WO2010028840A1 - Dérivé d'acide 2-éthoxy-benzoïque - Google Patents

Dérivé d'acide 2-éthoxy-benzoïque Download PDF

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Publication number
WO2010028840A1
WO2010028840A1 PCT/EP2009/006605 EP2009006605W WO2010028840A1 WO 2010028840 A1 WO2010028840 A1 WO 2010028840A1 EP 2009006605 W EP2009006605 W EP 2009006605W WO 2010028840 A1 WO2010028840 A1 WO 2010028840A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
ethoxy
formula
acid
Prior art date
Application number
PCT/EP2009/006605
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German (de)
English (en)
Inventor
Thomas Rillmann
Jessica Schönborn
Christof Schumann
Original Assignee
Stada Arzneimittel Ag
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Filing date
Publication date
Application filed by Stada Arzneimittel Ag filed Critical Stada Arzneimittel Ag
Priority to EP09778480A priority Critical patent/EP2344466A1/fr
Publication of WO2010028840A1 publication Critical patent/WO2010028840A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to a 2-ethoxy-benzoic acid derivative.
  • Repaglinide also referred to as 2-ethoxy-4 - [[(S) -3-methyl-1- (2-piperidin-1-ylphenyl) butylcarbamoyl] methyl] benzoic acid, and its physiologically acceptable salts have valuable pharmacological properties, in particular a hypoglycemic effect, which is why Repaglinide is used to treat diabetes mellitus.
  • repaglinide shows a tendency to decompose, therefore, corresponding compositions are stable for relatively short periods of time.
  • “stability” is understood to mean the definition worked out by the Working Group for Pharmaceutical Process Engineering (APV) according to which "stability” means the specification-compliant quality of the drug until the end of the period of time specified by the manufacturer.
  • the quality of the drug is determined by the active ingredient content and the purity, the sensory perceptible, physico-chemical and microbiological properties, with the active ingredient content should not fall below 90% of the declared value by the end of the term.
  • the object of the present invention is therefore to provide an agent which improves the stability of repaglinide in pharmaceutical compositions.
  • salts is understood to mean any salt of the compound (I) and its stereoisomers, in particular a salt with an inorganic or organic acid or base.
  • the compound is (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl]] -methylbenzoic acid (Ia)
  • (S, S) -2-Ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] -aminocarbonyl] -methylbenzoic acid (Ia) and salts thereof are preferably Used alone or in combination to improve the stability of S-repaglinide.
  • the compound (Ia) and its salts can also be used to improve the stability of R repaglinide and mixtures of S and R repaglinide, especially a racemic mixture thereof.
  • the compound is (R, R) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl] ] -methylbenzoic acid (Ib)
  • the compound may be the meso compound (R, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl]] - methylbenzoic acid of the formula (Ic)
  • the present invention further relates to a physiologically acceptable salt of the compound of the invention.
  • the physiologically acceptable salt can be used in pharmaceutical applications, such as in the preparation of solid, repaglinide-containing dosage forms.
  • the compound of the formula (I) or of the formulas (Ia), (Ib) and (Ic) according to the invention can be converted in a simple manner into a physiologically tolerated salt with inorganic or organic acids or bases.
  • Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid and fumaric acid are particularly preferred as acids and as bases sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, arginine and lysine.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising repaglinide and one or more compounds selected from the group consisting of the compounds of formulas (Ia), (Ib) and (Ic) and their pharmaceutically acceptable salts according to the invention.
  • repaglinide in the context of the present invention S-repaglinide, R-repaglinide and also a mixture of S and R repaglinide, in particular a racemic mixture thereof, as well as pharmaceutically acceptable salts of the aforementioned.
  • the compound or the compounds of the formula (I) or of the formulas (Ia), (Ib) and / or (Ic) together with a proportion of 0.01 wt. % to 1% by weight are contained in the composition, based on the weight of the repaglinide contained in the composition, preferably in an amount of from 0.01% by weight to 0.5% by weight, more preferably in one proportion from 0.01% by weight to 0.2% by weight and even more preferably in a proportion of from 0.01% by weight to 0.1% by weight. It has been found that even relatively small amounts of the compound of the invention or a pharmaceutically acceptable salt thereof is sufficient to significantly improve the stability of repaglinide.
