[go: up one dir, main page]

WO2002102788A1 - Sels cristallins de derives de benzoylbenzofurane - Google Patents

Sels cristallins de derives de benzoylbenzofurane Download PDF

Info

Publication number
WO2002102788A1
WO2002102788A1 PCT/EP2002/006417 EP0206417W WO02102788A1 WO 2002102788 A1 WO2002102788 A1 WO 2002102788A1 EP 0206417 W EP0206417 W EP 0206417W WO 02102788 A1 WO02102788 A1 WO 02102788A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
crystalline compound
compound according
alkyl
crystalline
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.)
Ceased
Application number
PCT/EP2002/006417
Other languages
German (de)
English (en)
Inventor
Claus Meese
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UCB Pharma GmbH
Original Assignee
Schwarz Pharma AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schwarz Pharma AG filed Critical Schwarz Pharma AG
Publication of WO2002102788A1 publication Critical patent/WO2002102788A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • CHF Congestive heart failure
  • Class III agents are currently the drug of choice for the treatment of arrhythmias in drug therapy (Yap, Am. J. Cardiol. 84 (1999) 83 R). These drugs are characterized by the fact that they extend the action potential and thereby the repolarization time, primarily by blocking the potassium channel, without adversely affecting the excitation conduction.
  • Class III drug is currently amiodarone (2-butyl-3-benzofuranyl 4- [2- (diethylamino) ethoxy] -3,5-diiodophenyl ketone) (Singh, Am. J. Cardiol 84 (1999) 103 R).
  • Amiodarone is an effective antiarrhythmic drug with a complex spectrum of pharmacological effects.
  • class I Na + channel
  • class II ⁇ -receptor
  • class IV Ca 2+ channel
  • amiodarone is still the most commonly prescribed antiarrhythmic drug.
  • the main cause of the toxic effects associated with amiodarone is primarily the long residence time in the organism, which leads to the accumulation of amiodarone and its active metabolites in the organism during therapy.
  • European patent EP B 703 910 describes a class of new compounds with a shorter half-life, which have a cleavable ester bond and which are rapidly cleaved in vivo to a pharmacologically inactive metabolite. This eliminates the serious side effects associated with the long half-life of amiodarone and its metabolites for this class of compounds.
  • the advantages of this so-called “soft drug” concept are also discussed by Juhasz and Bodor (Pharmazie 55 (2000) 3) and Raatikainen et al (J Pharmacol Exp Ther 295 (2000) 779).
  • a disadvantage of the compounds disclosed in EP B 703 910 is the fact that the compounds disclosed are only in the form of amorphous salts. On closer inspection, the disclosed hydrochloride salts are found to be thermally labile. In addition, the production process for these amorphous salts described in EP 703 910 can only be insufficiently scaled up on an industrial scale, since, owing to the low initial purity of the amorphous salts produced, they require further, complex cleaning - steps required.
  • ATI- (S) -2042 and ATI- (R) -2055 are particularly preferred.
  • the sulfate salts disclosed in WO 01/29018 are also amorphous and have the disadvantages of low purity and low thermal stability described above.
  • Figure 1 shows the mean ATI-2042 plasma concentration after individual oral administration of 10 mg / kg of crystalline ATl-2042 (based on the free base) tartrate salt (capsule or oily suspension) or citrate salt (oily suspension) on six male beagles Dogs.
  • the plasma concentration of ATI-2042 was determined by HPLC with an LLOQ (lowest detection limit) of 22.5 ng / mL.
  • Figure 2 shows the mean ATI-2042 plasma concentration after single oral administration of crystalline ATI-2042 tartrate (active substance content 15 mg / kg; based on the free base) in oily suspension to six male beagle dogs.
  • the plasma concentration of ATI-2042 in the plasma was determined by LC-MS / MS with an LLOQ (lowest detection limit) of 1 ng / mL.
  • Antiarrhythmically active "soft drug” compounds of the general formula A are known from EP 703 910 and WO 01/29018:
  • R 2 alkyl or heteroalkyl with 1-20 C atoms; Alkenyl or alkynyl with 2-20
  • X O, S or NH.
  • the compound of formula A can be achiral or can exist as a racemate or as an essentially pure enantiomer.
  • a preferred compound has the formula B (ATI 2042).
  • the compound of formula B can be present as a racemate or as an essentially pure R or S enantiomer, pure enantiomers being preferred and the S enantiomer being a pharmacologically very particularly advantageous compound.
  • the compound of the formula C (ATI 2055) is known from WO 01/29018 as a further preferred compound.
  • the compound of the formula C can exist as a racemate or as an essentially pure R or S enantiomer, enantiomers being preferred and the R enantiomer being a pharmacologically very particularly advantageous compound.
  • Crystallization of the disclosed amorphous hydrochloride and sulfate salts is problematic and has not been successful so far.
  • WO 01/29018 also describes salts of organic acids, e.g. Citrates, malonates and succinates are proposed, but this is only an exemplary list without concrete disclosure. There is no indication that, in contrast to the known inorganic salts, these salts can be crystallized or have any other advantage in comparison with the non-crystallizable sulfate salt disclosed as an exemplary embodiment.
