HUT60489A - Process for producing 2-ethyl-4-/(2'-/1h-tetrazol-5-yl/-biphenyl-4-yl)-methoxy/-quinoline hydrochloride and pharmaceutical compositions comprising same - Google Patents

Description

London, United Kingdom

PROCEDURE 2- £ Τ1ί-4-ΖΪ2 * - / 1Η-1τΓ2τ ^ Η- ^ Τ4Α2ϋΒ-5-ΐν-ΒΙΕΕΝΙΒ ^ £ j = ZT WT / \ LC, Y'i> {^ í2S! ^F £ _

-4-IL) RAKER K17-A.KIN KILLER-KUKLUKIDF PREFERRED BY APPLICATION DAY 02/02/1992 ·

priority:

08.08.1991 (9102727.6) Great Eritrea

The present invention relates to a process for the preparation of 2-ethyl-4-Zt2 * - (1H-1H-tert -4,4-tetrazol-5-yl) -biphenyl-4-ylmethoxy] quinoline hydrochloride which is substantially free of other physical modifications. in the form of a crystalline gamma crystalline form having a melting point of 185-192% and having an X-ray powder diffraction spectrum of δ = 6.6, 11.9, 12.4, 14.3, 15.5, 19.0,

19.3, 19,), 2u, 3, 22.8, 23.1, 24.3, 25.7, 27.5, 28.7 and 29.4 °. According to the invention, the starting 2-ethyl-4-ZT2 * - / Di l _T-he- ^ 3 _r r4-tetrazol-5-yl / biphenyl-4-yl) -mstoxl7-quinoline hydrochloride with one or more polar organic heating in the presence of a solvent, optionally partially evaporating the resulting solution, optionally adding an organic solvent or diluent containing no hydroxyl group to the resulting concentrate and cooling to 0-2.

158/874

Π '= pg • ·

Represented by: Dr. Jalaovszky Györgyné, lawyer

Associate: Dr. László Tóth-Urbán lawyer

489> 5 / ^

PUBLISHING EDITION / V - '<ύ i, _C </. H / $ 7

158/874

PROCEDURE 2-STYL-4-ZC2 '- / 1H-1H- _T -374-TK ₁ T.alpha.-57LL / ~ Biy2NIL-4-1L) -MET0XX / -CAN0LIN-HYDROCHLORIDE-7H) AlXlT7h7TRA-ILPEAIAL JIMIBLIC INDUSTRIAL. , London, United Kingdom

inventors:

BARKEK Alan -Charles, ááaco le sfiald, Cheshire,

ROBBRTS David mthony, tíaaclesfleld, Cheshire,

PEARCE Robert James, Macclesfleld, Cheshire,

RUS3ELL Simon Thoraas, Macclesfleld, cheshire,

Great Britain

Date Posted: 02/02/1992 ·

Priority: 08/02/1991 (9102727.6)

Object of Great Britain «1 the invention relates to 2-ethyl-4-ZT2 '- / LLI-l, 2,3,4-tetrazol-5-yl / -blfenll-4-yl) methoxy-7 ^{^,"} novel quinoline hydrochloride physical form. This compound is partially

- 2 or completely antagonizes one or more physiological effects of angiotensins, in particular angiotensin II (hereinafter referred to as "All"), and may accordingly be used as an active ingredient in pharmaceutical preparations. The invention further relates to a pharmaceutical composition comprising a new physical modification of 2-ethyl-4- (T2 * - (1H-1,2,3,4-tetrazol-5-yl) -biphenyl-4 * yl) -phethoxy] -quinoline hydrochloride. for the preparation of preparations. The pharmaceutical compositions of the present invention are useful in the treatment of hypertension, congestive heart failure and / or hyperaldosteronism in warm-blooded persons (including humans), and for the prevention or treatment of any disease or disorder in which the renin-angiotensin-aldosterone system is significant. plays a causal role.