  • composition is solid and is preferably present in the form of a tablet.
  • the present invention further relates to a process for the preparation of a pharmaceutical composition according to the invention, wherein in the process repaglinide and one or more different compounds according to the invention and / or one or more inventive, physiologically acceptable salts in one or more carriers and / or in a or more diluents are incorporated.
  • carriers or diluents it is possible to use all carriers or diluents known from the prior art which are suitable as excipients or diluents for repaglinide.
  • the present invention further relates to a process for the preparation of a compound according to the invention, wherein in the process a 4-alkoxycarbonyl-3-ethoxy-phenylmalonic acid of the formula (IV)
  • R is a methyl or ethyl radical, or a reactive derivative thereof optionally prepared in the reaction mixture, with 1- (2-piperidino-phenyl) -3-methyl-1-butylamine of the formula (III)
  • Suitable reactive derivatives of a compound of the formula (IV) are, for example, their esters, such as the methyl, ethyl or benzyl esters, their thioesters, such as the methylthio or ethylthioester, their halides, such as the acid chloride, their anhydrides or imidazolides.
  • the reaction is preferably carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride , Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, eg, phosphorus trichloride ,
  • the reaction can also be carried out without a solvent.
  • water formed during the reaction can be separated by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a desiccant such as magnesium sulfate or a molecular sieve.
  • the deprotection is carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as methanol, methanol / water, ethanol, ethanol / water, water / Isopropanol or water / dioxane at temperatures from -10 0 C to 120 0 C, for example at a temperature from room temperature to boiling temperature of the reaction mixture.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid
  • a base such as sodium hydroxide or potassium hydroxide
  • a suitable solvent such as methanol, methanol / water, ethanol, ethanol / water, water / Isopropanol or water / dioxane at temperatures from -10 0 C to 120 0 C, for example at a temperature from
  • the present invention furthermore relates to the compound 4-alkoxycarbonyl-3-ethoxy-phenylmalonic acid of the formula (IV)
  • the compound of the formula (IV) is a useful synthetic building block in the preparation of the compound of the formula (I) or (Ia), (Ib) or (Ic) according to the invention.
  • the present invention further relates to the compound 4-alkoxycarbonyl-3-ethoxy-phenylmalonic acid alkyl ester of the formula (V)
  • R, R 2 and R 3 are independently of one another a methyl or an ethyl radical, wherein in the case where R 2 and R 3 are a methyl radical, R is likewise a methyl radical.
  • the compound of formula (V) is a useful one
  • the present invention furthermore relates to the compound 2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] -aminocarbonyl] -methylbenzoic acid alkyl ester of the formula (II)
  • the compound of the formula (II) is a useful synthetic building block in the preparation of the compound of the formula (I) or (Ia), (Ib) and (Ic).
  • the salts can thereby salts of the compound (II), ie salts of (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl ] aminocarbonyl]] - methylbenzoic acid alkyl ester of (R, R) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl]] methylbenzoic acid alkyl ester and (R, S) -2-ethoxy-4- [di- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonyl]] methylbenzoic acid alkyl ester be with any inorganic or organic acids or bases.
  • physiologically acceptable salts of the compound (II) with inorganic or organic acids or bases are preferred.
  • Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid and fumaric acid are particularly preferred as acids and as bases sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, arginine and lysine.
  • the present invention further relates to the racemate of the enantiomeric pair (Ia) and (Ib), which can also be used to improve the stability of repaglinide.
  • the present invention furthermore relates to the racemate of the compound of the formula (II) which contains the enantiomers (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidinophenyl) -3-methyl 1-butyl] aminocarbonyl]] - methylbenzoic acid alkyl ester and (R, R) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] -aminocarbonyl] ] -methylbenzoic acid alkyl ester in equimolar amount.
  • the separation of enantiomers of the aforementioned racemates is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts or optionally derivatives such.