  • amorphous salts Another disadvantage of the previously known amorphous salts is their low thermal stability.
  • the hydrochloride salt of a compound B (ATI-S-2042) was exposed to a temperature of 80 ° C. for 72 hours, the compound was broken down by over 27%.
  • the sulfates of B (neutral hemisulfate and acidic hydrogen sulfate) suffer 36% and 19% decomposition, respectively, under the same conditions. Free base B is even more unstable, being 93% degraded under the thermal load described.
  • the sulfate salts of compounds A, B and C have solubility and compatibility problems when they need to be formulated into common pharmaceutical solvents (see Table 3).
  • the inventors have now identified a class of high-purity, stable, crystalline salts which are excellent for use in the manufacture of pharmaceuticals.
  • the crystalline salts according to the invention are derived from compounds of the formulas A and have the general formula I.
  • R 2 alkyl or heteroalkyl with 1-20 C atoms; Alkenyl or alkynyl with 2-20
  • NR 3 R 4 can be part of a heterocyclic group which is selected from morpholine, triazole, imidazole, pyrrolidine,
  • Y is an anion of an organic acid selected from the group of mono-, di-, and tricarboxylic acids and also alkyl sulfonic acids.
  • Examples include acetic acid, propionic acid, pyruvic acid, butyric acid, ⁇ -, ⁇ - or ⁇ -hydroxybutyric acid, valeric acid, ⁇ - or ⁇ -hydroxyvaleric acid, caproic acid, ⁇ -hydroxycaproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, stearic acid, stearic acid, Glycolic acid, lactic acid, D-glucuronic acid, L-glucuronic acid, D-galacturonic acid, glycine, benzoic acid, hydroxybenzoic acid, gallic acid, salicylic acid, vanillic acid, cumaric acid, caffeic acid, hippuric acid, orotic acid, L-tartaric acid, D-tartaric acid, D, L-tartaric acid, meso-tartaric acid, fumaric acid, L-malic acid, D-malic acid, D, L-malic acid,
  • Y is an anion of an organic acid selected from the group of di- and tricarboxylic acids.
  • Di- and tricarbonate salts of the general formula I can be crystallized particularly well, can be prepared in great purity and are surprisingly stable.
  • the di- and tricarbonate salts of the formula I are compatible with the customary auxiliaries for pharmaceutical preparations.
  • the anions of aliphatic di- and tricarboxylic acids are particularly suitable for the preparation of the stable, crystalline compounds of the general formula I.
  • Y is an anion of an acid selected from the group consisting of citric acid, fumaric acid, maleic acid and tartaric acid.
  • the substituent R 1 is selected from the group H, OH, halogen, lower alkyl or lower alkoxy, with H being particularly preferred.
  • X is an oxygen atom.
  • hal 1 and hal 2 are iodine (I).
  • the radical R 2 is an alkyl, alkenyl, benzyl or phenyl, an alkyl being particularly preferred.
  • R 2 An alkyl having 1-10 and in particular an alkyl having 1-7 C atoms is very particularly preferred as the radical R 2 .
  • the most preferred radical for R 2 is lower alkyl, for example 2-butyl, 2- (3-methyl) -butyl, tert-butyl or neo-pentyl.
  • R 2 alkyl with 1-10 C atoms
  • Another object of the invention are crystalline salts of the general formula II, which are derived from the compounds of the formula B (ATI-2042) known per se:
  • the compound of the general formula II is present as an essentially pure enantiomer and particularly preferably as an S-enantiomer (ATI- (S) -2042).
  • the Y in formula II is an anion of a mono-, di- or tricarboxylic acid, in particular an aliphatic di- or tricarboxylic acid, citric acid, fumaric acid, maleic acid and tartaric acid being very particularly preferred.
  • the compound is a crystalline ATI- (S) -2042 citrate, crystalline ATI- (S) -2042 fumarate, crystalline ATI- (S) - 2042 maleate or crystalline ATI- (S) - 2042 tartrate.
  • the compound is crystalline ATI- (S) -2042 L-tartrate, in particular ATI- (S) -2042 L-monohydrogen tartrate, or crystalline ATI- (S) -2042 L-citrate, in particular ATI- (S ) -2042 dihydrogen citrate.
  • Another object of the invention are crystalline salts of the general formula III, which are derived from the compounds of the formula C known per se:
  • the compound of the general formula III is present as an essentially pure enantiomer, and very particularly preferably as an R enantiomer.
  • the Y in formula III is an anion of a mono-, di- or tricarboxylic acid, in particular an aliphatic
  • the di- or tricarboxylic acid with citric acid, fumaric acid, maleic acid and tartaric acid being particularly preferred.
  • the compound is crystalline ATI- (R) -2055 citrate, crystalline ATI- (R) -2055 fumarate, crystalline ATI- (R) -2055 maleate or crystalline ATI- (R) -2055 tartrate ,
  • essentially pure enantiomer means that at least 90% of the compound is in the form of one enantiomer and less than 10% is in the form of the opposite enantiomer.
  • An essentially pure S enantiomer thus contains less than 10% of the R enantiomer, preference is given to enantiomers which consist of more than 95%, particularly preferably 97% and very particularly preferably more than 99% of an enantiomer.
  • anion of an organic acid is understood to mean anions which are derived from branched or unbranched aliphatic, alicyclic or aromatic hydrocarbon compounds which, in addition to carbons, can also contain heteroatoms, such as N, S or O, and which contain at least one acid group.
  • said organic acids contain the acid groups COOH or SO 3 H.
  • anion of an organic acid is understood to mean anions of those acids which are selected from the group of monocarboxylic acids, dicarboxylic acids, tricarboxylic acids and alkylsulfonic acids.
  • “Monocarboxylic acids”, “dicarboxylic acids” and “tricarboxylic acids” mean saturated and unsaturated, branched and unbranched, aromatic, aliphatic or alicyclic organic compounds which accordingly have one, two or three COOH groups.
  • aliphatic monocarboxylic acids are especially acetic acid, propionic acid, pyruvic acid, butyric acid, ⁇ -, ß- or ⁇ -hydroxybutyric acid, valeric acid, ⁇ - or ⁇ -hydroxyvaleric acid, caproic acid, ⁇ - hydroxycaproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, glyceric acid, stearic acid Lactic acid, D-glucuronic acid, L-glucuronic acid, D-galacturonic acid and glycine.
  • aromatic monocarboxylic acids are in particular special benzoic acid, hydroxybenzoic acid, gallic acid, salicylic acid, vanillic acid, cumaric acid, caffeic acid, hippuric acid and orotic acid.
  • aliphatic dicarboxylic acids are in particular L-tartaric acid, D-tartaric acid, D, L-tartaric acid, meso-tartaric acid, fumaric acid, L-malic acid, D-malic acid, D, L-
  • An example of an aromatic dicarboxylic acid is phthalic acid.
  • Examples of aliphatic tricarboxylic acids are propane tricarboxylic acid, citric acid and isocitric acid.
  • citrate means all salts of citric acid, i.e. monohydrogen citrate, dihydrogen citrate and neutral citrate.
  • fumarate means all salts of fumaric acid, i.e. monohydrogen fumarate and neutral fumarate.
  • maleate is understood to mean all salts of maleic acid, i.e. the monohydrogen maleates and neutral maleate.
  • tartaric acid i.e. the monohydrogen tartrate and neutral tartrate of D-tartaric acid, L-tartaric acid, D, L-tartaric acid or meso-tartaric acid.
  • Tartaric acid Tartaric acid
  • optically inactive tartaric acid meo-tartaric acid
  • racemate D, L-tartaric acid
  • alkyl sulfonic acids is understood to mean compounds of the general formula alkyl-SO 3 H.
  • a preferred example is methanesulfonic acid.
  • alkyl is understood to mean a radical of a saturated, aliphatic hydrocarbon group which can be branched or unbranched, substituted or unsubstituted. Branches of the chain can also form a ring with one another.
  • Substituents can, for example, hydroxyl, aldehyde, oxo, carboxyl, unsubstituted never drigalkoxy, unsubstituted lower alkoxycycylyl, unsubstituted lower alkylcarbonyl, unsubstituted lower alkylcyyloxy, unsubstituted lower alkylthio, unsubstituted lower alkylamine, unsubstituted lower alkylsulfinyl, unsubstituted lower alkylsulfonyl, halogen, thio, sulfoxide or nitrous oxide, sulfate, sulfon, sulfon, sulfon.
  • “Lower alkyl” means a radical of an alkyl consisting of 1 to 5 carbon atoms, as defined above. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, tert- Pentyl, etc.
  • hetero atom is understood to mean any atom that is not carbon or hydrogen.
  • heteroalkyl is understood to mean a radical of a saturated, aliphatic hydrocarbon group which can be branched or unbranched, substituted or unsubstituted and in which one or more heteroatoms are incorporated into the chain.
  • Preferred heteroatoms are oxygen, nitrogen and sulfur.
  • Branches of the chain can also form a ring with one another, for example hydroxyl, aldehyde, oxo, carboxyl, unsubstituted lower alkoxy, unsubstituted lower alkoxycycarbonyl, unsubstituted lower alkylcarbonyl, unsubstituted lower alkylacyloxy, unsubstituted lower alkylthio, unsubstituted lower alkylalkyl, unsubstituted lower alkylamino, unsubstituted lower alkylamino, unsubstituted lower alkylamino, unsubstituted lower alkylamino, unsubstituted lower alkylamino, unsubstituted lower alkylamino, unsubstituted lower alkylalkyl, unsubstituted lower alkylalkyl , Sulfoxide, sulfate, sulfonate, nitro, amine or amide.
  • cycloalkyl is understood to mean a radical of a saturated, ring-shaped closed hydrocarbon group, which can be substituted or unsubstituted.
  • the alkyl ring preferably consists of 3 to 7 carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl.
  • Substituents can be for example, hydroxy, aldehyde, oxo, carboxyl, unsubstituted lower alkoxy, unsubstituted Niedrigalkoxcycarbonyl, unsubstituted Niedrigalkylcarbonyl, unsubstituted Niedrigalkylacyloxy, unsubsitusammlungs Niedri- galkylthio, unsubsitusammlungs lower alkylamine, unsubsitusammlungs Niedrigalkylsulfinyl, unsubsitutechnischs lower alkylsulfonyl, halogen, thio, sulfoxide, sulfate, sulfonate, nitro, amine or amide
  • the cycloalkyl can be fused with other ring systems, such as arylene or heteroarylene.
  • CrC 2 o alkyl-cycloalkyl is understood to mean a cycloalkyl group which is bonded to an alkyl group having 1-20 C atoms.
  • a particularly preferred alkyl group here is lower alkyl.
  • heterocycloalkyl is understood to mean a radical which differs from the cycloalkyl, as described above, in that at least one ring-forming heteroatom is present. Preferred heteroatoms are N, S and O. Examples of heterocycloalkyls are pyrrolidinyl, piperidinyl, indolinyl The heterocycloalkyl group can also be fused with other ring systems, such as arylene or heteroarylene.
  • C 1 -C 20 alkyl heterocycloalkyl is understood to mean a heterocycloalkyl group which is bonded to an alkyl group having 1-20 C atoms.
  • a particularly preferred alkyl group here is lower alkyl.
  • alkenyl or “alkynyl” are understood to mean radicals which differ from the alkylene, as defined above, in that they have at least one double or Have triple bond.
  • alkoxy is understood to mean the radical -O-alkyl.
  • lower alkoxy is understood to mean the radical -O-lower alkyl.
  • alkylcarbonyl is understood to mean the radical —C (O) alkyl.
  • lower alkylcarbonyl is understood to mean the radical —C (O) lower alkyl
  • alkoxycarbonyl is understood to mean the radical —C (O) —O-alkyl.
  • lower alkoxycarbonyl is understood to mean the radical —C (O) -O— lower alkyl
  • alkylacyloxy is understood to mean the radical -O-C (O) -alkyl.
  • lower alkylacyloxy is understood to mean the radical -O-C (O) -lower alkyl
  • Aryl is understood to mean a radical which contains one or more aromatic hydrocarbon rings, rings with 5, 6 or 7 carbon atoms each being connected in a ring being preferred. Examples are phenyl, naphthyl or anthracyl. A preferred aryl is the phenyl group.
  • the aryl groups can be substituted or be unsubstituted. Suitable substituents are, for example, hydroxy, halogen, nitro, amino, unsubstituted alkoxy, unsubstituted alkyl, oxo, carboxy.
  • CC 20 alkyl aryl “lower alkyl aryl” and “C 2 -C 20 alkenyl aryl” are each understood to mean aryl groups which are attached to an alkyl having 1-20 C atoms, to a lower alkyl or to a Alkenyl are bonded with 2-20 carbon atoms.
  • a preferred lower alkyl aryl group is benzyl (-CH -C 6 H 5 ).
  • Phenyl is understood to mean the radical —C 6 H 5 , which can be substituted or unsubstituted. Suitable substituents are, for example, alkyl, alkoxy, halogen, nitro, amino or hydroxyl groups.
  • Heteroaryl is understood to mean a radical which contains one or more aromatic rings, at least one heteroatom being contained in the ring system. Preference is given to rings each having 5, 6 or 7 atoms connected to one another in a ring. Preferred heteroatoms are N, S and O. Examples are furan, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, quinoline, indole, thiazole, oxazole or acridine.
  • the heteroaryl groups can be substituted or unsubstituted. Suitable substituents are, for example, hydroxy, halogen, nitro, amino, unsubstituted alkoxy, unsubstituted alkyl , Oxo, Carboxy.
  • CrC 20 alkyl heteroaryl is understood to mean a heteroaryl group which is bonded to an alkyl group having 1-20 C atoms.
  • a particularly preferred alkyl group here is lower alkyl.
  • aryloxy is understood to mean the radical -O-aryl.
  • lower alkyl thio is understood to mean the radical —S lower alkyl.
  • lower alkyl amine is understood to mean the radical —NH lower alkyl
  • lower alkyl sulfiny Is understood to mean the radical -S (O) lower alkyl.
  • lower alkyl sulfonyl is understood to mean the radical -S ( ⁇ 2 ) lower alkyl.
  • the compounds of the formulas I, II and III according to the invention have some surprising advantages over the salts of the formulas A, B and C known from the prior art.
  • the crystalline compounds according to the invention thus have high thermal stability. Furthermore, the compounds according to the invention can be prepared in high purity by a simple process.
  • Table 1 shows that after 72 hours incubation of the crystalline salts ATI- (S) -2042- fumarate, ATI- (S) -2042-maleate, ATI- (S) -2042-tartrate and ATI- (S) -2042-citrate at 80 ° C the substances are still over 99% intact. In contrast, the amorphous salt ATI- (S) - 2042 hydrochloride is already over 27% degraded, while the free base has even been degraded by 92.7%.
  • Table 1 Heat treatment of ATI (S) -2042 salts; 72h, 80 ° C
  • the compounds according to the invention can be prepared in crystalline form and in high purity.
  • the simple crystallization process can thus be used for the inexpensive purification of the compounds according to the invention which can be scaled up easily on an industrial scale. If necessary, the purity can be lization can be increased still further.
  • Table 2 Purity analysis of crystalline ATI- (S) - 2042 salt preparations
  • a typical production process for the crystalline compounds of the formulas I, II according to the invention comprises the following stages:
  • the free bases (deprotonated structures of the formula A) can be used directly for salt formation by subjecting them to the above-mentioned process steps (c) to (f) in solution.
  • the organic solvent in step (c) of the process according to the invention is selected from 2-butanone, ethyl acetate, acetone, methanol, ethanol, propanol, cyclohexane, dimethylformamide, dimethyl acetate, acetonitrile, dichloromethane, chloroform, toluene, methylene chloride, dioxane , Tetrahydrofuran and other ethers. Dichloromethane, methanol and acetone and mixtures of dichloromethane and methanol are particularly preferably used.