Angiotensins are key contributors to the renin - angiotensin - aldosterone system involved in the regulation of homeostasis and fluid / electrolyte balance in warm bloods (including humans). u is converted from angiotensinogen (a plasma protein) in the plasma to angiotensin I by the action of renin and angiotensin I is converted to angiotensin ΙΙ by the angiotensin converting enzyme (aüü). Ali has a strong anticonvulsant effect primarily on the vascular system and increases vascular resistance and blood pressure. It is also known that angiotensins stimulate the release of aldosterone, leading to hypertension and hypertension through the sodium and fluid retention mechanism. For the therapeutic control of blood pressure and / or fluid / electrolyte balance, some solutions have already been developed to intervene in the functioning of the renin-angiotensin-aldosterone system. Such solutions include inhibition of renin or AGE. However, due to the potential risk of side effects and / or idiosyncratic reactions, alternatives are still required.

It is known that some solid compounds may exist in several distinct and different physical properties (e.g. different melting points and different solubilities. This phenomenon is called polymorphism. In some cases, some polymorphs may be more stable than others, The polymorphic active ingredients of the pharmaceutical compositions to be used in medical practice are to be used in physical form which is physically stable and reproducible in quality, substantially free of other physical modifications and impurities. because it is present occasionally, its biological value may differ ·

No. 412,848. European Patent Publication No. 4,123,125 discloses quinoline derivatives having Ali antagonistic activity. A very preferred representative of the compounds disclosed therein is 2-ethyl-4-Zr 2 '- (1H * 1,2,3,4-tetrazol-5-yl) -biphenyl-4-11) -methoxy-7 quinoline hydrochloride (hereinafter referred to as "Compound A"). In our studies, it has been found that the compound can be isolated in a number of physical forms, one of which is particularly advantageous for the preparation of pharmaceutical compositions due to its favorable properties, in particular its high stability.

According to the invention, Compound A is prepared in the form of a new physical form, hereinafter referred to as the gamma form, which is essentially anhydrous and essentially free of other physical modifications, and is a crystalline material melting at 185-192 ° C. powder diffraction spectrum 2β 8 8.6, 12.4,

14.3, 15.5, 19.0, 19.3, 20.3, 22.8, 23.1, 24.3, 25.7, 27.5, 20, 7 and 29.4 ° noticeable peak ·

Throughout the specification and claims, the term "A" is essentially anhydrous, crystalline gamma modification * (hereinafter "gamma modification A"), which is substantially free of other physical modifications. containing at least 95% by weight of the compound A in the form of a gamma modification.

The X-ray powder diffraction spectrum can be recorded in a known manner, for example using a Philips Pv.1130 X-ray generator equipped with a wide focus copper tube. The X-ray powder diffraction spectrum of the crystalline gamma form of Compound A is illustrated in Figure 1, while the spectrum shown in Figure 1 is taken up with 0.5 g of the test compound in a standard-depth Philips sample holder. The recording was performed in a range of 2 → 4 to 40 °, in 0.02 ° increments, with a 4 sec measurement time for each data point, and a step intensity curve was recorded. Note that, in practice, the values of 2 <9 from the device may vary slightly from device to device so that the values reported above cannot be considered absolute values.

The melting characteristics of the samples of Compound A vary with the purity of the sample, degree of hydration, and physical modifications of the sample. The melting characteristics

- determined by known methods, such as di-essential scanning calorimetric mooring. the melting characteristics of the "A ⁿ compound" are the same as in Example 3.

Compound A may be prepared by methods known per se for the preparation of related derivatives (for example, those listed in EP 412 348). The preparation of Compound A is described in detail in the Examples. These known methods provide substances that differ in their crystalline structure from the hydration or solvation state of the crystals to the gamma form of Compound A. the melting characteristics of the term, their X-ray powder diffraction spectrum and their infrared transformation spectrum are different; módosulatáétól. ' Compound A is prepared _; Most suitable methods for the preparation of Iru give rise to a physical modification of the compound '', V, hereinafter referred to as the 'alpha modification', which is thermodynamically less stable than the gamma modification. As a paddle, we tell you 412,848. The compound A * ^1, prepared according to the procedure described in Example 25, EP-A-25, is formed in the majority of its physical carbon black, melting point 178-181 ° C with decomposition and having an X-ray powder diffraction spectrum of 2 0-7.21, 17 and 11 at 40 ° * show a sharp, specific peak. The characteristic X-ray powder diffraction spectrum of the alpha form of Compound A is shown in Figure 2 and the characteristic X-ray powder diffraction spectrum of the gamma form of compound ^f '1 is shown in Figure 1. Obviously, from the comparison of the spectra • • 4

-0valid r.hrx as differences. The gamma variant of .z has a more dense crystalline structure than the al.h .. inode-o mulat and is therefore more suitable for therapeutic purposes than the alpha variant.

The gamma-form of the compound of the present invention is prepared by heating the parent compound A in the presence of v <g polar organic solvents. In this case, the volume of the resulting solution is reduced by partial evaporation, optionally adding an organic solvent or diluent containing chitrozole cap and the resulting mixture is cooled to about Q-2.

The starting compound A may be a bulk form of the alpha form obtained by the procedures described below.

Polar organic solvents include, for example, organic solvents such as methanol, ethylene, propunol, 2-methoxyethyl alcohol or mixtures thereof which are shaken with hydroxyl groups. In particular, ethanol-methanol mixtures containing up to about 1 volume of methanol can be used.

organic solvents which do not contain a didroxyl group include, for example, ethyl acetate and butyl acetate.

Preferably, the parent compound A 'and polar organic solvent are maintained at a temperature of about 40-130 °, usually at the boiling point of an aqueous solvent or solvent, or at a temperature close to a.h. The molarization must be carried out for a sufficient period of time to allow the starting material to be converted in its entirety into the desired .uine modification. The heating usually requires several hours, preferably at least 1 to 12 hours.

Beds preferably play as follows

· · ·

A solution of the starting compound A in a hydroxyl containing solvent (preferably ethanol) is maintained at or near the boiling point of the solvent, and another lower polar solvent (preferably methanol) is added to the solution, followed by the lower boiling solvent. it is removed by distillation and a solvent (preferably ethyl acetate) which does not contain a hydroxyl group is added to the residue.

In another preferred embodiment, the starting compound is added to ethanol (e.g., industrial denatured alcohol) containing up to 10% by volume of methanol, kept at or near the boiling point of the solvent for at least 2 hours, and then cooled to about 0-20 ° C. It is cooled.

It should be noted that it is not necessary to completely dissolve the starting compound A in the polar solvent, i.e., a suspension of the starting compound A in the polar solvent may also be used in the process of the invention.

Optionally előtisztíthatjuk the initial ^"W compound. During the pre-purification, Compound A is first converted to the free base and then to the sodium salt, which is purified by extraction with a suitable organic solvent mixture, and finally the resulting material is again converted to the hydrochloride salt.

Due to its favorable physical properties, the gamma form of Compound A can be used very favorably as active ingredients in pharmaceutical formulations, particularly solid dosage forms for oral administration such as tablets, capsules and powder formulations. These pharmaceutical compositions may be prepared by known pharmaceutical technology techniques.

The present invention further relates to a process for the preparation of a pharmaceutical composition comprising the gamma form of Compound A as an active ingredient by converting the gamma form of Compound ^B A into a pharmaceutical composition using conventional pharmaceutical carrier, diluent and / or excipient.

As already stated, ^W A ^? The compound is useful in the prevention and treatment of diseases and disorders in warm-blooded animals (including humans) requiring reduction of vasoconstriction and fluid retention due to one or more physiological effects of Ali caused by the renin-angiotensin-aldosterone system. Accordingly, Compound A may be used to treat hypertension, congestive heart failure and / or hyperaldosteronism in warm-blooded persons (including humans) and other diseases or disorders in which the renin-angiotensin-aldosterone system plays an important causative role.

