol, ethanol, propanol and 2-methoxyethanol, or a mixture of two or more thereof.
5. A process as claimed in claim 3 in which the polar solvent is a mixture of ethanol containing up to about 10% by volume of methanol.
6. A process as claimed in claim 3, 4 or 5 in which the non-hydroxylic solvent is selected from ethyl acetate and butyl acetate.
7. A process as claimed in any one of claims 3 - 6 in which the heating is carried out at an elevated temperature from about 40 to 130°C.
8. A process as claimed in any one of claims 3 - 7 in which the heating is carried out for at least 1 to 12 hours.
9. A process for the manufacture of a crystalline form of the compound: 2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline hydrochloride, as defined in claim 1 or 2 hereof, which comprises dissolving a source of said compound by heating in one hydroxylic solvent at or near the boiling point of said solvent, adding another more polar and lower boiling hydroxylic solvent and then removing the lower boiling point solvent by fractional distillation prior to addition of a suitable non-hydroxylic solvent.
10. A process for the manufacture of a crystalline form of the compound: 2-ethyl-4-1(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline hydrochloride, as defined in claim 1 or 2 hereof, which comprises heating a source of said compound in a mixture of ethanol containing up to 10% by volume of methanol at or near the boling point of said mixture for at least 2 hours, followed by cooling the mixture to about 0 to 20°C.
11. A crystalline form of the compound:
2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline hydrochloride, as defined in claim 1 or 2 hereof, obtainable by the process of any one of claims 3 to 10.
2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline hydrochloride, as defined in claim 1 or 2 hereof, obtainable by the process of any one of claims 3 to 10.
12. A source of the compund: 2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride containing a crystalline form having an X-ray powder diffraction pattern including strong specific peaks at about 2.THETA. = 7.21, 10.17 and 11.40°
and suitable for use in a process as claimed in any one of claims 3 to 10.
and suitable for use in a process as claimed in any one of claims 3 to 10.
13. A pharmaceutical composition which comprises a crystalline form of the compound: 2-ethyl-4-[(2'-(1H-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline hydrochloride, as defined in claim 1 or 2 hereof, together with a pharmaceutically acceptable diluent or carrier.
20-Jan-1992
20-Jan-1992
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9102727.6 | 1991-02-08 | ||
| GB919102727A GB9102727D0 (en) | 1991-02-08 | 1991-02-08 | Pharmaceutical agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2060825A1 true CA2060825A1 (en) | 1992-08-09 |
Family
ID=10689748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002060825A Abandoned CA2060825A1 (en) | 1991-02-08 | 1992-02-07 | Therapeutic agent |
Country Status (12)
| Country | Link |
|---|---|
| CN (1) | CN1064809A (en) |
| AP (1) | AP9200355A0 (en) |
| AU (1) | AU1189392A (en) |
| CA (1) | CA2060825A1 (en) |
| GB (2) | GB9102727D0 (en) |
| HU (1) | HUT60489A (en) |
| IE (1) | IE920243A1 (en) |
| IL (1) | IL100793A0 (en) |
| MX (1) | MX9200532A (en) |
| PT (1) | PT100097A (en) |
| WO (1) | WO1992013853A1 (en) |
| ZA (1) | ZA92729B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW297025B (en) * | 1992-02-14 | 1997-02-01 | Squibb & Sons Inc | |
| WO2008151257A2 (en) | 2007-06-04 | 2008-12-11 | Synergy Pharmaceuticals Inc. | 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 |
| EP2328910B1 (en) | 2008-06-04 | 2014-08-06 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| AU2009270833B2 (en) | 2008-07-16 | 2015-02-19 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| EP2968439A2 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| US10011637B2 (en) | 2013-06-05 | 2018-07-03 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase C, method of making and using same |