  • the organic solvent is selected in step (e) of the process from 2-butanone, ethyl acetate, acetone, methanol, ethanol, propanol, cyclohexane, dimethylformamide, dimethyl acetate, acetonitrile, chloroform, toluene, methylene chloride, Dioxane, tetrahydrofuran and other ethers.
  • 2-butanone, ethyl acetate and acetone are particularly preferably used in stage (e).
  • YH is a mono, di or tricarboxylic acid.
  • YH is an aliphatic di- or tricarboxylic acid, citric acid, fumaric acid, maleic acid and L-tartaric acid being very particularly preferred.
  • stage (e) of the process can be strongly temperature-dependent. While some of the crystalline salts according to the invention already form at room temperature (RT), lowering the temperature, for example to 0-5 ° C., is advantageous for other salts. Corresponding amorphous salts or corresponding free bases of the compounds of the general formulas A, B or C can be obtained again from the highly pure crystalline compounds of the general formulas 1, 11 or III, if necessary. In this way, an end product A, B or C described in EP 703 910 or in WO 01/29018 can also be produced in a highly pure form in a simple and easily scalable manner in accordance with the teaching of the present patent.
  • corresponding amorphous salt is understood to mean an amorphous salt which is obtained from a crystalline salt by exchanging the acid anion to obtain the basic chemical structure of the formulas A, B or C.
  • a “corresponding free base” is accordingly the free base A, B or C of a crystalline salt I, II or III.
  • the crystalline compounds of the general formulas I, II and III are used directly for the preparation of pharmaceutical compounds.
  • the invention therefore relates to pharmaceutical compounds which are a crystalline compound of the formula I.
  • R 2 alkyl or heteroalkyl with 1-20 C atoms; Alkenyl or alkynyl with 2-20 C atoms; Cycloalkyl, CrC 2 oalkyl-cycloalkyl, heterocycloalkyl, C-
  • X O, S or NH;
  • the compound can optionally be present as a racemate or as an essentially pure enantiomer.
  • Y is an anion of an organic acid selected from the group of the mono-, di- and tricarboxylic acids.
  • Y particularly preferably represents a pharmaceutically acceptable anion of a di- or tricarboxylic acid and is very particularly preferably selected from citrate, fumarate, maleinate and L-tartrate.
  • the substituent R 1 is selected from the group H, OH, halogen, lower alkyl or lower alkoxy, with H being particularly preferred.
  • X is an oxygen atom.
  • hal 1 and hal 2 are iodine.
  • the radical R 2 is an alkyl, alkenyl, benzyl or phenyl, an alkyl being particularly preferred. Most notably an alkyl having 1-10 and in particular an alkyl having 1-7 C atoms is preferred.
  • the most preferred radical for R 2 is lower alkyl, for example 2-butyl or 2- (3-methyl) -butyl.
  • R 2 alkyl with 1-10 C atoms
  • Another preferred subject of the invention are pharmaceutical compounds which are a crystalline compound of the formula II
  • Y has the meaning given above and wherein the compound is present as a racemate or as an essentially pure enantiomer.
  • the pharmaceutical formulation comprises a crystalline compound of the general formula II, which is used as in the we ⁇
  • the pharmaceutical formulation comprises a crystalline compound of the formula II in which Y is a pharmaceutically acceptable anion of a mono-, di- or tricarboxylic acid, in particular an aliphatic di- or tricarboxylic acid, and wherein citrate, fumarate, Maleate and tartrate are particularly preferred.
  • the therapeutic formulation comprises a compound selected from the group consisting of crystalline ATI-S-2042 citrate, crystalline ATI-S-2042 fumarate, crystalline ATI-S-2042 maleate or crystalline ATI-S-2042 tartrate.
  • Another preferred subject of the invention are pharmaceutical formulations comprising crystalline compounds of the general formula III:
  • Y has the meaning given above and wherein the compound is present as a racemate or as a substantially pure enantiomer.
  • the therapeutic formulation comprises a crystalline compound of the general formula III, which is used as in the considerable pure enantiomer, very particularly preferably as an essentially pure R enantiomer.
  • the therapeutic formulation comprises a crystalline compound of the general formula III, where the Y is a pharmaceutically acceptable anion of a mono-, di- or tricarboxylic acid, in particular an aliphatic di- or tricarboxylic acid and wherein citrate, fumarate, maleinate and tartrate are particularly preferred.
  • the compound is selected from the group consisting of crystalline ATI- (R) -2055 citrate, crystalline ATI- (R) -2055 fumarate, crystalline ATI- (R) -2055 maleate or crystalline ATI- (R) -2055 tartrate.
  • the compounds of the general formulas I, II or III according to the invention are in principle suitable both for the preparation of oral or parenteral, nasal, inhalative, rectal or transdermal administration forms, preference being given to oral or parenteral administration.
  • formulations can therefore be either liquid, semi-solid or solid.