  • esters or amides-forming optically active substance in particular acids and their activated Derivatives or alcohols, and separating the thus obtained diastereomeric salt mixture or derivatives, for. Due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
  • optically active acids are, for.
  • D and L forms of tartaric acid or dibenzoyltartaric acid di-o-toluenoic, malic, mandelic, camphorsulfonic, glutamic, aspartic or quinic acid.
  • optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.
  • the present invention further relates to the use of a compound of the formula (V)
  • Figure 1 A 1 H-NMR spectrum of the compound (Ia) in dimethyl sulfoxide (DMSO) at a temperature of 60 0 C;
  • Figure 1 B 13 C-NMR spectrum of the compound (Ia) in DMSO at a temperature of 60 0 C.
  • the isolated ethyl 2-ethoxy-4-bromomethylbenzoate (IX) was characterized by mass spectroscopy and 1 H NMR spectroscopy.
  • the 2-ethoxy-4-cyanomethyl-benzoic acid ethyl ester (VIII) was from the residue by means of 100 ml isolated to a temperature of 0 0 C and tempered isopropanol under reduced pressure at a temperature of 40 0 C dried. The product thus obtained was purified by HPLC.
  • the isolated 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid (VII) was characterized by mass spectroscopy and 1 H NMR spectroscopy.
  • the isolated ethyl 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid (VI) was characterized by mass spectroscopy and 1 H NMR spectroscopy.
  • the isolated 4-ethoxycarbonyl-3-ethoxy-phenylmalonic acid (IV) was characterized by mass spectroscopy and 1 H NMR spectroscopy.
  • the compound (Ib) was prepared using the (R, R) stereoisomer of the compound (II) as in Example 9.
  • the isolated mixture of enantiomers was measured by means of polarized light and showed no optical activity; the enantiomeric compounds (II) are thus equimolar in the mixture, i. in the form of a racemate, before.
  • the mixture was separated on a chiral column, with two fractions containing equal amounts of (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl 1-butyl] aminocarbonyl]] - methylbenzoic acid ethyl ester (II) or (R, R) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl] 1-butyl] aminocarbonyl]]] - methylbenzoic acid ethyl ester (II).
  • compositions of tablets are given as embodiments of the pharmaceutical composition of the invention.
  • Table 1 compositions of tablets are given as embodiments of the pharmaceutical composition of the invention.
  • the tablets were prepared by treating S-repaglinide with (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl]] methylbenzoic acid (Ia), poloxamer, cellulose (microcrystalline), croscarmellose nathum and magnesium stearate and the resulting mixture was compressed into tablets.
  • compositions of tablets are given as embodiments of the pharmaceutical composition of the invention.
  • Table 2 compositions of tablets are given as embodiments of the pharmaceutical composition of the invention.
  • the tablets were prepared by first S-repaglinide with (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl] ] - methylbenzoic acid (Ia), mixed with lactose monohydrate and one part of magnesium stearate, compacted and then granulated. The resulting granules were mixed with sodium carboxymethyl starch and the other portion of magnesium stearate and the mixture was compressed into tablets.
  • Table 3 shows compositions of tablets as
  • the tablets were prepared by treating S-repaglinide with (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl]] methylbenzoic acid (Ia), poloxamer, cellulose (microcrystalline), crospovidone and magnesium stearate and the resulting mixture was compressed into tablets.
  • the tablets were prepared by treating S-repaglinide with (S, S) -2-ethoxy-4- [di- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonyl]] methylbenzoic acid (Ia), poloxamer, cellulose (microcrystalline), sodium carboxymethyl starch and stearic acid and the resulting mixture was compressed into tablets.
  • Table 5 shows compositions of tablets as comparative examples. Table 5:
  • the tablets were prepared by mixing S-repaglinide with poloxamer, cellulose (microcrystalline), croscarmellose sodium and magnesium stearate and compressing the resulting mixture into tablets.
  • compositions according to Example 15 and Comparative Example 1 were under stress conditions stored (40 0 C and 75% relative humidity or 25 ° C and 60% relative humidity rh)) 8, or 12 weeks in a blister pack with molding and rear walls made of aluminum.
  • the compositions were tested for impurities by HPLC before and after storage.
  • the results of the study are summarized in Tables 6 and 7, in which the data in% by weight are based on the active ingredient. Table 6:

