CA1292000C - Solid forms of 2-ethoxy-4-[n-(1-(2-piperidino- phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid - Google Patents
Solid forms of 2-ethoxy-4-[n-(1-(2-piperidino- phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acidInfo
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- CA1292000C CA1292000C CA000512269A CA512269A CA1292000C CA 1292000 C CA1292000 C CA 1292000C CA 000512269 A CA000512269 A CA 000512269A CA 512269 A CA512269 A CA 512269A CA 1292000 C CA1292000 C CA 1292000C
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- 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
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- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Abstract Solid forms of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-amino-carbonylmethyl]-benzoic acid The invention relates to new solid forms of the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, the enantiomers and the salts thereof which have valuable pharmacological properties, namely an effect on intermediate metabolism, particularly a hypoglycaemic effect.
Description
Solid forms of 2-ethoxy-4-~N-~1-(2-piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]-benzoic acid This invention relates to new solid forms of the compound 2-ethoxy-4-[N~ (2-piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]~benzoic acid, the enantiomers and the salts thereo~ which have valuable pharmacological properties, namely an effect on intermediate metabolism, particularly a hypoglycaemic effect.
EP-A-147850 of 10th July 1985 twhich is not a prior publication) describes the compound 2-ethoxy-4-rN-(l-(2-piperidino-phenyl)-3-methy~ butyl)-amin carbonylmethyl]-benzoic acid with a melting point of 90-92C (acetone/petroleum ether; Form (A)).
According to Example 11 o EP~A-147850, this compound is obtained by catalytic hydrogenation of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-me-thyl-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid and like its physiologically acceptable addition salts and enantiomers it has valuable pharmacological properties, namely an effect on intermediate metabolism, particu-larly a hypoglycaemic activity.
Surprisingly, it has now been founa that the same compoundr namely 2-ethoxy-4-~N-tl-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, is obtained in other solid forms when crystallised from other solvents or mixtures of solvents. Form (B), which has a melting point of from 140 to 142C, may be obtained by crystalli-sation from an ethanol/water mixture and the foamy form, Form (C), which has a melting range Erom 75 ,~ ~
to 85C, may be obtained from the 1:1 methanol adduct (melting point: 85 to 90C), which occurs on crystal-lisation from methanol, by heating at 60C in vacuo (5 Torr) over phosphorus pentoxide, whereupon the methanol is eliminated.
In the dissolved state these forms are identical, as is clear from the corresponding solution spectra, e~g. the IR spectra in methylene chloride (see Figures A, B and C). However, in the solid state, the forms differ in their melting characteristics and their solid spectra, e.g. as shown by the corres-ponding IR-KBr spectra (see Figures A', B' and C').
Thus viewed from one aspect the present invention provides the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl3-benzoic acid ;n solid form having an infra red (IR-KBr) spectrum substantially as shown in either of Figures B' and C', and the enantiomers and salts thereof.
Viewed from another aspect, the invention provides the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid in solid form having a melting point of a-bout 140-142C or about 75-85C, and the enantiomers and salt~ thereof.
Viewed from a third aspect, the invention provides the compound 2-ethoxy-4-[N-(1-(2~piperidino-phenyl)-3-methyl-1-butyl~-aminocarbonylmethyl]-benzoic acid in the solid form obtained by crystallization from an ethanol/water mixture or by removal of methanol from the methanol adduct thereof, and the enantiomers and salts thereof.
In order to measure infra-red absorption, forms (A), (B) and tC) were dissolved in methylene chloride (40 mg of substance per ml of methylene chloride) or intimately triturated with potassium bromide and then compressed hydraulically to form a tablet (approx. 1 mg of substance/300 mg of KBr).
In the case of the solutions, the IR spectra were measured with an IR spectrometer (Perkin Elmer Type 299) in a sodium chloride cell (layer thickness 0.2 mm) by comparison with a pure methylene chloride solution and, in the case of the potassium bromide tablets, with an IR spectrometer (Perkin ~lmer Type 298) by comparison with air.
The infra rea spectra of Forms (A), (B) and (C) are shown in the Figures heretor in which:
Figure A, which is in two parts Al and A2, shows the infra red spectrum of Form A dissolved in methylene chloride;
Figure B, which is in two parts Bl and B2, shows the infra red spectrum of Form B dissolved in me~hylene chloride;
Figure C, which is in two parts Cl and C2, shows the infra red spectrum of Form C dissolved in methylene chloride;
Figure A', which is in two parts A'l and A'2, shows the infra-red spectrum of solid Form A;
Figure B', which is in two parts B'l and B'2, shows the infra-red spectrum of solid Form B; and Figure C', which is in two parts ~'1 and C'2, shows the infra-red spectrum of solid Form C.
The forms can be con~erted into one another by suitable recrystallisation and drying. Thus, the low-melting form (A) may be obtained by recrystallising the high-~elting form (B) from acetone/petroleum ether and the high melting form (B) may be obtained by recrystallising the low melting form (A) from ethanol/water. By recrystallising the high melting form (B) from methanol a 1:1 adduct with methanol is obtained and from this the foamy form (C) may be obtained by eliminating the methanol.
Irrespective of the nature of the process used to synthesise the compound according to t,he invention, therefore, the high melting or low melting or foamy form can be obtained as desired by a suitable choice of solvent or mixture of solvents during crystallisa tion and by suitable drying. This is important in the practical use of the solid forms, whether or not they are accompanied by galenic excipients in pharmaceutical compositions, particularly for lowering blood sugar in the treatment of Type II
diabetes; this is because different solid forms may have different shelf lives and/or different resorption qualities _ vivo and may thus give ~ different pattern of biological activity.