Antagonism of one or more physiological effects of All, in particular inhibition of the interaction of Ali with effect mediated receptors, was investigated by the following pharmacological methods:

The * ¹ test »

The assay was performed in vitro by incubating the test compound in a buffered mixture containing a known amount of radiolabeled ΑΙΙ and an angiotensin-responsive tissue surface fraction in an initial concentration of 100 micromolar (or less). The surface cell membrane fraction was isolated from the guinea pig adrenal gland, which is known to

- 9 responds. The interaction of radiolabeled ull with the receptor (defined by rapid removal of unbound radioactively labeled material in a known manner and measurement of the amount of radioactively labeled material bound to the cell membrane) is antagonized by substances capable of binding to receptor sites on the membrane. Under these conditions, these substances displace radiolabeled All from the membrane. The atagonization insect killers can be easily determined by comparing the radioactivity measured in the membrane after incubation with a solution of the test compound in a known comma to that measured after incubation with a solution containing no test compound. Compounds that inhibited the binding of radioactively labeled Ali by at least 50% at a concentration of 10 µM in the above experiment were re-tested at lower concentrations to determine the effect of IC 50 (active agent that suppressed the binding of radioactively labeled Ali). in determining the concentration) of the tested active ingredient is usually involving four orders of magnitude concentration range, which is placed in the middle of the expected IC ^ _Ü value I0 and the value determined by the ^ _o, 5-09 depicting suppression function of the concentration graph.

Under the conditions of the above assay, Compound A generally exhibited significant inhibitory activity at concentrations of 50 micromolar or much lower.

ⁿ B ^w test »

The assay was performed in vitro in isolated rabbit aorta held in physiological saline at 37 ° C. The extent to which this compound inhibits AH-induced muscle contraction was investigated. To check whether the effect observed is based on a specific inhibition of All, we also tested under the same conditions whether the compound inhibited organ contraction caused by noradrenaline ·

The ^M 'compound exerted a marked inhibitory effect usually 50 micromolar or much less final concentration »metabolize the circumstances of the above test, ·' ^l ö ^{n test;}

The assay was performed in vivo in terminally anesthetized or alert rats. Prior to the study, animals were implanted with an anesthetic catheter during anesthesia to measure changes in blood pressure. The test compound was administered orally or parenterally to the animals to determine their ability to counteract the antihypertensive effect of Ali. Based on the specific inhibition of Ali, we also tested under the same conditions whether the drug suppresses the blood pressure-induced increase in blood pressure. Compound A generally expressed a specific Ali dose of 50 mg / kg or less in the above assay. antagonistic effect. Toxic Symptoms or Other Nsmkwan Pharmacology! no effects were observed.

^ ^ Lvizj underneath;

studies were performed in vivo. Rats, silk monkeys and dogs were kept on a low sodium diet and given daily a sufficient amount of iris semide (a known saluretic agent). With this preparation, we stimulated the biosynthesis of All in the animals. Animals are anesthetized into the body of animals • «• · • · ·«

- 11 compartments were built to measure changes in blood pressure »then the test compound was administered orally or parenterally and the change in blood pressure was measured.

Compound "A" · under the conditions of the above assay generally exhibited a significant antihypertensive effect at doses of 5 mg / kg or less, indicating the Al1 antagonist activity of the compound. Toxic Symptoms or Awesome Pharmacology! no effects were observed.

Compound A is up to 50 mg / kg body weight (preferably up to 10 mg / kg body weight) in human medicine and usually up to 5 mg / kg body weight (preferably up to 1 mg / kg body weight) kg daily). the amount of active ingredient is sometimes administered in divided doses daily. It will be apparent to one of ordinary skill in the art that the precise amount of drug required for treatment will vary with the route of administration, the size, age and sex of the patient and the type and severity of the disease or disorder being treated.

In addition to human medicine, Compound A can also be used in veterinary medicine for the treatment of warm-blooded livestock such as dogs, cats, horses and cattle. Dosages required for veterinary treatment may be similar to those used in human medicine.

The invention is illustrated in detail by the following non-limiting Examples. Unless otherwise stated in the Examples, (i) Concentration and evaporation in a rotary evaporator under reduced pressure # - 12 - (ii) Operations carried out at room temperature (18-26 ° C)!

(111) The yield figures quoted are for information only »and are not a maximum!

(iv) spectra were recorded at 200 uHz in deuterochloroform, and chemical shift values were plotted on ppm units of tetramethylsilane internal standard.