Abstract

La présente invention concerne un dérivé d'acide 2-éthoxy-benzoïque et un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne en outre une composition pharmaceutique, comprenant du répaglinide et le composé selon l'invention et/ou un sel physiologiquement acceptable de celui-ci. En outre, l'invention concerne un procédé de production de la composition pharmaceutique et un procédé de production de dérivé d'acide 2-éthoxy-benzoïque. L'invention concerne en outre des molécules qui sont utiles pour la production du composé selon l'invention. En outre, l'invention concerne un racémique du composé selon l'invention et un racémique d'un précurseur de celui-ci.
PCT/EP2009/006605 2008-09-12 2009-09-11 Dérivé d'acide 2-éthoxy-benzoïque WO2010028840A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09778480A EP2344466A1 (fr) 2008-09-12 2009-09-11 Dérivé d'acide 2-éthoxy-benzoïque

Applications Claiming Priority (2)

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DE102008046995.5 2008-09-12
DE102008046995A DE102008046995B4 (de) 2008-09-12 2008-09-12 2-Ethoxy-benzoesäurederivat

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0058779A2 (fr) * 1981-01-10 1982-09-01 Dr. Karl Thomae GmbH Carboxamides, leur préparation et leur utilisation comme médicaments
WO1993000337A1 (fr) * 1991-06-21 1993-01-07 Dr. Karl Thomae Gmbh Acides (s)(+)-2-ethoxy-4-[n-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoique
US20040249188A1 (en) * 2003-05-29 2004-12-09 Dr. Reddy's Laboratories Limited Process for the preparation of 3-ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid. (an intermediate of repaglinide)
WO2009004485A2 (fr) * 2007-06-06 2009-01-08 Actavis Group Ptc Ehf Répaglinide sensiblement exempt d'impureté dimère

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1215040C (zh) * 2002-11-12 2005-08-17 上海三维制药有限公司 4－羧甲基－2－乙氧基苯甲酸乙酯的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0058779A2 (fr) * 1981-01-10 1982-09-01 Dr. Karl Thomae GmbH Carboxamides, leur préparation et leur utilisation comme médicaments
WO1993000337A1 (fr) * 1991-06-21 1993-01-07 Dr. Karl Thomae Gmbh Acides (s)(+)-2-ethoxy-4-[n-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoique
US20040249188A1 (en) * 2003-05-29 2004-12-09 Dr. Reddy's Laboratories Limited Process for the preparation of 3-ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid. (an intermediate of repaglinide)
WO2009004485A2 (fr) * 2007-06-06 2009-01-08 Actavis Group Ptc Ehf Répaglinide sensiblement exempt d'impureté dimère

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GRELL W ET AL: "REPAGLINIDE AND RELATED HYPOGLYCEMIC BENZOIC ACID DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 41, 1 January 1998 (1998-01-01), pages 5219 - 5246, XP000872800, ISSN: 0022-2623 *
KRISHNA REDDY K V S R ET AL: "Impurity profile study of repaglinide", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, NEW YORK, NY, US, vol. 32, 1 January 2003 (2003-01-01), pages 461 - 467, XP002509504, ISSN: 0731-7085 *

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EP2344466A1 (fr) 2011-07-20
DE102008046995B4 (de) 2010-08-26
DE102008046995A1 (de) 2010-03-18

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