Viewed from a further aspect the present invention provides a process for prepar;ng the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl~-benzoic acid in Form (B) or Form (C) comprising recrys~allizing said compound from ethanol and water or from methanol with the subsequent removal of adducted methanol from the resultant solid, and subsequently i~ desired converting the compound into a salt thereof, particu-larly a physiologically acceptable salt with an organic or inorganic acid or base.
~2~
The compound to be recrystallized in this way may itself be prepared by the processes described in EP-A-147850 or preferably by reacting 3-methyl-1-(2-piperidino-phenyl)-1-butylamine with a compound of formula I
HOOC-CH2~ W
twherein W represents a carboxy group or a carboxyl group protected by a protecting group) or with a reactive derivatlve thereof, optionally prepared in the reaction mixture, if necessary with subsequent splitting off of any protecting group used; the new solid forms (B) and (C) may then be obtained by suitable subsequent crystalli-sation, by suitable final recrystallisation and/or drying, as described above.
Examples of reactive derivatives of a compound of formula I include the esters such as the methyl, ethyl and benzyl esters thereof, the thioesters such as the methylthio and ethylthioesters, the halides such as the acid chloride, the anhydri~es and imidazolides thereof.
The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence ~2~
of ethyl chloroformate, thionyl chloride, phosphorus tr;chloride, phosphorus pentoxide, N,N'-dicyclohexyl-carbodiimide, N,N'-dicyclonexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyl-diimidazole or triphenylphosphine/carbon tetrachloride, or an amino group activating agent, such as phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of between -25 and 250C, but prefer-ably at temperatures of between -10C and the boiling temperature of the solvent used. The reaction may also be carried out without a solvent, and any water formed during the reaction may be removed by azeotropic aistillation, e.g. by heating with toluene using a water separator or by adding a drying agent such as magnesium sulphate or molecular sieve.
Any subsequent splitting off of a protecting group is preferably carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol/water, ethanol, ethanol/
water, water/isopropanol or water/dioxan at tempera-tures of between -10 and 120C, e.g. at temperatures of between amhient temperature and the boiling temperature of the reaction mixture.
A tert.butyl group used as a protecting group may also be split off thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity ~2~?~
of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid.
Moreover, a benzyl group used as a protecting group may also be split off hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/
charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide.
The subsequent crystallisation is carried out in situ from the reaction mixture containing ethanol/water or, as a final recrystallisation, by dissolving in a mixture of ethanol and water, optionally with heating, and cooling, optiona71y accompanied by trituration and/or seeding (form B), or by dissolving in acetone and adding petroleum ether (form A) or by dissolving ~optionally with heating) in methanol, subsequent cooling accompanied by trituration and/or seeding and heating the isolated solid methanol adducts, preferably in vacuo, in the presence of a drying agent such as phosphorus pentoxide (form C).
The new forms of the compound obtained may, moreover, be conve~ted into the salts thereof, particularly the physiologically acceptable salts with inorganlc or organic acids or bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, ma7eic or fumaric acid and suitable bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanol-amine, triethanolamine, ethylenediamine or lysine.
The compounds used as starting materials are obtained by me~hods known from the literature.
As already mentioned hereinbefore, 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocar~on~l-methyl]-benzoic acid has valuable pharmacological properties, namely an ef~ect on intermediate metabolism, but particularly a hypoglycaemic activity.
For example, the high melting form (B) of the compound
EP-A-147850 of 10th July 1985 twhich is not a prior publication) describes the compound 2-ethoxy-4-rN-(l-(2-piperidino-phenyl)-3-methy~ butyl)-amin carbonylmethyl]-benzoic acid with a melting point of 90-92C (acetone/petroleum ether; Form (A)).
According to Example 11 o EP~A-147850, this compound is obtained by catalytic hydrogenation of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-me-thyl-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid and like its physiologically acceptable addition salts and enantiomers it has valuable pharmacological properties, namely an effect on intermediate metabolism, particu-larly a hypoglycaemic activity.
Surprisingly, it has now been founa that the same compoundr namely 2-ethoxy-4-~N-tl-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, is obtained in other solid forms when crystallised from other solvents or mixtures of solvents. Form (B), which has a melting point of from 140 to 142C, may be obtained by crystalli-sation from an ethanol/water mixture and the foamy form, Form (C), which has a melting range Erom 75 ,~ ~
to 85C, may be obtained from the 1:1 methanol adduct (melting point: 85 to 90C), which occurs on crystal-lisation from methanol, by heating at 60C in vacuo (5 Torr) over phosphorus pentoxide, whereupon the methanol is eliminated.
In the dissolved state these forms are identical, as is clear from the corresponding solution spectra, e~g. the IR spectra in methylene chloride (see Figures A, B and C). However, in the solid state, the forms differ in their melting characteristics and their solid spectra, e.g. as shown by the corres-ponding IR-KBr spectra (see Figures A', B' and C').
Thus viewed from one aspect the present invention provides the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl3-benzoic acid ;n solid form having an infra red (IR-KBr) spectrum substantially as shown in either of Figures B' and C', and the enantiomers and salts thereof.
Viewed from another aspect, the invention provides the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid in solid form having a melting point of a-bout 140-142C or about 75-85C, and the enantiomers and salt~ thereof.
Viewed from a third aspect, the invention provides the compound 2-ethoxy-4-[N-(1-(2~piperidino-phenyl)-3-methyl-1-butyl~-aminocarbonylmethyl]-benzoic acid in the solid form obtained by crystallization from an ethanol/water mixture or by removal of methanol from the methanol adduct thereof, and the enantiomers and salts thereof.
In order to measure infra-red absorption, forms (A), (B) and tC) were dissolved in methylene chloride (40 mg of substance per ml of methylene chloride) or intimately triturated with potassium bromide and then compressed hydraulically to form a tablet (approx. 1 mg of substance/300 mg of KBr).
