MXPA99008872A - Nitro-benzamide useful as anti-arrhythmic agent - Google Patents

Abstract

Hydrated N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride characterised in that it:(i) comprises water in the range of from 1.7 to 2.4 molar equivalents;and/or (ii) has a melting point above 145°C and/or, (iii) provides an infra red spectrum containing peaks at 3510, 3342, 3076, 1665, 1598, 1343, 1330, 1216 and 801 cm-1;and/or (iv) provides a solid state nuclear magnetic resonance spectrum containing chemical shifts substantially as represented in Table I;and/or (v) provides an X-ray powder refraction (XRPD) pattern substantially as represented in Table II;a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

Description

USEFUL NITROBENZAMIDE AS ANTIARRHYTHMIC AGENT DESCRIPTIVE MEMORY This invention relates to a novel pharmaceutical composition, to a process for the preparation of the pharmaceutical composition and to the use of the pharmaceutical composition in medicine. The international patent application, publication number WO 96/13479 describes certain compounds of the formula (A): (TO) or a salt thereof, or a solvate thereof, characterized in that: Ar represents substituted or unsubstituted aryl, wherein optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms, any of the two substituents together with the carbon atoms to which they are attached can form a fused hererocyclic ring of five to six atoms wherein one, two or three of the atoms are oxygen or nitrogen; A represents a n-alkylene group of C1-, wherein each carbon is optionally substituted with 1 or 2 Ci-e alkyl groups; R1 represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of R2, R3 and R4 represents nitro; the remaining elements of the group of R2, R3 and 4 represent hydrogen; X represents a portion of -CO-NH-; and Z represents a n-alkylene group of C 2-4, wherein each carbon is optionally substituted with 1 or 2 C 1-6 alkyl groups. Example 2 of WO 96/13479 is the unsolvated hydrochloride salt, N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino]? Ro? Il] -4-nitrobenzamide hydrochloride (hereinafter also referred to as "the hydrochloride"), whose melting point described is 141-2 ° C. It has now been discovered that N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide hydrochloride exists in a novel hydrated form, the form of which is particularly suitable for the handling and the bulk preparation and also indicates that it has superior formulation properties. This novel hydrated form can be prepared by an efficient, economical and reproducible process, in particular suitable for a large-scale preparation. Also, the novel form has useful pharmaceutical properties and is considered a useful antiarrhythmic agent that combines class 11 I / class IV antiarrhythmic properties, thus showing an improved pharmacological profile over pure class III antiarrhythmic agents, in particular showing a low proarrhythmic potential , which easily restores the contractile function of ischemic myocardium. It is considered useful in particular for the treatment of atrial or ventricular cardiac arrhythmias.

Thus, the present invention provides N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide hydrochloride hydrate (hereinafter also referred to as compound (I) ' ), characterized in that: (i) it comprises water in the range of 1.7 to 2.4 molar equivalents; and / or (i) has a melting point above 145 ° C and / or (iii) provides an infrared spectrum containing peaks at 3510, 3342, 3076, 1665, 1598, 1343, 1330, 1216 and 801 crr ?1; and / or (iv) provides a solid-state nuclear magnetic resonance spectrum that contains chemical shifts basically as depicted in Table I; and / or (v) provides a powder X-ray refractive diagram (XRPD, for its acronym in English) substantially as depicted in table II. Suitably, the compound (I) comprises from 1.8 to 2.3 or 1. 9 to 2.1 molar equivalents of water, especially 2.0 molar equivalents. Suitably, the melting point of compound (I) is in the range of 150 ° C to 154 ° C, for example 150 ° C, 151 ° C, 152 ° C, 153 ° C and 154 ° C. In another aspect, compound (I) provides an infrared spectrum containing peaks at 3510, 3342, 3307, 3076, 1665, 1632, 1598, 1548, 1520, 1343, 1330, 1310, 1267, 1240, 1216, 1162, 1147 , 1119, 1105, 1048, 1036, 1025, 981, 921, 891, 873, 854, 801, 767, 720, 626, 573, 553 and 500 crt? 1.