(v) microelement data for the products conformed to the expected structure · ls_ £ É2áa

Creating the Iclland A wailUt

A mixture of 3.3 g of tributyltin chloride, 1.13 g of sodium azide and 22.5 ml of water was kept at room temperature for 4 hours, and the mixture was extracted with toluene and azeotroped with water to remove the extract. To a solution of tributyltin azide azide in 15 ml of toluene, d, 9 g of 4 * - (2-ethyl-quinolin-4-yloxy) -methyl-7-biphenyl-2-carbonitrile is added and the mixture is refluxed for 90 minutes. gave 15 ml of a toluene solution of 2-ethyl-4- (C2 * - (2- (tributyl-8-stannyl) -2H-1,2,3,4-tetraol-5-yl) -biphenyl-4-yl) - contains methox27-clnoline, 2.5 g of sodium nitrite, 10 ml of water and 10 ml of 12% w / v solution slowly over 1 hour, >> 03 aqueous hydrochloric acid

Λ give it. The temperature of the mixture is kept below 5 ° C during the addition of the reagent. A solution of 1.43 g of sulxamic acid in 10 ml of water is then added at a temperature below 5 ° C and the mixture is stirred for 1 hour. wash with water (10 mL) followed by toluene (10 mL) then add to tetrahydrofuran (40 mL) · The semi-solid dissolves and then crystalline white solid

- 13 substances precipitate out. After cooling for 1 hour, the solid was filtered off, washed with 5 ml of tetrahydrofuran and dried. Melting point 179-1890 ° C, m.p. 2-ethyl-4- (T2 * - 1H-tetrazol-5-yl) -biphenyl-4-ylmethoxy-quinoline hydrochloride, m.p.

NMR. spectral data (? d 6 -d 8): 1.46 (t, 3H), 3.18 (q, 2h), 5.68 (s, 2ii), 7.22 (d, 2li), 7.5-7. Δ U, 7H), 7.83 (t, 111), 8.08 (t, 1H), 8.18 (d, 1H), 8.32 (d, 18).

The starting material 4 * - (T 2 -ethylquinolin-4-yloxy) methyl 7 * biphenyl-2-carbonitrile was prepared as follows.

1.73 g of 2-ethyl-4-quinolone (analogous to that described in Org. Synth., Vol. III, pp. 374 and 593), aniline and methyl propionyl acetate, 3.1 g of 4 * - ( A mixture of bromomethyl) biphenyl-2-carbonitrile, solid potassium carbonate (1.81 g) and N-methylpyrrolidone (40 mL) was stirred for 36 hours under nitrogen. The mixture was added dropwise at 15-25 ° C to 100 ml of water and stirred for 30 minutes. The suspended solid was filtered off, washed with water and dried under reduced pressure at 60 ° C. The resulting solid was recrystallized from tert-butyl methyl ether. 1.9 g of 4 * - (2-ethyl-quinolin-4-yloxy) -methyl-7-biphenyl-2-carbonitrile are obtained as an oily solid, m.p. 151-153 ° C.

IW NMR (JOU1 _3): 1.4 (t, 3H), 2.37 (q, 2H), 5.35 (s, 2H), 6.76 (s, 1H), 7.4 to 7, Δ (m, 3H), 7.6-7.8 (m, h), 8.0 (d, 111), 8.25 (d, H1).

The 4 * - (bromomethyl) biphenyl-2-carbonitrile used as starting material in the previous reaction was prepared as follows:

(i) 30 g of 4-methylphenylboronic acid, 36.4 g of 2-bromobenzonitrile, 0.4 g of palladium (II) chloride, 200 ml of methanol and 200 ml of toluene ···

To a mixture of 14 ol is added 200 ml of a 2 M aqueous solution of sodium carbonate at 5 ° C with stirring. The mixture warms to about 20 ° C and a solid precipitates. The reaction mixture was refluxed for 2 hours, then allowed to cool and 100 ml of water and 5 g of diatomaceous earth were added. The mixture was stirred for 15 minutes and then filtered through diatomaceous earth. The organic phase was separated from the filtrate, washed with 2M aqueous sodium carbonate solution, water, harsh, and the filtrate was evaporated, and the resulting solid was recrystallized from petroleum ether (b.p. 110-120 ° C). 4 * -methyl-biphenyl-2-carbonitrile is obtained which is used without further purification.