  • Formulations of preparation include, for example, infusion or injection solutions, tablets, powders, granules, capsules, dragees, pellets, aqueous solutions, oils, sprays, microcapsules, microparticles, suppositories, aerosols etc.
  • the compounds according to the invention can be introduced into the pharmaceutical formulation in crystalline form, in which they are then present, for example in the form of aqueous or oily crystal suspensions, embedded in a suitable matrix or bound to microparticles.
  • the crystalline compounds of the general formulas I, II or III are suspended in an oily phase.
  • the oily phase can consist, for example, of vegetable oils, such as, for example, olive oil, peanut oil, almond oil, poppy seed oil or sesame oil, or of semisynthetic or synthetic glycerides, in particular triglycerides.
  • Preferred as the oily phase is a triglyceride with predominantly saturated fatty acids, predominantly medium chain fatty acids with 8-12 C Atoms.
  • Corresponding preparations are commercially available as Miglyol TM (from Condea).
  • the oily suspension can also contain a wetting agent.
  • Suitable wetting agents are, for example, surfactants and condensation products made from polyols and carboxylic acids, such as, for example, fatty acid esters of C 3 -C 5 alcohols.
  • Corresponding preparations are commercially available, for example, as Imwitor TM (from Condea) and are described in pharmacopoeias.
  • An object of the invention is therefore an oily suspension containing
  • an oily vehicle preferably consisting of a vegetable oil or a glyceride
  • a wetting agent preferably consisting of condensation products from polyethylenes and carboxylic acids.
  • the oily suspension contains a compound of the general formula II as pharmaceutical active ingredient, and very particularly preferably the oily suspension contains ATI-2042 citrate or ATI-2042 tartrate.
  • oily suspensions containing the crystalline compounds according to the invention can be administered orally, but are also suitable for parenteral, in particular subcutaneous, or rectal administration.
  • the crystalline compounds are stable in the oily suspensions when stored over the test period of 6 months, as shown in Table 3.
  • the crystalline compounds of general formulas I, II or III can also be used directly in capsules, e.g. in gelatin capsules, which are then available orally.
  • Figure 1 shows the average plasma concentration of ATI 2042 citrate and ATI 2042 tartrate after oral administration in the form of an oily suspension or as a capsule in beagle dogs. It follows from this that the compounds according to the invention are orally well absorbed. A slight retardation effect can also be achieved by administration in the form of oily suspensions.
  • Figure 2 shows the plasma levels of beagle dogs when ATI 2042 tartrate was administered in an oily suspension in higher concentrations.
  • the crystal compounds according to the invention can be micronized by methods known per se and then processed in pharmaceutical formulations.
  • Another object of the invention is the preparation of a storage-stable pharmaceutical formulation containing the crystalline salts of the general formulas I, II or III.
  • a storage-stable pharmaceutical formulation can still contain the compounds according to the invention in crystalline form when administered to the patient; alternative However, the crystals can be dissolved or melted immediately before use.
  • the invention therefore furthermore relates to the production of pharmaceutical formulations, characterized in that the crystalline compounds of the formulas I, II or III according to the invention are brought into galenic forms in which the said compounds are no longer or no longer exclusively in crystalline form.
  • the compounds of the general formulas I, II or III are first prepared by crystallization in a simple and highly pure form and then melted or dissolved for use in corresponding pharmaceutical formulations.
  • An example of this is the preparation of an injection solution by dissolving the crystalline salts of the general formulas I, II or III prepared according to the invention.
  • kits in which the salts according to the invention are stored in a suitable formulation, for example in a two- or multi-chamber cartridge, which allow the crystals to be dissolved or resuspended in a closed system.
  • the compounds according to the invention can also be stored in a suitable storage-stable formulation in a primary pack separated from a corresponding " physiological solvent (buffer, water, etc.).
  • Table 4 shows the solubility (mg / mL) of some salts of ATI- (S) -2042 in various common pharmaceutical solvents.
  • the compounds according to the invention are particularly suitable for the treatment of cardiac arrhythmias, in particular in patients with congestive heart failure (CHF).
  • CHF congestive heart failure
  • Specific indications of the compounds according to the invention are ventricular tachycardias and / or arrhythmias, supraventricular arrhythmias and atrial flames.
  • the compounds according to the invention can be used as accompanying therapy or for aftercare of heart attack patients.
  • the compounds according to the invention can also be used in suitable combinations, for example with vasodilators or ⁇ -blockers.