Suitably, the compound (I) provides an infrared spectrum basically as illustrated in Figure (I). Suitably compound (I) provides a solid-state nuclear magnetic resonance spectrum containing chemical shifts substantially as depicted in Table I. Suitably, compound (I) provides a X-ray powder refractive diagram (XRPD) substantially as depicted in Table II. The present invention encompasses the compound (I) isolated in pure form or when mixed with other materials, for example the known anhydrous form of the hydrochloride or any other material. Preferably, the compound (I) is in a crystalline form. Also, the invention provides a process for the preparation of N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide hydrate hydrochloride, characterized in that N- [3] hydrochloride - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide is hydrated in the presence of the required amount of water. Suitable hydration methods include conventional hydration methods such as crystallization, including recrystallization, of the hydrochloride from water or an aqueous solvent. A suitable aqueous solvent is an aqueous organic solvent, such as an aqueous alkanol, for example aqueous methanol, aqueous ethanol and aqueous propanol, or aqueous tetrahydrofuran or aqueous acetone, and mixtures thereof. Suitable aqueous solvents contain up to 15% water by volume, preferably 2.5% to 10% by volume. In general, crystallization and any recrystallization is carried out from low temperature to room temperature, properly at room temperature. Preferably, crystallization is initiated by sowing with crystals of the hydrated form, but this is not essential. Conveniently, the crystallization is effected by allowing the aqueous solvent to cool from an elevated temperature, which temperature of course depends on the nature of the solvent, an example being a temperature in the range of 50 ° C to 100 ° C. In a preferred embodiment of the process, the compound (I) is prepared from a solution of hydrochloride in aqueous ethanol at an elevated temperature, such as 60 ° C, allowing the product to crystallize on cooling and subsequently, if necessary, The product is recrystallized from an appropriate aqueous solvent, usually aqueous ethanol. The purification of the compound (I) is also carried out suitably by recrystallization of the inpuro compound (I) using this last mentioned procedure. In an alternative hydration, the hydrochloride is hydrated in an atmosphere of water vapor, at room temperature or, preferably, at an elevated temperature, for example 40 ° C, until compound (I) is formed; for convenience, hydration is continued until constant weight is achieved. In a subsequent hydration, N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide hydrate hydrochloride is prepared in situ in an aqueous solvent and then allowed to crystallize as described. described earlier. The hydrochloride is prepared according to known procedures, such as those described in WO 96/13479. The descriptions of WO 96/13479 are incorporated herein by reference. As used herein, "aqueous solvent" includes simple organic solvents or mixtures of organic solvents that contain enough water to provide a product with 1.7 to 2.4 molar equivalents of water ("the required level" or "the required amount" of water); usually, the present water level exceeds the required level. As used herein, the term "cardiac arrhythmia" refers to any variation of the normal cardiac rhythm, including without limitation, breast arrhythmia, premature palpitation, heart block, fibrillation, flutter, tachycardia, paroxysmal tachycardia, and premature ventricular contractions. As mentioned above, the compound of the invention has useful therapeutic properties; therefore, the present invention provides the compound (I) for use as an active therapeutic substance.

More specifically, the present invention provides a compound (I) for use in the treatment and / or prophylaxis of arrhythmia, especially cardiac arrhythmia, such as ventricular arrhythmia and also ischemic rhythm disorders. The compound (I) can be administered per se or preferably as a pharmaceutical composition also comprising a pharmaceutical acceptor vehicle. Therefore, the present invention also provides a pharmaceutical composition comprising the compound (I) and a pharmaceutical acceptor vehicle therefor. Usually, the compound (I) is administered in unit dosage form. An amount effective to treat the disorder described hereinbefore depends on such factors as the efficacy of a compound (I) chosen, the nature and severity of the disorders being treated and the weight of the mammal; however, a unit dose will usually contain 0.1 to 500 mg, for example 2 to 50 mg, of the compound of the invention. Usually, the unit dose will be administered once or more times a day, for example 2, 3, 4, 5 or 6 times a day, more often 2 to 4 times a day, so that the daily dose total is usually in the range of 0.1 to 2500 mg for an adult of 70 kg, more often 1 to 1000 mg, for example 1 to 200 mg, which is on the scale of approximately 0.02 to 3 mg / kg / day, more often 0.1 to 3 mg / kg / day, for example 0.15 to 2 mg / kg / day.

In the dose scale described above, no toxicological effect is indicated for the compounds of the invention. In such treatment, the active compound can be administered by any suitable route, for example, orally, parenterally or topically. For such use, the compound will usually be used in the form of a pharmaceutical composition together with a human or veterinary pharmaceutical carrier, diluent and / or excipient, although the exact form of the composition will of course depend on the mode of administration. The compositions are prepared by mixing and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, troches, lozenges, restorative powders, injectable solutions or suspensions. and in infusion, suppositories and transdermal media. Oral administration compositions are preferred, in particular compositions suitable for the oral route, since they are more convenient for general use. Commonly, tablets and capsules for oral administration are presented in a unit dose, and contain conventional excipients, such as binding agents, fillers, diluents, tablet-forming agents, lubricants, disintegrants, colorants, flavors and wetting agents. The tablets may be coated according to methods known in the art.

Suitable fillers that are employed include cellulose, mannitol, lactose, lactose and other similar agents; suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate; suitable lubricants include, for example, magnesium stearate; Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate. Solid oral compositions can be prepared by conventional mixing methods, filling, tabletting or the like. The repeated mixing operations can be used to distribute the active agent in those compositions employing large amounts of fillers. Said operations are of course conventional in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monoleate or acacia, non-aqueous vehicles (which may include edible oils) for example, almond oil, fractionated coconut oil, oily esters, such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents. For parenteral administration, unit dose forms of fluids are prepared when they contain a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and concentration, can be suspended or dissolved. Typically, parenteral solutions are prepared by dissolving the active compound in a vehicle and sterilizing with a filter before filling a suitable vial or ampoule and sealing them. Conveniently, adjuvants, such as a local anesthetic preservatives and pH stabilizing agents also dissolve in the vehicle. To improve stability, the composition can be frozen after being introduced into the bottle and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the active compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide, before suspending it in the sterile vehicle. Conveniently, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound. For topical administration, the composition may be in the form of a transdermal ointment or patch for the systematic release of the compound and may be prepared in a conventional manner, for example, as described in standard textbooks, such as Dermatological! Formulations - B.W. Barry (Drugs and the Pharmaceuticai Sciences - Dekker) or Harry Cosmetic / ogy (Leonard Hill Books). In addition, said compositions may contain other active agents, such as anti-hypertensive agents and diuretics. As is common in the art, compositions will usually be accompanied by printed or written instructions for use for the medical treatment in question. As used herein, the term "pharmaceutical acceptance" encompasses compounds, compositions and ingredients for veterinary and human use, for example, the term "pharmaceutical acceptance salt" encompasses a salt of veterinary acceptance. In addition, the present invention provides a method for the treatment and / or prophylaxis of arrhythmia, especially cardiac arrhythmia, such as ventricular arrhythmia and also ischemic rhythm disorders in a human or non-human mammal; which comprises administering a non-toxic effective amount of compound 1 to a human or non-human mammal in need thereof. For convenience, the active ingredient can be administered as a pharmaceutical composition already defined above and this forms a particular aspect of the present invention. In the treatment and / or prophylaxis of arrhythmia and / or ischemic arrhythmia disorders, the compound (I) can be ingested in doses as described above.

Similar dose regimens are suitable for the treatment and / or prophylaxis of non-human mammals. In another aspect, the present invention provides the use of the compound (I) for the manufacture of a medicament for the treatment of arrhythmia, especially cardiac arrhythmia, such as ventricular arrhythmia and also ischemic rhythm disorders. No adverse toxicological effect is indicated when compound (I) is administered at the dose scales mentioned above. The following examples illustrate the invention, but do not limit it in any way.