(ii) a mixture of 3.86 g of 4 * -methyl-biphenyl-2-carbonitrile, 3.92 g of libromo-buccamide, 0.15 g of azobis (isobutyronitrile) and 75 ml of chlorobenzene for 3 hours. Keep at 0. An additional 0.3 g of l-bromosuccinimide and 0.05 g of azobis (isobutyronitrile) were added and the mixture was heated for a further 15 minutes, then the heating was stopped and the mixture was stirred at room temperature for 16 hours. Water (50 mL) was added, and after stirring for 30 min, the mixture was filtered. The filtrate was separated and the organic layer was washed with water (50 mL), dried over magnesium sulfate, filtered and the solvent was evaporated from the filtrate. The solid residue was recrystallized from cyclohexane. 3.9 g of solid 4'-bromomethyl) -biphenyl-2-carbonitrile are obtained.

1 H NMR (DMSO): 4.55 (s, 2H), 7.4-7-85 (m, 8H).

Example 2

Purification of the product obtained in Example 1

50.0 g of 2-et11-4- / T2 * 4 · ♦ 4 prepared according to Example 1

- (1H-1,2,3,4-Tetrazol-5-yl / biphenyl-4-yl) rocloidide in 125 ml of methyl tert-butyl ether, 175 of butanol and 150 ml of 10% w / v - aqueous sodium chloride solution is suspended in a 10 DEG-12 DEG C. mixture. A suspension of 50 µl of a 10% w / v aqueous solution of sodium chloride, 25 ml of water and 20 g of a 48% aqueous solution of sodium hydroxide is added at 10-12 ° C. The mixture was thoroughly mixed and the layers were separated and the organic layer was added to a 10 ° C mixture of 200 ml of methyl tert-butyl ether, 30 ml of butanol and 23.5 g of concentrated aqueous hydrochloric acid. The mixture was stirred for 1 hour at 10 ° C and then purified 2-ethyl-4- (C2 * - (1H-1,2,3 _t- 4-tetrazol-5-yl / biphenyl-4-yl) - the methoxy-17-quinoline hydrochloride was filtered off. The solid was washed with methyl tert-butyl ether (2 x 100 mL), slurried in 500 µl of water, filtered and washed with water (150 mL), dried under reduced pressure at 30 ° C for 16 h. 46.0 g of partially hydrated purified material are obtained, m.p. 147-15 ° C.

Example 3

Preparation of Gamma Modification of Compound A .....

5.0 g of 2-ethyl "4" / T2 * - (1H-1,2,3,4-tetrazol-5-yl) -biphenyl-yl} -methoxy-quinoline obtained according to Example 2. hydrochloric acid and 50 ml of absolute ethanol are refluxed and 40 ml of methanol are added to the boiling mixture. The mixture is refluxed until the solids dissolve (about 1 hour), 50 ml of distillate are removed from the resulting solution by distillation for about 30 minutes, and the mixture is cooled to room temperature and stirred for 16 hours. To the concentrate was added ethyl acetate (50 mL) and the mixture was stirred at 0-5 ° C for 1 hour. The solid is out. ·· * ♦ · · · · · · · «« 4, *,: · ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 16 filtered, washed with 5 mL of ethyl acetate and dried under reduced pressure at 25 ° C for 64 h to give 4.42 g of a substantially anhydrous solid as a crystalline solid, which was obtained as 2-ethyl-4- / T 2 · - / Gamma modification of ifi-1,2,3,4-1 etrazo-5-1 l -b if eni-4-yl) methoxy-quinoline hydrochloride. The product melts at 189-191 ° C. The X-ray powder diffraction spectrum of the product is shown in Figure 1. Differential scanning calorie aesthetic analysis indicates that the resulting material changes in state starting at 18.8 ° v and ending at 192.5 ° 0.

Alternatively, 2-ethyl-4-2T2 '- / H-l, 2,3,4-tetrazol-5-yl / biphenyl-4-yl) methoxy _and 7 quinoline hydrochloride industrial methylated spirit (ca. A suspension of 5 volumes of a mixture of methanol and 95% by volume ethanol is refluxed for at least 2 hours, the suspension is cooled to room temperature and the solid is filtered off. The gamma form of Compound A is obtained in a substantially anhydrous state. / 1 has the same physical constants as above.

4 · Example

Preparation of Compound ¹¹ of form consisting essentially of alpha form

930 mg of 2-ethyl-4- (T2 '- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -biphenyl-4-yl) -methoxy] -quinoline, 10 ml of ethanol, 5 ml of methanol and The mixture was allowed to stand for 2 hours. The volatile material was evaporated, 2u ml of ethanol was added to the residue and the volatile material was evaporated. This operation is repeated twice more. The resulting residue was triturated with ether (2 x 30 mL) and the ether discarded. The solid residue was taken up in ethyl acetate (40 mL) and ethanol (6 mL)

- Let's go. The solution is concentrated by rapid evaporation to about half its original volume and the resulting concentrate is cooled to room temperature. 160 mg of light, a crystalline melting point from 179 to 182 ° 0 for 2-ethyl-4- _</ t2 * - / H-tetrazol-5-yl / biphenyl-4-yl) methoxy / quinoline hydrochloride # decomposes at the melting point of the substance.

Λ the product obtained consists predominantly of the alpha form. The mother liquor was evaporated under reduced pressure to a final volume of about .10 ml and the concentrate was exposed to 0-5. An additional 240 mg of crystalline material was isolated # m.p. 177-179 ° C (dec). This product also consists predominantly of alpha form according to X-ray powder diffraction data.

The X-ray powder diffraction spectrum of the alpha form obtained by the above procedure is shown in Figure 2.

The starting material, 2-ethyl-4- (T2 '- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -biphenyl-4-yl) -methoxy] -7-quinoline, was prepared by to give the sodium salt of 2-ethyl-4-quinolone (a compound prepared according to the procedure described in Org. Aynth. 1955 »Coll. Vol. 1x1, 374 and 593) in 5-dimethylformamide 5- / 5- (4 * 2-ethyl-4-ZC2 * - / - (bromomethyl) -biphenyl] -7-2- (triphenylmethyl) -2H-tetrazole (a compound prepared according to the procedure described in European Patent Application 291969). 2- (triphenylmethyl) -2H-5-yl-tetruzol / biphenyl-4-yl) methoxy _{<X7-quinoline} 173-174 ° C while there was thus obtained solid.

Nuclear Magnetic Resonance Spectrum: 1.4 (t, 3H), 2.96 (q, 2h), 5-16 (s, 2H), 6.73 (s, li), 6.9-6.94 (m, 6h), 7.18-7.32 (m, 13II), 7.33-7.55 (m, 410, 7.67 (dt, 1H), 7.99 (m, 2ii), 8.11 ( d, Iri).

- 18 Calculated: 0: 81.4 7 »a

H, 5.4 E, 10.8 based on:

found:

0: 81.1

H, 5.4 E, 10.9

5 · Example

Preparation of a pharmaceutical composition

Known pharmaceuticals are prepared by technological processes for the following formulation for human or veterinary use.

tablets for horses: 'The compound (gamma modification) 5 mg / tablet Croscarmellose sodium 2 Π ..crocrystalline cellulose 16 u úaktóz 76 Π . ..a gné z 1 um- s z t ea onto it 1 fiction

Claims (14)

Patent claims 1 to 5 1. 2-Ethyl-4-Zt 2 - [(1,3-1,4-cetrazol-5-yl) -biphenyl] -methoxy-cholia-n.-hydrochloride is essentially anhydrous from other physical modifications. a substantially free, crystalline gamma modification having a melting point of 185-192% and having an x-ray powder diffraction spectrum of 2 * 9- = 8.6, 11.9, 12.4, 14.3, 15.5 · 19.0, 19.3, 19.9, 2u, 3, 22.8, - 23.1, 24.3, 25.7, 27.5, 28.7 and 29 , A peak at 4 °. 2. 2 * -ethyl-4- (T2 * - (1H-1,2,3,4-tetrazol-5-yl) -biphenyl-4-yl) -methoxy] -quinoline hydrochloride is essentially anhydrous, other physical a crystalline modification substantially free of modifications having an X-ray powder diffraction spectrum as shown in Figure 1. 3. A process for the preparation of 2-ethyl-4- (T2 * - (1H-1,2,3,4-tetrazol-5-yl) -biphenyl-4-yl) -methoxy-7-quinoline hydrochloride according to claim 1 or 2. in the form of polymorph as defined in claim, characterized in that the starting 2-ethyl-4-Zt2 '- / H-l, 2,3,4-tetrazol-5-yl / biphenyl-4-yl) quinolin-7 -metoxJ _s heating the hydrochloride in the presence of one or more polar organic solvents, optionally concentrating the resulting solution by partial evaporation, optionally adding an organic solvent or diluent containing no hydroxyl group to the resulting concentrate and cooling the mixture to about 2%. The process according to claim 3, wherein the polar solvent is methanol, ethanol, propanol, 2-methoxy-ethanoX or mixtures thereof. A process according to claim 3, characterized in that the polar solvent is a maximum of 10 volumes by volume of methanol. containing ethanol. 6. a 3-4. Process according to any one of claims 1 to 3, characterized in that ethyl acetate or butyl acetate is used as the solvent without hydroxyl group. 7. The process according to any one of claims 1 to 4, wherein the mixture is maintained at 40-130 °. Process according to any one of claims 3-7 ·, characterized in that the heating is carried out for at least 1 to 12 hours. 9. A process for the preparation of 2-ethyl-4- (T2 * - (1H-1,2,3,4,4-tetrazol-5-yl-biphenyl-4'-yl) -methoxy-7-cinnoline hydrochloride according to claim 1 or 2. A process as defined in claim 1, wherein the starting 2-ethyl-4-ZT2 '- (1H-1,2,3,4-tetx'azol-5-yl / biphenyl-4-yl) methoxide E7-quinoline hydrochloride is dissolved in a solvent containing a hydroxyl group at or near the boiling point of the solvent; solvent was added. 10. A process for the preparation of 2-ethyl-4- (trans-1H-1,2,3,4-tetrazol-5-yl) -biphenyl-4-yl) -methoxy-7-quinoline hydrochloride according to claim 1 or Form as defined in claim 2, characterized in that the starting 2-ethyl-4- (2C2 '- (1H-1,2,3,4-tetrazol-5-yl) -biphenyl-4-yl) -methoxy] ETA containing up to 10 vol methanol ú ~ 7-quinoline hydrochloride kbridot 21 - the oldószereleg _v fc.ráspontján maintained at or near at least 2 hours and methanol, and the mixture was cooled to 20 ° u ^ is - nol. The crystalline 2-ethyl-4- (T2- (1x1-1,2,3,4-tetrazol-5-yl) biphenyl-4-yl) methoxy according to claim 1 or 2, - quinoline hydrochloride modification, characterized in that it is a compound of claims 3-10. The process according to any one of claims 1 to 6. 12. A 3-lu. The starting material for the process according to any one of claims 1 to 4, which is crystalline in the form of 2-ethyl-4- (T 2 * - / 1 H -1,2,3,34-tetrazol-5-yl / biphenyl-4-yl) -ethoxy-7-quinolone hydrochloride. It has a sharp peak at 2 = 7.21, 10.17 and 11.40 in the X-ray powder diffraction spectrum. 13. A pharmaceutical composition, wherein the active ingredient is 2-ethyl-4- / t2 * - (1H-1,2,3,4-tetrazol-5-yl) bilen-1-yl. 1) -n-t-oxy / -hydrate 1-hydride in the form of a crystalline modification as defined in claim 1 or 2 together with pharmaceutical diluents, carriers and / or other excipients. 14. A process for the preparation of a pharmaceutical composition according to any one of claims 3-10. A conventional pharmaceutical diluent for the 2-ethyl-4 &apos; by use of carriers and / or other excipients known in the art of pharmaceutical preparation to form a pharmaceutical composition. DISCLOSURE