In the case of the solutions, the IR spectra were measured with an IR spectrometer (Perkin Elmer Type 299) in a sodium chloride cell (layer thickness 0.2 mm) by comparison with a pure methylene chloride solution and, in the case of the potassium bromide tablets, with an IR spectrometer (Perkin ~lmer Type 298) by comparison with air.
The infra rea spectra of Forms (A), (B) and (C) are shown in the Figures heretor in which:
Figure A, which is in two parts Al and A2, shows the infra red spectrum of Form A dissolved in methylene chloride;
Figure B, which is in two parts Bl and B2, shows the infra red spectrum of Form B dissolved in me~hylene chloride;
Figure C, which is in two parts Cl and C2, shows the infra red spectrum of Form C dissolved in methylene chloride;
Figure A', which is in two parts A'l and A'2, shows the infra-red spectrum of solid Form A;
Figure B', which is in two parts B'l and B'2, shows the infra-red spectrum of solid Form B; and Figure C', which is in two parts ~'1 and C'2, shows the infra-red spectrum of solid Form C.
The forms can be con~erted into one another by suitable recrystallisation and drying. Thus, the low-melting form (A) may be obtained by recrystallising the high-~elting form (B) from acetone/petroleum ether and the high melting form (B) may be obtained by recrystallising the low melting form (A) from ethanol/water. By recrystallising the high melting form (B) from methanol a 1:1 adduct with methanol is obtained and from this the foamy form (C) may be obtained by eliminating the methanol.
Irrespective of the nature of the process used to synthesise the compound according to t,he invention, therefore, the high melting or low melting or foamy form can be obtained as desired by a suitable choice of solvent or mixture of solvents during crystallisa tion and by suitable drying. This is important in the practical use of the solid forms, whether or not they are accompanied by galenic excipients in pharmaceutical compositions, particularly for lowering blood sugar in the treatment of Type II
diabetes; this is because different solid forms may have different shelf lives and/or different resorption qualities _ vivo and may thus give ~ different pattern of biological activity.
Viewed from a further aspect the present invention provides a process for prepar;ng the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl~-benzoic acid in Form (B) or Form (C) comprising recrys~allizing said compound from ethanol and water or from methanol with the subsequent removal of adducted methanol from the resultant solid, and subsequently i~ desired converting the compound into a salt thereof, particu-larly a physiologically acceptable salt with an organic or inorganic acid or base.
~2~
The compound to be recrystallized in this way may itself be prepared by the processes described in EP-A-147850 or preferably by reacting 3-methyl-1-(2-piperidino-phenyl)-1-butylamine with a compound of formula I
HOOC-CH2~ W
twherein W represents a carboxy group or a carboxyl group protected by a protecting group) or with a reactive derivatlve thereof, optionally prepared in the reaction mixture, if necessary with subsequent splitting off of any protecting group used; the new solid forms (B) and (C) may then be obtained by suitable subsequent crystalli-sation, by suitable final recrystallisation and/or drying, as described above.
Examples of reactive derivatives of a compound of formula I include the esters such as the methyl, ethyl and benzyl esters thereof, the thioesters such as the methylthio and ethylthioesters, the halides such as the acid chloride, the anhydri~es and imidazolides thereof.
The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence ~2~
of ethyl chloroformate, thionyl chloride, phosphorus tr;chloride, phosphorus pentoxide, N,N'-dicyclohexyl-carbodiimide, N,N'-dicyclonexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyl-diimidazole or triphenylphosphine/carbon tetrachloride, or an amino group activating agent, such as phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of between -25 and 250C, but prefer-ably at temperatures of between -10C and the boiling temperature of the solvent used. The reaction may also be carried out without a solvent, and any water formed during the reaction may be removed by azeotropic aistillation, e.g. by heating with toluene using a water separator or by adding a drying agent such as magnesium sulphate or molecular sieve.
Any subsequent splitting off of a protecting group is preferably carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol/water, ethanol, ethanol/
water, water/isopropanol or water/dioxan at tempera-tures of between -10 and 120C, e.g. at temperatures of between amhient temperature and the boiling temperature of the reaction mixture.
A tert.butyl group used as a protecting group may also be split off thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity ~2~?~
of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid.
Moreover, a benzyl group used as a protecting group may also be split off hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/
charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide.
The subsequent crystallisation is carried out in situ from the reaction mixture containing ethanol/water or, as a final recrystallisation, by dissolving in a mixture of ethanol and water, optionally with heating, and cooling, optiona71y accompanied by trituration and/or seeding (form B), or by dissolving in acetone and adding petroleum ether (form A) or by dissolving ~optionally with heating) in methanol, subsequent cooling accompanied by trituration and/or seeding and heating the isolated solid methanol adducts, preferably in vacuo, in the presence of a drying agent such as phosphorus pentoxide (form C).
The new forms of the compound obtained may, moreover, be conve~ted into the salts thereof, particularly the physiologically acceptable salts with inorganlc or organic acids or bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, ma7eic or fumaric acid and suitable bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanol-amine, triethanolamine, ethylenediamine or lysine.
The compounds used as starting materials are obtained by me~hods known from the literature.
As already mentioned hereinbefore, 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocar~on~l-methyl]-benzoic acid has valuable pharmacological properties, namely an ef~ect on intermediate metabolism, but particularly a hypoglycaemic activity.
For example, the high melting form (B) of the compound
2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l~butyl)-aminocarbonylmethyl~-benzoic acid was investigated for its hypoglycaemic activity as follows:
1. Hypoglycaemic activity The hypoglycaemic activity of the test substance was investigated on female rats of our own strain weighing from 180-220 g which had not been fed for 24 hours before the start of the test. The substance under investigation was suspended in 1.5% methyl cellulose immediately before the start of the test and was administered by oesophageal tube.
Blood samples were taken immediately before adminis-trakion of the substance and 1, 2, 3 and 4 hours afterwards, in each case from the retroorbital venous plexus. 50 microlitre batches were deproteinated with 0.5 ml of 0.33 N perchloric acid and centrifuged.
Glucose was determined in the supernatant using the hexokinase mekhod with the aid of an analytical photometer. The results were evaluated statistically using Student's t-tesk taking p = 0.05 as the limit of significance.
The following Table shows the values found in percent compared with the control:
n 0.1 mg/kg Substance 1 2 3 4 h 2. Acute toxicity The toxic effect of a single dosage administered orally (suspended in 1~ methyl cellulose) was tested in male and female mice of our own strain weighing from 20-26 g over an observation period of 14 days, and was found to be:
Substance approximate acute toxicity
1. Hypoglycaemic activity The hypoglycaemic activity of the test substance was investigated on female rats of our own strain weighing from 180-220 g which had not been fed for 24 hours before the start of the test. The substance under investigation was suspended in 1.5% methyl cellulose immediately before the start of the test and was administered by oesophageal tube.
Blood samples were taken immediately before adminis-trakion of the substance and 1, 2, 3 and 4 hours afterwards, in each case from the retroorbital venous plexus. 50 microlitre batches were deproteinated with 0.5 ml of 0.33 N perchloric acid and centrifuged.
Glucose was determined in the supernatant using the hexokinase mekhod with the aid of an analytical photometer. The results were evaluated statistically using Student's t-tesk taking p = 0.05 as the limit of significance.
The following Table shows the values found in percent compared with the control:
n 0.1 mg/kg Substance 1 2 3 4 h 2. Acute toxicity The toxic effect of a single dosage administered orally (suspended in 1~ methyl cellulose) was tested in male and female mice of our own strain weighing from 20-26 g over an observation period of 14 days, and was found to be:
Substance approximate acute toxicity
3 ~1000 mg/kg p.o. (0 out of 6 animals died) In view of its pharmacological properties the compound prepared according to the invention and the physio-logically acceptable salts thereof are suitable for the treatment of diabetes mellitus. For this purpose the compound or ~he salts thereof, optionally combined with other active substances, may be formulated together with at least one pharmaceutical carrier or excipient, for example in conven~ional galenic preparation form such as plain or coated tablets, capsules, powders or suspensions.
The single dosage in adults will conveniently be 1-50 mq, preferably 2.5 - 20 mg, once or twice a day.
Viewed from a still further aspect the invention provides a pharmaceutical compositon comprising the compound of the invention in Form (B) or Form ~9?,~
(C) or an enantiomer or physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
According to a further aspect the invention provides a method of treatment of human or non-human warm-blooded animals to combat diabetes mellitus, which method comprises administering to said animal the compound of the invention in Form (B) or Form (C) or an enantiomer or physiologically acceptable salt thereof.
According to a still further aspect the invention provides the use of the compound of the invention in Form (B) or Form (C) or an enantiomer or physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of diabetes mellitus.
The Examples are intended to illustrate the invention in a non-limiting fashion. Percentages and ratios are by weight unless otherwise indicated.
The melting points referred to in the Examples were determined in an ElectrothermalR melting point apparatus with visual observation of the sample of substance located in a capillary tube fused at one end.
Example 1 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenYl)-3-methYl-l-butyl)-aminocarbonylmethyl]-benzoate To a solution of 2.9 g (11.9 mmol) of 3-methyl-1-(2-piperidino-phenyl~ butylamine in 29 ml of acetonitrile are added, successively, 3 g (11.9 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mmol) of triphenylphosphine, 3.3 ml (23.8 mmol) of triethylamine and 1.15 ml (11.9 mmol) of carbon tetrachloride. The mixture is then stirred for 15 hours at ambient temperature, the solvent is eliminated in vacuo and the residue is partitioned between ethyl acetate and water. The or~anic extract is dried over sodium sulphate, filtered and concen-trated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).
Yield: 4.9 g (85% of theory), Melting point: 143-145C (petroleum ether~
Calculated: C 72.47 H 8.39 N 5.83 Found: 72.37 8.45 6.07 Example 2 Hiqh melting form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonYlmethyl]-benz-oic acid A mixture of 4.7 g (9.7 mmol) of ethyl 2-ethoxy-
The single dosage in adults will conveniently be 1-50 mq, preferably 2.5 - 20 mg, once or twice a day.
Viewed from a still further aspect the invention provides a pharmaceutical compositon comprising the compound of the invention in Form (B) or Form ~9?,~
(C) or an enantiomer or physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
According to a further aspect the invention provides a method of treatment of human or non-human warm-blooded animals to combat diabetes mellitus, which method comprises administering to said animal the compound of the invention in Form (B) or Form (C) or an enantiomer or physiologically acceptable salt thereof.
According to a still further aspect the invention provides the use of the compound of the invention in Form (B) or Form (C) or an enantiomer or physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of diabetes mellitus.
The Examples are intended to illustrate the invention in a non-limiting fashion. Percentages and ratios are by weight unless otherwise indicated.
The melting points referred to in the Examples were determined in an ElectrothermalR melting point apparatus with visual observation of the sample of substance located in a capillary tube fused at one end.
Example 1 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenYl)-3-methYl-l-butyl)-aminocarbonylmethyl]-benzoate To a solution of 2.9 g (11.9 mmol) of 3-methyl-1-(2-piperidino-phenyl~ butylamine in 29 ml of acetonitrile are added, successively, 3 g (11.9 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mmol) of triphenylphosphine, 3.3 ml (23.8 mmol) of triethylamine and 1.15 ml (11.9 mmol) of carbon tetrachloride. The mixture is then stirred for 15 hours at ambient temperature, the solvent is eliminated in vacuo and the residue is partitioned between ethyl acetate and water. The or~anic extract is dried over sodium sulphate, filtered and concen-trated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).
Yield: 4.9 g (85% of theory), Melting point: 143-145C (petroleum ether~
Calculated: C 72.47 H 8.39 N 5.83 Found: 72.37 8.45 6.07 Example 2 Hiqh melting form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonYlmethyl]-benz-oic acid A mixture of 4.7 g (9.7 mmol) of ethyl 2-ethoxy-
4-rN-(l-(2-piperidino-phenyl)-3-methyl-l-butyl) aminocarbonylmethyl]-benzoate and 14.7 ml of lN
sodium hydroxide solution is stirred in 47 ml of ethanol for 2 hours at 60C, then neutralised with 14.7 ml of lN hydrochloric acid and cooled to 0C.
The mixture is filtered to remove the precipitated colourless crystals, the crystals are washed with ice water and with a little ice cold ethanol and dried at 100C/l Torr.
Yield: 3.9 9 (88% of theory), Melting point: 140-142C
Calculated: ~ 71.65 H 8.02 N 6.19 Found: 71.90 8.08 6.34 On further recrystallisation from ethanol/water (2/1) the melting point remains constant.
Example 3 Low meltiny form (A) of 2-ethoxy-4-[N-(1-(2-piperidino-~henyl)-3-meth~l-l-butyl)-aminocarbonYlmethvl]
benzoic acid 1.0 g of the high melting form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid is dissolved at ambient temperature in 5 ml of acetone and 5 ml of petroleum ether (60-70C3 are added. On trituration, crystallisation gradually sets in. The same quantity of petroleum ether is added again and, after crystal-lisation has ended, the mixture is filtered. The crystals are washed with petroleum ether and the almost colourless crystals are dried for 2 hours at 60C/0.1 Torr.
Yield: 0.7 g, Melting point: 95-98C (clear above 135C) Calculated: C 71.65 ~ 8.02 N 6.19 Found: 71.80 8.04 5.92 The IoR~ spectra for this form (see Figures A and A') are identical to the I.R. spectra for the form (A~, melting point 90-92C, ~escribed in the European Published Patent Application EP-A-147850 mentioned hereinbefore.
Example 4 High meltinq form (B) of 2-ethoxy-4-[N-~1-(2-piperidino-~henyl~-3-methyl-1-butyl)-aminocarbonYlmethyl]-_nzoic acid 1.0 g of the low melting form (A) of 2-ethoxy-4-[N-(1-(2~piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]-benzoic acid is dissolved in 10 ml of ethanol/water (2/1) whilst hea~ing over a steam bath. The mixture is then cooled to 0C whereupon crystallisation begins. The mixture is filtered, the residue is washed with a little ice cold ethanol and dried at 100C/l Torr.
Yield: 0.8 g, Melting point: 140-142C
Exam~ 5 Foamy form (C) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonY~lmeth benzoic acid 1.5 g of the high melting form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid are dissolved in 5 ml of methanol with heating. The solution is then cooled to 0C with trituration. The crystals precipitated are separated by fil~ering~ washed with a little cold methanol and dried for 2 hours at 60C/0.1 Torr.
Yield of adduct (with 1 x CH30H): 1.2 g, Melting point: 85-90C
Calculated: (x 1 CH30H): C 69.39 H 8.32 N 5.78 Found: 69.20 8.20 5.92 The above adduct is converted into the methanol-free foamy form (C) by heating for 24 hours at 60C/5 Torr over phosphorus pentoxide.
Melting range: 75-85C
Calculated: C 71.65 H 8.02 N 6.19 Found: 71.82 8.06 6.03 Example 6 Tablets containing 5 mg_of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonYlmethyl]-benzoic acid ,, Composition:
1 tablet contains:
Active substance (1) 5.0 mg Corn starch (2) 62.0 mg Lactose (3) 48.0 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate (5) 1.0 mg 120.0 mg Preparation Components 1, 2, 3 and 4 are mixed together and moistened with water. The moist mixture is passed through a 1.5 mm mesh screen and dried at about 45C. The dry granulate is passed through a screen with a mesh size of 1.0 mm and mixed with component
sodium hydroxide solution is stirred in 47 ml of ethanol for 2 hours at 60C, then neutralised with 14.7 ml of lN hydrochloric acid and cooled to 0C.
The mixture is filtered to remove the precipitated colourless crystals, the crystals are washed with ice water and with a little ice cold ethanol and dried at 100C/l Torr.
Yield: 3.9 9 (88% of theory), Melting point: 140-142C
Calculated: ~ 71.65 H 8.02 N 6.19 Found: 71.90 8.08 6.34 On further recrystallisation from ethanol/water (2/1) the melting point remains constant.
Example 3 Low meltiny form (A) of 2-ethoxy-4-[N-(1-(2-piperidino-~henyl)-3-meth~l-l-butyl)-aminocarbonYlmethvl]
benzoic acid 1.0 g of the high melting form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid is dissolved at ambient temperature in 5 ml of acetone and 5 ml of petroleum ether (60-70C3 are added. On trituration, crystallisation gradually sets in. The same quantity of petroleum ether is added again and, after crystal-lisation has ended, the mixture is filtered. The crystals are washed with petroleum ether and the almost colourless crystals are dried for 2 hours at 60C/0.1 Torr.
Yield: 0.7 g, Melting point: 95-98C (clear above 135C) Calculated: C 71.65 ~ 8.02 N 6.19 Found: 71.80 8.04 5.92 The IoR~ spectra for this form (see Figures A and A') are identical to the I.R. spectra for the form (A~, melting point 90-92C, ~escribed in the European Published Patent Application EP-A-147850 mentioned hereinbefore.
Example 4 High meltinq form (B) of 2-ethoxy-4-[N-~1-(2-piperidino-~henyl~-3-methyl-1-butyl)-aminocarbonYlmethyl]-_nzoic acid 1.0 g of the low melting form (A) of 2-ethoxy-4-[N-(1-(2~piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]-benzoic acid is dissolved in 10 ml of ethanol/water (2/1) whilst hea~ing over a steam bath. The mixture is then cooled to 0C whereupon crystallisation begins. The mixture is filtered, the residue is washed with a little ice cold ethanol and dried at 100C/l Torr.
Yield: 0.8 g, Melting point: 140-142C
Exam~ 5 Foamy form (C) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonY~lmeth benzoic acid 1.5 g of the high melting form (B) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid are dissolved in 5 ml of methanol with heating. The solution is then cooled to 0C with trituration. The crystals precipitated are separated by fil~ering~ washed with a little cold methanol and dried for 2 hours at 60C/0.1 Torr.
Yield of adduct (with 1 x CH30H): 1.2 g, Melting point: 85-90C
Calculated: (x 1 CH30H): C 69.39 H 8.32 N 5.78 Found: 69.20 8.20 5.92 The above adduct is converted into the methanol-free foamy form (C) by heating for 24 hours at 60C/5 Torr over phosphorus pentoxide.
Melting range: 75-85C
Calculated: C 71.65 H 8.02 N 6.19 Found: 71.82 8.06 6.03 Example 6 Tablets containing 5 mg_of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonYlmethyl]-benzoic acid ,, Composition:
1 tablet contains:
Active substance (1) 5.0 mg Corn starch (2) 62.0 mg Lactose (3) 48.0 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate (5) 1.0 mg 120.0 mg Preparation Components 1, 2, 3 and 4 are mixed together and moistened with water. The moist mixture is passed through a 1.5 mm mesh screen and dried at about 45C. The dry granulate is passed through a screen with a mesh size of 1.0 mm and mixed with component
5. The finished mixture is compressed in a tablet press with dies measuring 7 mm in diameter, provided with a dividing notch, to form tablets.
Weight of tablet: 120 mg Example 7 Coated tablets containing 2.5 mg of 2-ethoxy-4-[N~ (2-piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]-benzoic acid 1 tablet core contains:
Active substance ~1) 2.5 mg Potato starch (2) 44.0 mg Lactose (3) 30.0 mg Polyvinylpyrrolidone (4) 3.0 mg Magnesium stearate (5) 0.5 mg 80.0 mg Preparation Components 1, 2, 3 and 4 are thoroughly mixed and moistened with water. The moist mass is passed through a screen with a 1 mm mesh, dried at about 459C and the granulate is then passed through the same screen again. After component 5 has been added, convex tablet cores with a diameter o 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax~
Weight of coated tablet: 120 mg Example 8 Tablets containinq 10 mg of 2-ethoxy-4-[~-~1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl~-benzoic acid Composition:
1 tablet contains:
Active substance10.0 mg Powdered lactose70.0 mg Corn starch 31.0 mg Polyvinylpyrrolidone 8.0 mg Magnesium stearate1.0 mg 120.0 mg Pre~aration The mixture of active substance, lactose and cornstarch is moistened with a 20% ~olution of polyvinyl-pyrrolidone in water. The moist mass is granulated through a screen with a mesh size of 1.5 mm and dried at 45C. The dried granulate is rubbed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate.
Weight of tablet: 120 mg Die:7 mm diameter with dividing notch Example 9 Coated tablets containing 5 mq of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l~butyl)-aminocarbonyl-methyl]-benzoic acid 1 tablet core contains:
Active substance 5.0 mg Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone4.0 mg Magnesium stearate 1.0 mg 130 mg PreParation The mixture of active substance, calcium phosphate and corn starch is moistened with a 15~ solution of polyvinylpyrrolidone in water. The moist mass is passed through a screen with a 1 mm mesh, dried at 45C and then passed through the same screen again. After the specified quantity of magnesium stearate has been added, tablet cores are produced by compressing.
Weight of core: 130 mg Die: 7 mm diameter A coating of sugar and talc is applied to the ~ablet cores thus produced in a known manner. The finished coated tablets are polished with wax.
Weight of coated tablet: 180 mg
Weight of tablet: 120 mg Example 7 Coated tablets containing 2.5 mg of 2-ethoxy-4-[N~ (2-piperidino-phenyl)-3-methyl-1-butyl)-amino-carbonylmethyl]-benzoic acid 1 tablet core contains:
Active substance ~1) 2.5 mg Potato starch (2) 44.0 mg Lactose (3) 30.0 mg Polyvinylpyrrolidone (4) 3.0 mg Magnesium stearate (5) 0.5 mg 80.0 mg Preparation Components 1, 2, 3 and 4 are thoroughly mixed and moistened with water. The moist mass is passed through a screen with a 1 mm mesh, dried at about 459C and the granulate is then passed through the same screen again. After component 5 has been added, convex tablet cores with a diameter o 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax~
Weight of coated tablet: 120 mg Example 8 Tablets containinq 10 mg of 2-ethoxy-4-[~-~1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl~-benzoic acid Composition:
1 tablet contains:
Active substance10.0 mg Powdered lactose70.0 mg Corn starch 31.0 mg Polyvinylpyrrolidone 8.0 mg Magnesium stearate1.0 mg 120.0 mg Pre~aration The mixture of active substance, lactose and cornstarch is moistened with a 20% ~olution of polyvinyl-pyrrolidone in water. The moist mass is granulated through a screen with a mesh size of 1.5 mm and dried at 45C. The dried granulate is rubbed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate.
Weight of tablet: 120 mg Die:7 mm diameter with dividing notch Example 9 Coated tablets containing 5 mq of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l~butyl)-aminocarbonyl-methyl]-benzoic acid 1 tablet core contains:
Active substance 5.0 mg Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone4.0 mg Magnesium stearate 1.0 mg 130 mg PreParation The mixture of active substance, calcium phosphate and corn starch is moistened with a 15~ solution of polyvinylpyrrolidone in water. The moist mass is passed through a screen with a 1 mm mesh, dried at 45C and then passed through the same screen again. After the specified quantity of magnesium stearate has been added, tablet cores are produced by compressing.
Weight of core: 130 mg Die: 7 mm diameter A coating of sugar and talc is applied to the ~ablet cores thus produced in a known manner. The finished coated tablets are polished with wax.
Weight of coated tablet: 180 mg
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonylmethyl]-benzoic acid in solid form having an infrared (IR-KBr) spectrum substantially as shown in either of Figures B' and C', and the enantiomers and the salts thereof.
2. The compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonylmethyl]-benzoic acid in solid form having a melting point of about 140-142°C or about 75-85°C, and the enantiomers and salts thereof.
3. The compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonylmethyl]-benzoic acid in the solid form obtained by crystallization from an ethanol/water mixture or by removal of methanol from the methanol adduct thereof, and the enantiomers and salts thereof.
4. 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid as claimed in any one of claims 1 to 3 with a melting point of about 140-142°C, the enantiomers and the salts thereof.
5. 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)-benzoic acid as claimed in any one of claims 1 to 3 with a melting point of about 75-85°C, the enantiomers and the salts thereof.
6. A compound as claimed in any one of claims 1 to 3 being in the form of a physiologically acceptable salt.
7. A compound as claimed in claim 4 being in the form of a physiologically acceptable salt.
8. A compound as claimed in claim 5 being in the form of a physiologically acceptable salt.
9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
10. A pharmaceutical composition comprising a compound as claimed in claim 4 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
11. A pharmaceutical composition comprising a compound as claimed in claim 5 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
12. A process for preparing the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid in Form (B) or Form (C) comprising recrystallizing said compound from ethanol and water or from methanol with the subsequent removal of adducted methanol from the resultant solid, and subsequently if required converting the compound into a salt thereof.
13. A process for preparing the compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid in Form (B) or Form (C) comprising recrystallizing said compound from ethanol and water or from methanol with the subsequent removal of adducted methanol from the resultant solid, and subsequently if required converting the compound into a physiologically acceptable salt with an organic or inorganic acid or base.
14. A process as claimed in claim 12, wherein 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)aminocarbonylmethyl]-benzoic acid is first prepared by reacting 3-methyl-1-(2-piperidino-phenyl)-1-butyl-amine with a compound of formula I
(I) (wherein W represents a carboxy group or a carboxy group protected by a protecting group) or with a reactive derivative thereof, if necessary with subsequent splitting off of any protecting group
(I) (wherein W represents a carboxy group or a carboxy group protected by a protecting group) or with a reactive derivative thereof, if necessary with subsequent splitting off of any protecting group
A process as claimed in claim 14, wherein the reaction is carried out in the presence of an acid activating or dehydrating agent, and at a temperature of between -25 and 250°C.
16. A process a claimed in claim 15 wherein the reaction is carried out in the presence of an inorganic or tertiary organic base.
17. Use of a compound as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof for the treatment of diabetes mellitus.
18. Use of a compound as claimed in claim 4 or a physiologically acceptable salt thereof for the treatment of diabetes mellitus.
19. Use of a compound as claimed in claim 5 or a physiologically acceptable salt thereof for the treatment of diabetes mellitus.
20. A process for the manufacture of a therapeutic agent for the treatment of diabetes mellitus, which process comprises incorporating a compound as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof as active pharmaceutical ingredient in the therapeutic agent, together with a suitable diluent or carrier.
21. A process for the manufacture of a therapeutic agent for the treatment of diabetes mellitus, which process comprises incorporating a compound as claimed in claim 4 or a physiologically acceptable salt thereof as active pharmaceutical ingredient in the therapeutic agent, together with a suitable diluent or carrier.
22. A process for the manufacture of a therapeutic agent for the treatment of diabetes mellitus, which process comprises incorporating a compound as claimed in claim 5 or a physiologically acceptable salt thereof as active pharmaceutical ingredient in the therapeutic agent, together with a suitable diluent or carrier.
23. A commercial package containing a compound as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof as active pharmaceutical ingredient, together with instructions for the use thereof in the treatment of diabetes mellitus.
24. A commercial package containing a compound as claimed in claim 4 or a physiologically acceptable salt thereof as active pharmaceutical ingredient, together with instructions for the use thereof in the treatment of diabetes mellitus.
25. A commercial package containing a compound as claimed in claim 5 or a physiologically acceptable salt thereof as active pharmaceutical ingredient, together with instructions for the use thereof in the treatment of diabetes mellitus.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833347565 DE3347565A1 (en) | 1983-12-30 | 1983-12-30 | NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DEP3522604.8 | 1985-06-25 | ||
| DE19853522604 DE3522604A1 (en) | 1983-12-30 | 1985-06-25 | NEW SOLID FORMS OF 2- (GAMMA) THOXY-4- (N- (1- (2- (2-PIPERIDINO-PHENYL) -3-METHYL-1-BUTYL) -AMINOCARBONYLMETHYL) -BENZOESIC ACID, MEDICINAL PRODUCTS CONTAINING THESE FORMS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1292000C true CA1292000C (en) | 1991-11-12 |
Family
ID=37847099
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000471120A Expired CA1225398A (en) | 1983-12-30 | 1984-12-28 | Phenylacetic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them |
| CA000512269A Expired - Lifetime CA1292000C (en) | 1983-12-30 | 1986-06-24 | Solid forms of 2-ethoxy-4-[n-(1-(2-piperidino- phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000471120A Expired CA1225398A (en) | 1983-12-30 | 1984-12-28 | Phenylacetic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them |
Country Status (26)
| Country | Link |
|---|---|
| EP (2) | EP0147850B1 (en) |
| JP (2) | JPH0623200B2 (en) |
| KR (1) | KR900005320B1 (en) |
| AT (1) | ATE44027T1 (en) |
| AU (2) | AU577815B2 (en) |
| BG (1) | BG61519B2 (en) |
| CA (2) | CA1225398A (en) |
| CS (1) | CS409791A3 (en) |
| DD (1) | DD231348A5 (en) |
| DE (4) | DE3347565A1 (en) |
| DK (2) | DK167439B1 (en) |
| ES (7) | ES8605500A1 (en) |
| FI (2) | FI80447C (en) |
| GR (2) | GR82614B (en) |
| HK (1) | HK87492A (en) |
| HU (1) | HU194548B (en) |
| IE (1) | IE57700B1 (en) |
| IL (2) | IL73963A (en) |
| LU (1) | LU90301I2 (en) |
| MX (1) | MX9202772A (en) |
| NL (1) | NL980034I1 (en) |
| NO (3) | NO162819C (en) |
| NZ (2) | NZ210657A (en) |
| PT (2) | PT79772B (en) |
| SG (1) | SG55492G (en) |
| ZA (2) | ZA8410103B (en) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3523466A1 (en) * | 1985-07-01 | 1987-01-08 | Thomae Gmbh Dr K | NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DE3347565A1 (en) * | 1983-12-30 | 1985-07-11 | Thomae Gmbh Dr K | NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| ES2136600T3 (en) * | 1991-06-21 | 1999-12-01 | Boehringer Ingelheim Pharma | USE OF ACID (S) (+) - 2-ETOXI-4- (N- (1- (2-PIPERIDINO-FENIL) -3-METHYL-1-BUTYL) AMINO CARBONYL METHYL) -BENZOIC FOR THE PREPARATION OF A LONG ANTIDIABETIC DURATION. |
| SG43036A1 (en) * | 1991-06-21 | 1997-10-17 | Thomae Gmbh Dr K | (S) (+) -2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl- 1-buthyl]aminocarbony methyl] - benzoic a cid |
| FR2763590B1 (en) * | 1997-05-22 | 2000-03-24 | Synthelabo | ACID DERIVATIVES [[[(ARYLMETHYL) AMINO] CARBONYL] ALKYL] - AROMATICS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| JP2003520226A (en) | 2000-01-21 | 2003-07-02 | ノバルティス アクチエンゲゼルシャフト | Combination comprising a dipeptidyl peptidase-IV inhibitor and an antidiabetic agent |
| US20040102477A1 (en) * | 2002-08-23 | 2004-05-27 | Dr. Reddy's Laboratories Limited | Polymorphic forms of (S)-Repaglinide and the processes for preparation thereof |
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| US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
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| AP2015008621A0 (en) | 2013-02-14 | 2015-07-31 | Novartis Ag | Substituted bisphenyl butanoic nep 'neutral endopeptidase' inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3100535A1 (en) * | 1981-01-10 | 1982-08-12 | Dr. Karl Thomae Gmbh, 7950 Biberach | "NEW CARBONIC ACID DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS" |
| DE3100575A1 (en) * | 1981-01-10 | 1982-09-02 | Dr. Karl Thomae Gmbh, 7950 Biberach | "NEW BENZOESAEURS, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS" |
| SU1170969A3 (en) * | 1982-07-06 | 1985-07-30 | Др.Карл Томэ,Гмбх (Фирма) | Method of producing derivatives of phenylacetic acid or their salts |
| FR2554875B1 (en) * | 1983-11-10 | 1986-02-28 | Dba | HYDRAULIC BRAKE AMPLIFIER |
| DE3347565A1 (en) * | 1983-12-30 | 1985-07-11 | Thomae Gmbh Dr K | NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DE3523466A1 (en) * | 1985-07-01 | 1987-01-08 | Thomae Gmbh Dr K | NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
-
1983
- 1983-12-30 DE DE19833347565 patent/DE3347565A1/en not_active Withdrawn
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1984
- 1984-12-20 DK DK613184A patent/DK167439B1/en active Protection Beyond IP Right Term
- 1984-12-20 NZ NZ210657A patent/NZ210657A/en unknown
- 1984-12-24 JP JP59272685A patent/JPH0623200B2/en not_active Expired - Lifetime
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- 1984-12-27 EP EP84116359A patent/EP0147850B1/en not_active Expired
- 1984-12-27 ES ES539078A patent/ES8605500A1/en not_active Expired
- 1984-12-27 AT AT84116359T patent/ATE44027T1/en active
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- 1984-12-28 FI FI845145A patent/FI80447C/en active IP Right Grant
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1985
- 1985-06-25 DE DE19853522604 patent/DE3522604A1/en not_active Withdrawn
- 1985-08-05 ES ES545880A patent/ES8604545A1/en not_active Expired
- 1985-08-05 ES ES545882A patent/ES8604547A1/en not_active Expired
- 1985-08-05 ES ES545879A patent/ES8604544A1/en not_active Expired
- 1985-08-05 ES ES545883A patent/ES8604548A1/en not_active Expired
- 1985-08-05 ES ES545881A patent/ES8604546A1/en not_active Expired
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1986
- 1986-06-10 EP EP86107890A patent/EP0207331B1/en not_active Expired - Lifetime
- 1986-06-16 GR GR861558A patent/GR861558B/en unknown
- 1986-06-23 FI FI862650A patent/FI82689C/en not_active IP Right Cessation
- 1986-06-24 DK DK296686A patent/DK167573B1/en not_active IP Right Cessation
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1991
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