EXAMPLE 1 Preparation of hydrated N-r3-rr2- (3,4-dimethoxyphenyl) ethylamino-1-propyl-nitrobenzamide hydrochloride A solution of 9: 1 ethanol.water (v / v) (7.5 liters) was added to N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide hydrochloride ( 2.44 kg, 4.86 moles). Then, the stirred suspension was heated to 60 ° C to give a clear solution; this solution was filtered hot, then cooled to 30 ° C in a water bath; a small sample was removed and scraped to induce crystallization. The crystals were added to the bulk solution and allowed to stir and crystallize overnight at room temperature. The resulting suspension was cooled in an ice bath for 2 hours. The solid product was filtered, washed with 9: 1 ethanol: water (v / v) (1.5 liters), then with ethanol (750 ml) and dried in a vacuum oven equipped with a filtered air vent at 30- 33 ° C to constant weight to give the title product as a yellow solid.

EXAMPLE 2 Preparation of hydrated N-r3-rr2- (3,4-dimethoxyphenol) ethylamino-1-propyl-4-nitrobenzamide hydrochloride A homo that contained trays of cotton wool saturated with water was preheated to 40 ° C. N- (3 - ((2- (3,4-dimethoxyphenyl) ethyl] amino) propyl) -4-nitrobenzamide hydrochloride (100 g) was placed in a partially covered tray in the oven and allowed to hydrate at 40 ° C. C. When the product achieved constant weight, it was removed from the oven and exposed to the atmosphere to equilibrate to room temperature to give 109.1 g of the title compound as a yellow solid.

EXAMPLE 3 Preparation of hydrated N-r3-rr2-f3,4-dimethoxyphenyl) etipamino-1-propyne-4-nitrobenzamide hydrochloride N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide hydrochloride (100 g) was suspended in industrial methyl alcohols (IMS) (300 mi) and water (34 mi). The mixture was heated to produce a solution; The hot solution was cooled to room temperature in a water bath for 30 minutes. The resulting suspension was stirred at room temperature overnight, then cooled in an ice bath for 1.5 hours. The solid product was filtered and washed with IMS (100 ml) and exposed to the atmosphere to equilibrate at room temperature to give 104.2 g of the title product as a yellow solid.

EXAMPLE 4 Preparation of hydrated N-r3-rr2-f3,4-dimethoxyphenyl) ethylamino-1-propyl-4-nitrobenzamide hydrochloride A solution of N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide (211 g) in tetrahydrofuran (THF, 650 ml) was stirred at room temperature; concentrated hydrochloric acid (62 ml) was added. The reaction temperature reached 50 ° C. The mixture was cooled in an ice bath at 25 ° C, then stirred at room temperature overnight. The suspension was cooled in an ice bath for 2 hours, the crystalline product was filtered, washed with THF (250 ml) and exposed to the atmosphere to equilibrate to room temperature to produce the title compound as a yellow solid.

SPECTROSCOPIC DATA OF HYDROCHLORIDE N-r3-rf2- (3,4-PIMETOXIFEN1HETIL1AM1NO1PROPIL1-4-NITROBENZAMIPA HYDRATED (A) 13C solid-state nuclear magnetic resonance (NMR) The chemical shifts of the 13C CP-MAS NMR spectrum at 90.55 MHz are shown in Table I. The samples were packed with minimal grinding in a rotating zirconia rotor. Magical angle (MAS) of 4 mm equipped with a Kel-F cap, using sufficient material (ca 50 mg) to fill the rotor shortly before the space of the lid. No further preparation of samples was required. The spectra were performed at room temperature on an AMX360 instrument at a frequency with MAS of 10 kHz; the spectra were obtained by cross-polarization (CP) from the Hartmann-Hahn balanced protons in a 50 kHz field. The contact time of the CP was 1.6 ms, and the repetition time was 15s. The protons were uncoupled in an 80 kHz field during acquisition by using a sequence of 2-pulse phase modulated mixed material (TPPM) (150 ° strike angle, 7th phase alternation). The chemical shifts made external reference to the carboxylate signal of a glycine test sample at 176.4 ppm relative to TMS and prove to be accurate within +/- 0.5 ppm.

TABLE I Chemical shifts C13 (ppm) 28. 8 32.0 38.1 49.9 52.3 56.0 56.8 109.9 11.2 123.6 128.8 129.8 131.7 139.3 147.0 149.5 166.2 (B X-ray powder diffraction (XRPD) A summary of the XRPD angles characteristic of compound (I) is shown in Table 2. A powder X-ray diffractometer PW1710 (X-Cu source) was used. to generate the spectrum using the following acquisition conditions: Cu anode tube Generator voltage 40 kV Generator voltage 30 mA Start angle 3.5 ° 20 Final angle 35.0 ° 20 Step size 0.005 Time per step 0.25 s TABLE II XRPD diffraction angles Diffraction Angle (° 20) 12.78 14,675 16,070 17,765 21,185 23,875 25,430 25,885 26,370 27,020 27,455 29,320 (C) Infrared spectrum The infrared absorption spectrum of a mineral oil dispersion of compound (I) was obtained using a 2000 FT-IR spectrometer from Perkin-Elme at a resolution of 2 cm "1. The data were digitized at intervals of 0.5 cm "1. The spectrum appears in figure (I).

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4- nitrobenzamide hydrated hydrate, characterized in that: (i) it comprises water in the range of 1.7 to 2.4 molar equivalents; and / or (ii) has a fusion point per enzyme of 145 ° C and / or (ii) provides an infrared spectrum containing peaks at 3510, 3342, 3076, 1665, 1598, 1343, 1330, 1216 and 801 cm "1; and / or (iv) provides a solid-state nuclear magnetic resonance spectrum that contains chemical shifts basically as depicted in Table I, and / or (v) provides a powder X-ray refractive diagram (XRPD). ) - Substantially as shown in Table II

2. A compound according to claim 1, further characterized in that it comprises from 1.8 to 2.3 t 1.9 to 2.1 molar equivalents of water

3. A compound according to claim 1 or '2, further characterized in that it comprises 2.0 molar equivalents

4. A compound according to one of claims 1 to 3, further characterized in that it has a melting point on the scale of 150 ° C to 154 ° C.

5. - A compound according to any of claims 1 to 4, further characterized by having a melting point of 150 ° C, 151 ° C, 152 ° C, 153 ° C or 154 ° C.

6. A compound according to any of claims 1 to 5, further characterized by providing an infrared spectrum containing peaks at 3510, 3342, 3307, 3076, 1665, 1632, 1598, 1548, 1520, 1343, 1330, 1310 , 1267, 1240, 1216, 1162, 1147, 1119, 1105, 1048, 1036, 1025, 981, 921, 891, 873, 854, 801, 767, 720, 626, 573, 553 and 500 cm "1. - A compound according to any of claims 1 to 6, further characterized in that it provides an infrared spectrum basically as illustrated in Figure I. 8.- A process for preparing N- [3 - [[2- (3-hydrochloride , 4-dimethoxyphenyl] amino] propyl] -4-nitrobenzamide hydrate, according to claim 1, further characterized in that N- [3 - [[2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] hydrochloride] -4-Nitrobenzamide is hydrated in the presence of the necessary amount of water 9. A process according to claim 8, further characterized in that the hydrochloride is crystallized or recrystallizes from water or an aqueous solvent. 10. A pharmaceutical composition comprising the compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, and a pharmaceutical acceptance vehicle. 11. The compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, further characterized by being used as an active therapeutic substance. 12. The compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, further characterized in that it is used in the treatment and / or prophylaxis of arrhythmia and disorders. of ischemic rhythm. 13. The use of the compound (I) according to claim 1 or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia and rhythm disorders. ischemic