  • the dosage of the compounds according to the invention depends on age, gender, weight, the general state of health and the type and severity of the patient's disease, any comedications, the form of administration and type.
  • the dosage for oral administration is in the range of 0.05 to 100 mg / kg.
  • the patient is often initially discontinued with high initial doses.
  • these can be between 100 and 3000 mg per day. Dosages between 200 and 2000 mg per day and in particular between 500 and 1500 mg per day are preferred.
  • the dosage can be gradually reduced to the oral maintenance dose.
  • This is typically lower than the initial oral dose and, for the compounds according to the invention, can be between 100 mg and 1000 mg per day, preferably between 150 mg and 800 mg per day, particularly preferably between 180 mg and 700 mg per day and very particularly preferably between 200 and 600 mg a day.
  • the compounds according to the invention are slowly injected in dissolved form, for example in a dosage of 1-20 mg / kg body weight, preferably 2-10 mg / kg body weight and particularly preferably 3-7 mg / kg. In a typical embodiment, an amount of 5mg / kg body weight is used over a period of time injected for at least 3 minutes. If necessary, a new injection can be made after an injection-free phase of about 20 minutes.
  • the pharmaceutical formulations according to the invention can also be applied by a single infusion.
  • 50-1000 mg, preferably 100-500 mg and particularly preferably 200-400 mg of the crystalline compound are dissolved in physiological solvent and infused over a period of 15-240 minutes.
  • the compounds according to the invention are in dissolved form in a concentration of 1-50 mg / kg, preferably 3-30 mg and particularly preferably in a concentration of 5-25 mg / kg over about 24 hours as a continuous infusion administered.
  • auxiliaries and additives which may be contained in the pharmaceutical formulations according to the invention, such as stabilizers, flavorings, antioxidants, preservatives, dispersing or solvents, buffers, electrolytes etc. are known to the person skilled in the art in the field of pharmaceutical preparations.
  • the (S) - (+) - 2-butanol of the esters produced has an optical purity (e.e.) of 99.5% (RhodiaChi x, USA).
  • melting point The melting points described (melting point) are uncorrected and were recorded on a Büchi Melting Point B-545 instrument, in individual cases also determined by differential thermal analysis (DSC).
  • LC-MS Combined liquid chromatography-mass spectrometry: Waters Integrity System, Thermabeam Mass Detector (El, 70 eV), m / z values and relative intensity are reported. Under the measurement conditions described, all salts of the ATI-2042 series have identical mass spectra.
  • Selected fragment ions are detected at (m / z, relative intensity in%): 128 (100.0%), 159 (17.6%), 250 (22.6%), 251 (22.6%), 278 (13.7%), 304 (8.9% ), 378 (12.5%), 404 (15.6%), 430 (9.8%), 504 (8.3%), 530 (6.2%), 548 (1.5%), 560 (2.8%), 576 (10.0%), 604 (1.5%), 688 (4.2%), 703 (1.3%, M + ).
  • Elemental analyzes Elemental analyzes were carried out by the company Pascher Microanalytical Laboratory (Remagen-Bandorf, Germany).
  • Aqueous 2N HCl (one molar equivalent) or 0.1NH 2 SO 4 (0.5 or 1.0 molar equivalent) are added to 3.3 g of a solution of the base of the compounds A, B or C in dichloromethane at room temperature and the mixture is stirred overnight , The solutions are extracted twice with methylene chloride and the combined extracts are dried under vacuum. The following were obtained:
  • the purity according to HPLC was 97.2%.
  • the melting point according to DSC determination is 136.8 ° C with decomposition (colorless crystals).
  • the purity according to HPLC was 98.1%.
  • the melting point according to DSC determination is 131 ° C (colorless crystals).
  • the purity according to HPLC was 98.0%.
  • the melting point according to DSC determination is 139.6 ° C (colorless crystals).
  • ATI-2042 was administered orally to 6 beagle dogs each as follows:
  • ATI 2042 tartrate 10 mg free base / kg in gelatin capsule, or as an oily suspension, as described in Example 11.
  • ATI 2042 citrate 10 mg free base / kg in oily suspension as described in Example 11.
  • ATI 2042 tartrate 15 mg free base / kg in oily suspension as described in Example 11.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des sels cristallins de dérivés de benzoylbenzofurane de formule générale (I) présentant une action antiarythmique. L'invention se rapporte en outre à des compositions pharmaceutiques contenant ces sels ainsi qu'à la production desdits sels cristallins.
PCT/EP2002/006417 2001-06-16 2002-06-12 Sels cristallins de derives de benzoylbenzofurane Ceased WO2002102788A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10129119.1 2001-06-16
DE10129119A DE10129119B4 (de) 2001-06-16 2001-06-16 Kristalline Salze von Benzoylbenzofuran-Derivaten, insbesondere von[2-(4-{1-[2-((S)-sec.-Butoxycarbonylmethyl)-benzofuran-3-carbonyl]-methanoyl}-2,6-diiod-phenoxy)-ethyl]-diethylamino und [2-(4-{1-[(3-Methyl-2-(S)-Butoxycarbonylmethyl)-benzofuran-3-carbonyl]- methanoyl}-2,6-diiodphenoxy)-ethyl]-diethylamino, deren Verwendung und Herstellung sowie diese Salze enthaltende Arzneimittel

Publications (1)

Publication Number Publication Date
WO2002102788A1 true WO2002102788A1 (fr) 2002-12-27

Family

ID=7688438

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/006417 Ceased WO2002102788A1 (fr) 2001-06-16 2002-06-12 Sels cristallins de derives de benzoylbenzofurane

Country Status (2)

Country Link
DE (1) DE10129119B4 (fr)
WO (1) WO2002102788A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609A1 (fr) * 1990-08-06 1992-02-19 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
US6130240A (en) * 1993-06-16 2000-10-10 Aryx Therapeutics, Inc. Compound for treatment of cardiac arrhythmia, synthesis, and methods of use
WO2001029018A2 (fr) * 1999-10-15 2001-04-26 Aryx Therapeutics Nouveaux composes enantiomeres pour le traitement des arythmies cardiaques et procedes d'utilisation
WO2002016340A1 (fr) * 2000-08-23 2002-02-28 Sanofi-Synthelabo Aminoalkoxybenzoyl-benzofuranes ou benzothiophenes, leur procede de preparation et les compositions les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609A1 (fr) * 1990-08-06 1992-02-19 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
US6130240A (en) * 1993-06-16 2000-10-10 Aryx Therapeutics, Inc. Compound for treatment of cardiac arrhythmia, synthesis, and methods of use
WO2001029018A2 (fr) * 1999-10-15 2001-04-26 Aryx Therapeutics Nouveaux composes enantiomeres pour le traitement des arythmies cardiaques et procedes d'utilisation
WO2002016340A1 (fr) * 2000-08-23 2002-02-28 Sanofi-Synthelabo Aminoalkoxybenzoyl-benzofuranes ou benzothiophenes, leur procede de preparation et les compositions les contenant

Also Published As

Publication number Publication date
DE10129119B4 (de) 2007-10-04
DE10129119A1 (de) 2003-02-06

Similar Documents

Publication Publication Date Title
DE69704679T2 (de) 4-phenylpiperidin-derivate
DE60112305T2 (de) Verfahren zur herstellung amlodipinmaleat
DE1643262B2 (de) l-Phenoxy^-hydroxy-S-alklyaminopropane, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DE20116125U1 (de) Amlodipinfumarat
DE1795792A1 (de) Die serumlipoidkonzentration vermindernde arzneimittel
DE2549841C2 (fr)
DE2707048C2 (de) 2-Alkyl-3-Benzoyl-Indolizinderivate, Verfahren zu deren Herstellung, sowie diese enthaltende Zusammensetzungen
DD219770A5 (de) Verfahren zur herstellung von piperidindion-derivaten
DE60131416T2 (de) Chirale fluochinolon-argininsalzformen
DE69311566T2 (de) Heterocyclische amine als calmodulin antagonisten
DE69121807T2 (de) 3-[(5-Methyl-2-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-b]-pyridin-2-amin-2-hydroxy-1,2,3-propantricarboxylat
DD280965A5 (de) Verfahren zur herstellung von antiarrhythmisch wirkenden mitteln
EP0618201A1 (fr) Thiadiazinones et leur utilisation pour le traitement d'affections cardiovasculaires ou asthmatiques
DE20116170U1 (de) Aspartatderivat des Amlodipins
DE60116514T2 (de) Amlodipinhemimaleat
DE10129119B4 (de) Kristalline Salze von Benzoylbenzofuran-Derivaten, insbesondere von[2-(4-{1-[2-((S)-sec.-Butoxycarbonylmethyl)-benzofuran-3-carbonyl]-methanoyl}-2,6-diiod-phenoxy)-ethyl]-diethylamino und [2-(4-{1-[(3-Methyl-2-(S)-Butoxycarbonylmethyl)-benzofuran-3-carbonyl]- methanoyl}-2,6-diiodphenoxy)-ethyl]-diethylamino, deren Verwendung und Herstellung sowie diese Salze enthaltende Arzneimittel
DE60112310T2 (de) Das Hydrochloridsalz von 5-[4-[2-(N-Methyl-N-(2-Pyridyl)Amino)Ethoxy]BenzylThiazolidin-2,4-Dion
DE69715196T2 (de) Modifizierte form des hydrochlorids der r(-)-n-(4,4-di(-3-methylthien-2-yl)but-3-enyl)-nipecotinsäure
DE20115218U1 (de) Amid-Derivat von Amlodipin
DE69022442T2 (de) Aminoalkoxyphenyl-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende Zusammensetzungen.
DD139842A5 (de) Verfahren zur herstellung quaternaerer ammoniumsalze von phenylpropylaminen und phenylbutylaminen
DE3004348C2 (fr)
EP0849265A1 (fr) Nouvelle forme polymorphique de mésylate de doxazosin (forme II)
DE69707080T2 (de) Pyrrolidinonderivate und ihre Verwendung als antipsychotische Arzneimittel
DE60023703T2 (de) Vorprodukte von bis-quaternären ammoniumsalzen und deren verwendung als prodrugs mit anti-parasitärer wirkung

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP