EP1218335A1 - Hydrated n-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride and it's use in pharmaceutical compositions - Google Patents

Hydrated n-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride and it's use in pharmaceutical compositions

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Publication number
EP1218335A1
EP1218335A1 EP00966293A EP00966293A EP1218335A1 EP 1218335 A1 EP1218335 A1 EP 1218335A1 EP 00966293 A EP00966293 A EP 00966293A EP 00966293 A EP00966293 A EP 00966293A EP 1218335 A1 EP1218335 A1 EP 1218335A1
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EP
European Patent Office
Prior art keywords
ethyl
propyl
dimethoxyphenyl
amino
hydrochloride
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.)
Withdrawn
Application number
EP00966293A
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German (de)
French (fr)
Inventor
Ian Robert Smithkline Beecham Pharmaceutic LYNCH
Graham Ralph SmithKline Beecham Pharmaceu SLATER
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1218335A1 publication Critical patent/EP1218335A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms any two substituents together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are 15 oxygen or nitrogen;
  • A represents a Ci .4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C1 _6 alkyl groups;
  • R represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of R2, 3 and R4 represents nitro the remaining members of the 20 group of R_2, R3 and R4 represent hydrogen;
  • X represents a -CO-NH- moiety
  • Z represents C2.4 n-alkylene group wherein each carbon is optionally substituted by 1 or
  • Example 2 of WO 96/13479 is the non-solvated hydrochloride salt, N-[3-[[2-(3,4- 25 dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride (hereinafter also referred to as 'the Hydrochloride 1 ), the disclosed melting point of which is 141-2°C.
  • N-[3-[[2-(3,4- 30 dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride exists in a novel hydrated form which form is particularly suitable for bulk preparation and handling and is also indicated to have superior formulation properties.
  • This novel hydrated form can be prepared by an efficient, economic and reproducible process particularly suited to large scale preparation.
  • the novel form also has useful pharmaceutical properties and is considered to be a useful anti-arrhythmic agent having combined Class Ill/Class IN anti-arrhythmic properties, therefore showing an improved pharmacological profile over pure class III anti-arrhythmic agents, in particular showing a low proarrhythmic potential, readily .restoring the contractile function of the ischaemic myocardium.
  • the present invention provides hydrated N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride (hereinafter also referred to as 'Compound (I)') characterised in that it:
  • Compound (I) comprises from 1.8 to 2.3 or 1.9 to 2.1 molar equivalents of water, especially 2.0 molar equivalents.
  • the present invention encompasses Compound (I) isolated in a purified form or in an impure form, such as when admixed with other materials, for example the known form of the Hydrochloride or any other material.
  • Compound (I) is in a puried form, especially a crystalline form.
  • the invention also provides a process for preparing hydrated N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride, characterised in that N- [3 - [[2-(3 ,4-dimethoxypheny l)ethyl] aminojpropyl] -4-nitrobenzamide hydrochloride is hydrated in the presence of a molar excess of water.
  • Suitable hydration methods include conventional hydration methods such as crystallisation, including recrystallisation, particularly via rapid cooling, of the Hydrochloride from water or an aqueous solvent.
  • a suitable aqueous solvent is an aqueous organic solvent such as an aqueous ethanol, for example a 9:1 mixture by volume of ethanol and water.
  • Crystallisation and any recrystallisation is generally carried out at low to ambient temperature, suitably at ambient temperature.
  • the crystallisation and any recrystallisation is carried out by rapid cooling.
  • the crystallisation or recrystallisation is carried out by cooling of the aqueous ethanolic solution of the Hydrochloride, for example by immersing the solution in an ice-bath.
  • the aqueous ethanol solution is prepared by dissolving the Hydrochloride in the aqueous ethanol at an elevated temperature, for example at the reflux temperature of the solvent.
  • Compound (I) is prepared from a solution of the Hydrochloride in aqueous ethanol at an elevated temperature such as 60°C, Compound (I) is then formed by cooling.
  • the Hydrochloride is prepared according to known procedures such as those disclosed in WO 96/13479. The disclosures of WO 96/13479 are incorporated herein by reference.
  • 'aqueous solvent' includes single organic solvents or mixtures of organic solvents which contain sufficient water to provide product with 1.7 to 2.4, especially 1.8 to 2.3 or 1.9 to 2.1 and preferably 2.0, molar equivalents of water ('the required level' or 'the required amount' of water); usually, the level of water present is in excess of the required level.
  • cardiac arrhythmia relates to any variation from the normal rhythm of heart beat, including, without limitation, sinus arrhythmia, premature heartbeat, heartblock, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.
  • the present invention accordingly provides Compound (I) for use as an active therapeutic substance.
  • the present invention provides a Compound (I) for use in the treatment of and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders.
  • Compound (I) may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound (I) and a pharmaceutically acceptable carrier therefor.
  • Compound (I) is normally administered in unit dosage form.
  • An amount effective to treat the disorder hereinbefore described depends upon 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.
  • a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention.
  • Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 1 to 1000 mg, for example 1 to 200 mg, that is in the range of approximately 0.02 to 3 mg/kg/day, more usually 0.1 to 3 mg/kg/day, for example 0.15 to 2 mg/kg/day.
  • the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes.
  • the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
  • compositions are prepared by admixture 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, granules, lozenges, pastilles, reconstitutable powders, i ⁇ jectable and infusable solutions or suspensions, suppositories and transdermal devices.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such 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 may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial 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 sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • the composition may be in the form of a transdermal ointment or patch for systemic delivery of the compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as
  • compositions may contain further active agents such as anti-hypertensive agents and diuretics.
  • active agents such as anti-hypertensive agents and diuretics.
  • the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the term 'pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • the present invention further provides a method for the treatment and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-toxic, amount of Compound (I) to a human or non-human mammal in need thereof.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • Compound (I) may be taken in doses, such as those described above. Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals.
  • the present invention provides the use of Compound (I) for the manufacture of a medicament for the treatment of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders. No adverse toxicological effects are indicated when Compound (I) is administered in the above mentioned dosage ranges.
  • Step size 0.020 °2 ⁇
  • the infrared absorption spectrum of a mineral oil dispersion of compound (I) was obtained using a Perkin-Elmer PE2000 FTIR spectrometer at 2 cm" 1 resolution.

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Abstract

A hydrated form of N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride, a process for preparing such a compound and the use of such a compound in medicine.

Description

HYDRATED N-[3-[[2-(3,4-DIMETHOXYPHENYL) ETHYL] AMINO] PROPYL] -4-NITRO BENZAMIDE HYDROCHLORIDE AND ITS USE IN PHARMACEUTICAL COMPOSITIONS
This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine. 5 International Patent Application, Publication Number WO 96/13479 discloses certain compounds of formula (A):
(A) 10 or a salt thereof, or a solvate thereof, characterised in that:
Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms any two substituents together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are 15 oxygen or nitrogen;
A represents a Ci .4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C1 _6 alkyl groups;
R represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of R2, 3 and R4 represents nitro the remaining members of the 20 group of R_2, R3 and R4 represent hydrogen;
X represents a -CO-NH- moiety; and
Z represents C2.4 n-alkylene group wherein each carbon is optionally substituted by 1 or
2 Cι _6 alkyl groups.
Example 2 of WO 96/13479 is the non-solvated hydrochloride salt, N-[3-[[2-(3,4- 25 dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride (hereinafter also referred to as 'the Hydrochloride1), the disclosed melting point of which is 141-2°C.
International Patent Application, Publication Number WO 98/43947 discloses a hydrated form of the Hydrochloride.
It has now been discovered that N-[3-[[2-(3,4- 30 dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride exists in a novel hydrated form which form is particularly suitable for bulk preparation and handling and is also indicated to have superior formulation properties. This novel hydrated form can be prepared by an efficient, economic and reproducible process particularly suited to large scale preparation. 35 The novel form also has useful pharmaceutical properties and is considered to be a useful anti-arrhythmic agent having combined Class Ill/Class IN anti-arrhythmic properties, therefore showing an improved pharmacological profile over pure class III anti-arrhythmic agents, in particular showing a low proarrhythmic potential, readily .restoring the contractile function of the ischaemic myocardium. It is considered to be particularly useful for the treatment of atrial or ventricular cardiac arrhythmias. Accordingly, the present invention provides hydrated N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride (hereinafter also referred to as 'Compound (I)') characterised in that it:
(i) provides a solid state nuclear magnetic resonance spectrum containing chemical shifts substantially as represented in Table I; and/or (ii) provides an X-ray powder refraction (XRPD) pattern substantially as represented in Table II; and/or (iii) provides an infra red spectrum substantially as illustrated in Figure (I).
Suitably, Compound (I) comprises from 1.8 to 2.3 or 1.9 to 2.1 molar equivalents of water, especially 2.0 molar equivalents. The present invention encompasses Compound (I) isolated in a purified form or in an impure form, such as when admixed with other materials, for example the known form of the Hydrochloride or any other material.
Preferably, Compound (I) is in a puried form, especially a crystalline form. The invention also provides a process for preparing hydrated N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride, characterised in that N- [3 - [[2-(3 ,4-dimethoxypheny l)ethyl] aminojpropyl] -4-nitrobenzamide hydrochloride is hydrated in the presence of a molar excess of water.
Suitable hydration methods include conventional hydration methods such as crystallisation, including recrystallisation, particularly via rapid cooling, of the Hydrochloride from water or an aqueous solvent.
A suitable aqueous solvent is an aqueous organic solvent such as an aqueous ethanol, for example a 9:1 mixture by volume of ethanol and water.
Crystallisation and any recrystallisation is generally carried out at low to ambient temperature, suitably at ambient temperature. In particular, the crystallisation and any recrystallisation is carried out by rapid cooling.
Preferably the crystallisation or recrystallisation is carried out by cooling of the aqueous ethanolic solution of the Hydrochloride, for example by immersing the solution in an ice-bath. Usually the aqueous ethanol solution is prepared by dissolving the Hydrochloride in the aqueous ethanol at an elevated temperature, for example at the reflux temperature of the solvent.
In a preferred form of the process, Compound (I) is prepared from a solution of the Hydrochloride in aqueous ethanol at an elevated temperature such as 60°C, Compound (I) is then formed by cooling. The Hydrochloride is prepared according to known procedures such as those disclosed in WO 96/13479. The disclosures of WO 96/13479 are incorporated herein by reference.
As used herein 'aqueous solvent' includes single organic solvents or mixtures of organic solvents which contain sufficient water to provide product with 1.7 to 2.4, especially 1.8 to 2.3 or 1.9 to 2.1 and preferably 2.0, molar equivalents of water ('the required level' or 'the required amount' of water); usually, the level of water present is in excess of the required level.
As used herein, the term "cardiac arrhythmia" relates to any variation from the normal rhythm of heart beat, including, without limitation, sinus arrhythmia, premature heartbeat, heartblock, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.
As mentioned above the compound of the invention has useful therapeutic properties: The present invention accordingly provides Compound (I) for use as an active therapeutic substance.
More particularly, the present invention provides a Compound (I) for use in the treatment of and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders.
Compound (I) may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
Accordingly, the present invention also provides a pharmaceutical composition comprising Compound (I) and a pharmaceutically acceptable carrier therefor. Compound (I) is normally administered in unit dosage form. An amount effective to treat the disorder hereinbefore described depends upon 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 normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention. Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 1 to 1000 mg, for example 1 to 200 mg, that is in the range of approximately 0.02 to 3 mg/kg/day, more usually 0.1 to 3 mg/kg/day, for example 0.15 to 2 mg/kg/day.
At the above described dosage range, no toxicological effects are indicated for the compounds of the invention. In such treatment, the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
Compositions are prepared by admixture 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, granules, lozenges, pastilles, reconstitutable powders, iηjectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such 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 may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial 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 sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, 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 systemic delivery of the compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as
'Dermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).
In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics. As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
As used herein the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt. The present invention further provides a method for the treatment and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-toxic, amount of Compound (I) to a human or non-human mammal in need thereof. Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
In the treatment and/or prophylaxis of arrhythmia and/or ischaemic arrhythmia disorders Compound (I) may be taken in doses, such as those described above. Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals.
In a further aspect the present invention provides the use of Compound (I) for the manufacture of a medicament for the treatment of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders. No adverse toxicological effects are indicated when Compound (I) is administered in the above mentioned dosage ranges.
The following Examples illustrate the invention but do not limit it in any way. Example 1
Preparation of N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4- nitrobenzamide, hydrochloride hydrate (Compound (I))
The Hydrochloride was prepared as disclosed in Example 2 of WO 96/13479
The Hydrochloride was then dissolved in aqueous ethanol (90% ethanol, 10% water by volume, 6.5ml) at reflux. The resulting solution was then immersed in an ice/water bath to initiate crystallisation. The solution was stirred overnight and allowed to warm to ambient temperature. The mixture was then cooled in iced water for 1-4 hours to complete crystallisation. The pale yellow product was isolated by filtration, washed with aqueous ethanol (90% ethanol, 10% water by volume, 2.5 ml) then ethanol (2.5ml) and dried at ambient temperature to provide 1.84 of Compound (I).
SPECTROSCOPIC DATA
(A) Solid State NMR
The 90.55MHz 13C CP-MAS NMR spectrum chemical shifts are tabulated in Table I. Data were recorded at ambient temperature and 10 kHz spinning frequency, on a Bruker AMX360WB spectrometer.
Table I
Cl3 Chemical shifts (ppm)
23.3 33.0 39.0 47.7 51.0 56.9 110.6 11 1.3 122.5
123.9 128.0 129.3 135.9 148.2 166.0
(B) X-Ray Powder Diffraction (XRPD)
A summary of the XRPD angles characteristic of the Compound I is given in Table II A PW1710 X-ray powder diffractometer (Cu X-ray source) was used to generate the spectrum using the following acquisition conditions:
Tube anode: Cu
Generator tension: 40 kV
Generator current: 30 mA
Start angle: 3.5 °2Θ
End angle: 35.0 °2Θ
Step size: 0.020 °2Θ
Time per step: 2.3 s
Table II
XRPD Diffraction Angles
Diffraction Angle (°2Θ) 10.5 11.9 13.1 13.6 14.2 15.8 16.2 16.9 19.3 19.6 21.0 21.3 22.1 23.2 23.6 24.4 25.0 25.8 26.3 27.3 27.8 28.2 28.9 29.4 29.7 30.6 31.4 32.9 (C) Infra Red spectrum
The infrared absorption spectrum of a mineral oil dispersion of compound (I) was obtained using a Perkin-Elmer PE2000 FTIR spectrometer at 2 cm"1 resolution.
Figure (I)
4000.0 3000 2000 1500 1000 450.0 cm-1

Claims

1. Hydrated N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride characterised in that it:
(i) provides a solid state nuclear magnetic resonance spectrum containing chemical shifts substantially as represented in Table I; and/or
(ii) provides an X-ray powder refraction (XRPD) pattern substantially as represented in Table II; and/or
(iii) provides an infra red spectrum substantially as illustrated in Figure (I).
2. A hydrate according to claim 1, comprising from 1.8 to 2.3 or 1.9 to 2.1 molar equivalents of water.
3 A hydrate according to claim 1 or claim 2, comprising 2.0 molar equivalents of water.
4 A hydrate according to any one of claims 1 to 3, in pure form or in impure form,
5. A process for preparing hydrated dimethoxyphenyl)ethyl]amino]propyl]-4- nitrobenzamide hydrochloride, characterised in that N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride is hydrated in the presence of a molar excess of water.
6. A process according to claim 5, wherein the hydration is earned out by crystallisation of the Hydrochloride from water or an aqueous solvent.
7. A process according to claim 6, wherein the aqueous solvent is a 9: 1 mixture by volume of ethanol and water.
8. A process according to claim 5, wherein the hydrate is prepared by cooling a solution of dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride in aqueous ethanol at an elevated temperature.
9. A pharmaceutical composition comprising the hydrate according to claim 1 and a pharmaceutically acceptable carrier therefor.
10. The present invention accordingly provides the hydrate according to claim 1, for use as an active therapeutic substance.
11. The hydrate according to claim 1, for use in the treatment of and/or prophylaxis of cardiac arrhythmia or ischaemic rhythm disorders.
12. A method for the treatment and/or prophylaxis of cardiac arrhythmia or ischaemic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the hydrate according to claim 1, to a human or non-human mammal in need thereof.
13. A use of the hydrate according to claim 1, for the manufacture of a medicament for the treatment of cardiac arrhythmia or ischaemic rhythm disorders.
EP00966293A 1999-10-08 2000-10-06 Hydrated n-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide hydrochloride and it's use in pharmaceutical compositions Withdrawn EP1218335A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9923934.5A GB9923934D0 (en) 1999-10-08 1999-10-08 Novel pharmaceutical
GB9923934 1999-10-08
PCT/GB2000/003862 WO2001027072A1 (en) 1999-10-08 2000-10-06 Hydrated n-[3-[[2-(3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitro benzamide hydrochloride and its use in pharmaceutical compositions

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EP1218335A1 true EP1218335A1 (en) 2002-07-03

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EP (1) EP1218335A1 (en)
JP (1) JP2003511438A (en)
AU (1) AU7673800A (en)
GB (1) GB9923934D0 (en)
WO (1) WO2001027072A1 (en)

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Publication number Priority date Publication date Assignee Title
EP1469827B1 (en) * 2002-01-09 2017-12-27 Emisphere Technologies, Inc. Polymorphs of sodium 4- (4-chloro-2-hydroxybenzoyl)amino butanoate

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Publication number Priority date Publication date Assignee Title
FR2726267B1 (en) * 1994-10-26 1998-01-02 Smithkline Beecham Lab NOVEL ARRHYTHMIC AGENTS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR PREPARING THEM
GB9706376D0 (en) * 1997-03-27 1997-05-14 Smithkline Beecham Plc Novel pharmaceutical

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Title
See references of WO0127072A1 *

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AU7673800A (en) 2001-04-23
JP2003511438A (en) 2003-03-25
WO2001027072A1 (en) 2001-04-19
GB9923934D0 (en) 1999-12-08

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