| TN2016000077A1 (en) | 2013-09-16 | 2017-07-05 | Astrazeneca Ab | Therapeutic polymeric nanoparticles and methods of making and using same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4920132A (en) * | 1987-11-03 | 1990-04-24 | Rorer Pharmaceutical Corp. | Quinoline derivatives and use thereof as antagonists of leukotriene D4 |
| HUT54991A (en) * | 1989-08-11 | 1991-04-29 | Ici Plc | Process for producing quinoline derivatives and pharmaceutical compositions comprising such compounds |
-
1991
- 1991-02-08 GB GB919102727A patent/GB9102727D0/en active Pending
-
1992
- 1992-01-27 IE IE024392A patent/IE920243A1/en unknown
- 1992-01-28 IL IL100793A patent/IL100793A0/en unknown
- 1992-01-31 ZA ZA92729A patent/ZA92729B/en unknown
- 1992-02-03 AP APAP/P/1992/000355A patent/AP9200355A0/en unknown
- 1992-02-05 WO PCT/GB1992/000214 patent/WO1992013853A1/en active Application Filing
- 1992-02-05 AU AU11893/92A patent/AU1189392A/en not_active Abandoned
- 1992-02-05 GB GB9202377A patent/GB2252557A/en not_active Withdrawn
- 1992-02-05 HU HU9200354A patent/HUT60489A/en unknown
- 1992-02-06 PT PT100097A patent/PT100097A/en not_active Application Discontinuation
- 1992-02-07 CA CA002060825A patent/CA2060825A1/en not_active Abandoned
- 1992-02-07 MX MX9200532A patent/MX9200532A/en unknown
- 1992-02-08 CN CN92101425A patent/CN1064809A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| HUT60489A (en) | 1992-09-28 |
| GB9202377D0 (en) | 1992-03-18 |
| MX9200532A (en) | 1992-08-01 |
| ZA92729B (en) | 1992-11-25 |
| AP9200355A0 (en) | 1993-08-03 |
| GB2252557A (en) | 1992-08-12 |
| AU1189392A (en) | 1992-09-07 |
| WO1992013853A1 (en) | 1992-08-20 |
| HU9200354D0 (en) | 1992-04-28 |
| CN1064809A (en) | 1992-09-30 |
| IL100793A0 (en) | 1992-09-06 |
| GB9102727D0 (en) | 1991-03-27 |
| IE920243A1 (en) | 1992-08-12 |
| PT100097A (en) | 1993-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101221864B1 (en) | Hydrates and polymorphs of 4-[[(7Ｒ)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide, methods for the production thereof, and use thereof as medicaments | |
| CA2141692C (en) | Prodrugs of imidazole carboxylic acids as angiotensin ii receptor antagonists | |
| CZ398191A3 (en) | Novel 4-amino alkyl-2(3h)-indolones and pharmaceutical compositions containing them | |
| US20020016351A1 (en) | New crystals of celecoxib | |
| JP4662979B2 (en) | Novel β-agonist, its production method and its use as a drug | |
| CA2060825A1 (en) | Therapeutic agent | |
| EP0507696A1 (en) | Antihistaminic and non-sedative derivatives of benzimidazol, process for their preparation and their medicinal use | |
| SK46793A3 (en) | Regenarative melting tank and method of working | |
| US7504516B2 (en) | Crystalline forms of candesartan cilexetil | |
| NZ209912A (en) | Imidazoline derivatives and pharmaceutical compositions | |
| IE912406A1 (en) | Process | |
| WO1989005799A1 (en) | Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same | |
| CA1330663C (en) | Thiazolidinedione derivatives | |
| JP3588363B2 (en) | Quinoxaline diones | |
| MXPA03005884A (en) | Amlodipine hemimaleate. | |
| WO1988001270A1 (en) | Pyridopyrimidinediones | |
| IE46821B1 (en) | 3,5-disubstituted-1h-1,2,4-triazoles | |
| EP0906309A1 (en) | Modified form of the r(-)-n-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride | |
| IE44184B1 (en) | Imidazole derivatives,processes for their preparation and pharmaceutical compositions containing them | |
| US4213986A (en) | Novel derivatives of imidazole and pharmaceutical compositions containing them and method of use | |
| US4081551A (en) | Oxime ethers having anti-depressive activity | |
| JP2002528541A (en) | N-oxides of heterocyclic compounds having TNF and PDE-IV inhibitory activity | |
| TWI221152B (en) | Method for preparing sodium-hydrogen exchanger type 1 inhibitor | |
| EP0170549B1 (en) | 4,5,6,7-Tetrahydrofuro-or 1H-pyrrolo[2,3-c]pyridine derivatives, their preparation and therapeutical use | |
| EP0277805A1 (en) | Ergolinyl heterocycles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |