CA2369267A1 - Method for producing amidines - Google Patents
Method for producing amidines Download PDFInfo
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- CA2369267A1 CA2369267A1 CA002369267A CA2369267A CA2369267A1 CA 2369267 A1 CA2369267 A1 CA 2369267A1 CA 002369267 A CA002369267 A CA 002369267A CA 2369267 A CA2369267 A CA 2369267A CA 2369267 A1 CA2369267 A1 CA 2369267A1
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- thienylmethylamide
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- amidoximo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for producing amidines that are not substituted on the nitrogen atom and salts thereof with inorganic or organic acids. According to said method, the corresponding carboxylic acid amidoxime s are reacted with Zn in the presence of carboxylic acids.
Description
METHOD FOR PRODUCING AMIDINES
The present invention describes a novel process for preparing amidines which are unsubstituted at the nitrogen and salts thereof with inorganic or organic acids, which comprises reacting appropriate carboxamide oximes with Zn in the presence of carboxylic acids, such as formic acid, acetic acid and propionic acid.
There are already a large number of synthesis methods for preparing amidines which are present as an important structural element in a number of biologically active molecules, such as fibrinogen antagonists (L. Alig et al., J. Med. Chem. ~?. (1992), 4407), Thrombin Inhibitors (H. Vieweg et al., Pharmazie ~7 (1982), 178) or Factor Xa Inhibitors (T. Nagahara et al., J. Med.
Chem. .~ (1993), 1811).
One of the best-tried methods is the two-step transformation of nitriles into amidines via imino esters known as the Pinner reaction (A. Dinner, Chem. Ber. ~,$ (1885), 2845). In general, a large excess of hydrogen chloride in alcohols is used to form the imino ester. The reaction times are frequently very long (J. B.
Medwid, J. Med. Chem. 3~ (1990), 1237). Owing to the concomitant cleavage of acid-labile protective groups or transesterification reactions, the method is unsuitable for preparing more complex molecules. The alternative base-catalyzed preparation of imino esters (F.C. Schaefer et al., J. Org. Chem. ?~ (1.961), 412) is limited to electron-deficient nitriles.
One variant of the Dinner reaction is the reaction of nitriles to amidines via thioamides and S-alkyl thioimino esters (H.
Bredereck, Chem. Ber. ~Q (1957), 1837). This method is widely employed for constructing the amidine functionality in complex compounds such as synthetic thrombin inhibitors (B. Voigt, Pharmazie, ~.$ (1983), 835). However, this method can only be employed for preparing small amounts on a laboratory scale. The chemicals used, hydrogen sulfide (malodorous and highly toxic), methyl iodide or dimethyl sulfate (carcinogenic alkylating agents) and the methyl mercaptan (malodorous and highly toxic) formed as byproduct require extensive safety measures and disposal facilities which can only be ensured in special plants.
Moreover, the products generally have to be purified by chromatography.
The present invention describes a novel process for preparing amidines which are unsubstituted at the nitrogen and salts thereof with inorganic or organic acids, which comprises reacting appropriate carboxamide oximes with Zn in the presence of carboxylic acids, such as formic acid, acetic acid and propionic acid.
There are already a large number of synthesis methods for preparing amidines which are present as an important structural element in a number of biologically active molecules, such as fibrinogen antagonists (L. Alig et al., J. Med. Chem. ~?. (1992), 4407), Thrombin Inhibitors (H. Vieweg et al., Pharmazie ~7 (1982), 178) or Factor Xa Inhibitors (T. Nagahara et al., J. Med.
Chem. .~ (1993), 1811).
One of the best-tried methods is the two-step transformation of nitriles into amidines via imino esters known as the Pinner reaction (A. Dinner, Chem. Ber. ~,$ (1885), 2845). In general, a large excess of hydrogen chloride in alcohols is used to form the imino ester. The reaction times are frequently very long (J. B.
Medwid, J. Med. Chem. 3~ (1990), 1237). Owing to the concomitant cleavage of acid-labile protective groups or transesterification reactions, the method is unsuitable for preparing more complex molecules. The alternative base-catalyzed preparation of imino esters (F.C. Schaefer et al., J. Org. Chem. ?~ (1.961), 412) is limited to electron-deficient nitriles.
One variant of the Dinner reaction is the reaction of nitriles to amidines via thioamides and S-alkyl thioimino esters (H.
Bredereck, Chem. Ber. ~Q (1957), 1837). This method is widely employed for constructing the amidine functionality in complex compounds such as synthetic thrombin inhibitors (B. Voigt, Pharmazie, ~.$ (1983), 835). However, this method can only be employed for preparing small amounts on a laboratory scale. The chemicals used, hydrogen sulfide (malodorous and highly toxic), methyl iodide or dimethyl sulfate (carcinogenic alkylating agents) and the methyl mercaptan (malodorous and highly toxic) formed as byproduct require extensive safety measures and disposal facilities which can only be ensured in special plants.
Moreover, the products generally have to be purified by chromatography.
Acnidines can also be prepared by hydrogenolytic cleavage of the N-O bond of carboxamide oximes (H.Jendralla et al., Tetrahedron ~1 (1995), 12047; B.D. Judkins, Synth. Commun. ~ (1996), 4351) using hydrogen and palladium/carbon catalysts. 'This method can not be used for the synthesis of amidines which may contain functionalities which can be hydrogenated, such as CC double bonds, benzyl-substituted 0 or N atoms, etc., in the molecule.
Recently, a number of synthetic medicaments, such as, for example, integrin receptor antagonists, and in particular fibrinogen receptor antagonists, or serinprotease inhibitors, in particular thrombin inhibitors, factor Xa inhibitors, factor VIIIa inhibitors, factor IXa inhibitors, urokinase inhibitors, tryplase inhibitors, complement inhibitors (for example Cls and Clr), have been described which contain thienylamidines as structural element: factor Xa inhibitors: RPR 120844 (Thromb.
Haemostasis $~,,, No 1, (1999), 157-160,); urokinase inhibitors:
(Fujisawa, WO 9811089); thrombin inhibitors: Eli Lilly W095/23609 (Ex. 65), BASF, WO 98/06741 (Ex. 1-9 etc.), Boehringer Ingelheim DE 19754490 (Ex. 98-103 etc.). It was possible to prepare the unsubstituted 2- or 3-thiophenecarboxamidines by the Pinner reaction described above in good yields (S. Gronowitz, Acta Chem.
Stand B 31, (1977), 771).
Small amounts of the complex substituted thienylamidines disclosed in the abovementioned patent applications have generally been made available via the thioamide route described above. In view of the abovementioned disadvantages of this method, a satisfactory route for preparing relatively large amounts of these compounds has hitherto not been described.
Catalytic hydrogenation of appropriate carboxamide oximes is likewise not suitable, owing to the generally known property of sulfur-containing compounds to poison hydrogenation catalysts (see R. Schroter, Houben-Weyl 11/1, p. 350 and. W.D. Rudolf, Houben-Weyl E6a, p.492).
Simple addition of ammonia under pressure in the presence of ammonium salts (F. C. Schaefer et al., J. Org. Chem. ~ (1962), 1255) gives only poor yields for thiophene carbonitriles.
It is an object of the present invention to provide a method by which even substituted amidines can be prepared in a simple manner, in good yields and on an industrial scale. Of particular interest are syntheses of aryl- and hetarylamidines, in particular of thienylamidines.
Recently, a number of synthetic medicaments, such as, for example, integrin receptor antagonists, and in particular fibrinogen receptor antagonists, or serinprotease inhibitors, in particular thrombin inhibitors, factor Xa inhibitors, factor VIIIa inhibitors, factor IXa inhibitors, urokinase inhibitors, tryplase inhibitors, complement inhibitors (for example Cls and Clr), have been described which contain thienylamidines as structural element: factor Xa inhibitors: RPR 120844 (Thromb.
Haemostasis $~,,, No 1, (1999), 157-160,); urokinase inhibitors:
(Fujisawa, WO 9811089); thrombin inhibitors: Eli Lilly W095/23609 (Ex. 65), BASF, WO 98/06741 (Ex. 1-9 etc.), Boehringer Ingelheim DE 19754490 (Ex. 98-103 etc.). It was possible to prepare the unsubstituted 2- or 3-thiophenecarboxamidines by the Pinner reaction described above in good yields (S. Gronowitz, Acta Chem.
Stand B 31, (1977), 771).
Small amounts of the complex substituted thienylamidines disclosed in the abovementioned patent applications have generally been made available via the thioamide route described above. In view of the abovementioned disadvantages of this method, a satisfactory route for preparing relatively large amounts of these compounds has hitherto not been described.
Catalytic hydrogenation of appropriate carboxamide oximes is likewise not suitable, owing to the generally known property of sulfur-containing compounds to poison hydrogenation catalysts (see R. Schroter, Houben-Weyl 11/1, p. 350 and. W.D. Rudolf, Houben-Weyl E6a, p.492).
Simple addition of ammonia under pressure in the presence of ammonium salts (F. C. Schaefer et al., J. Org. Chem. ~ (1962), 1255) gives only poor yields for thiophene carbonitriles.
It is an object of the present invention to provide a method by which even substituted amidines can be prepared in a simple manner, in good yields and on an industrial scale. Of particular interest are syntheses of aryl- and hetarylamidines, in particular of thienylamidines.
We have found that this object is achieved by a novel, generally applicable process for preparing amidines which are unsubstituted at the nitrogen and salts thereof with inorganic or organic acids, which comprises reacting an appropriate carboxamide oxime with Zn in the presence of carboxylic acids, such as formic acid, acetic acid and propionic acid, preferably acetic acid.
By the novel process, it is possible to prepare even substituted thienylamidines, preferably those in which the amidine function is either in the 2-position or in the 3-position and a further substituent is in one of the three other positions to the sulfur, where the substituent for its part is attached to the thiophene radical via a C, N or 0 atom.
In particular, the process according to the invention as claimed in claim 1 allows the preparation of amidines of the formula I
HN
NHZ
R_N ~ ~ C
S
in which n = 1-3 and R is as defined below C1-C6-alkyl-C0, where alkyl is straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C6-alkoxy-C0, where alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, benzyloxy, aryl such as phenyl or naphthyl, or heteroaryl, such as pyridyl, thienyl, furyl, benzothiazolyl or benzimidazolyl, where these aromatic compounds can be unsubstituted or further mono- or polysubstituted, examples of substituents being C1-C6-alkyl, C1-C6-alkoxy, halogen, amino, mono- or di-C1-C6-alkylamino, a a-amino acid fragment in the R or S configuration, whose N atom is protected in the customary manner as tert-butoxycarbonyl or benzyloxycarbonyl derivative or unprotected, preferably the amino acid fragments 3,4-dehydroproline, 4,5-dehydropipecolinic acid, azetidine, proline, pipecolinic acid, a dipeptide fragment which is unsubstituted or mono- or polysubstituted at the N-terminus, consisting of natural amino acids, the corresponding D-amino acids or amino acids in the L or D form, which are very similar to natural amino acids, preferably 5 combinations of the amino acids 3,4-dehydroproline, 4,5-dehydropipecolinic acid, azetidine, proline, pipecolinic acid, phenylalanine, phenylglycine, cyclohexylalanine, cyclohexylglycine, alanine, valine, glycine, particularly preferably combinations of the amino acids azetidine, proline, 10 3,4-dehydroproline, cyclohexylalanine, cyclohexylglycine, phenylglycine and phenylalanine, other radicals for R are given in the published integrin receptor antagonist and serine protease inhibitor applications, where R in 15 each case corresponds to the molecular fragment which is attached to the heterocyclic alkylamino-substituted amidine radical.
To this end, carboxamide oximes of the formula II
\ NHZ ( II ) R-N
n in which n and R are as defined in formula I are reacted with Zn in the presence of carboxylic acids, such as formic acid, acetic acid and propionic acid, preferably acetic acid, to the corresponding amidines of the formula I.
Compounds of the formula I may contain one or more centers of asymmetry. According to the process according to the invention, it is possible to prepare both pure enantiomers or diastereomers and mixtures of the enantiomers or diastereomers. In the reaction of the process according to the invention, the configuration at the centers of asymmetry is retained.
Thus, the process for preparing compounds of the formula I
provides simple access to the thrombin inhibitors of WO 98/06741, represented therein by the formula III
NH
'4-'B-E-~~ H ( III ) where D is S
.H
-N
The structural elements A, B, E in the meanings of WO 98/06741 correspond to particularly preferred compounds of the formula I
in which the unit A-B-E is represented by the radical R.
The carboxamide oximes required for carrying out the process according to the invention are prepared by known methods (F. Eloy et al., Chem. Rev. ~. (1962), 155) by reacting the corresponding nitriles with hydroxylamine or, preferably, its salts, particularly preferably hydroxylamine-hydrochloride. The corresponding hydroxylamine derivative is preferably employed in a 1- to 3-fold excess. The reaction is carried out in an inert solvent. Preferred solvents are alcohols, such as methanol, ethanol, n-propanol, iso-propanol or n-butanol, if appropriate in a mixture with methylene chloride, toluene or else water. If salts of the hydroxylamine are employed, at least one equivalent of a base which is stronger than hydroxylamine itself has to be added to liberate the hydroxylamine. It is also possible to employ an excess of base, based on the hydroxylamine salt.
Suitable bases are both inorganic bases, such as sodium carbonate (F. Tiemann, Chem. Ber. ~, (1884), 126), and metal alkoxides, such as sodium methoxide or potassium tert-butoxide (B. D.
Judkins, Synth. Commun. 2~ (1996), 4351), but particularly preferably also tertiary amines, such as triethylamine (H.
Jendralla et al., Tetrahedron ~, (1995), 12047) or diisopropylethylamine. The reaction takes place at a temperature as low as room temperature; however, to accelerate the reaction it is possible to heat the reaction mixture up to the boiling point of the reaction solution, but generally not to more than 80°C.
The isolation of the carboxamide oximes varies. In the case of crystallization from the reaction solution, the products are isolated by filtration. In other cases, the reaction mixture is concentrated and taken up in a water-immiscible solvent in which the products are readily soluble. This solution is washed with water which, if appropriate, has been acidified with mineral acid to pH 2, and is concentrated. The residues can be crystallized in a customary manner in a suitable solvent. However, it is generally also possible to subject the products to further reactions without further purification.
By the novel process, it is possible to prepare even substituted thienylamidines, preferably those in which the amidine function is either in the 2-position or in the 3-position and a further substituent is in one of the three other positions to the sulfur, where the substituent for its part is attached to the thiophene radical via a C, N or 0 atom.
In particular, the process according to the invention as claimed in claim 1 allows the preparation of amidines of the formula I
HN
NHZ
R_N ~ ~ C
S
in which n = 1-3 and R is as defined below C1-C6-alkyl-C0, where alkyl is straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C6-alkoxy-C0, where alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, benzyloxy, aryl such as phenyl or naphthyl, or heteroaryl, such as pyridyl, thienyl, furyl, benzothiazolyl or benzimidazolyl, where these aromatic compounds can be unsubstituted or further mono- or polysubstituted, examples of substituents being C1-C6-alkyl, C1-C6-alkoxy, halogen, amino, mono- or di-C1-C6-alkylamino, a a-amino acid fragment in the R or S configuration, whose N atom is protected in the customary manner as tert-butoxycarbonyl or benzyloxycarbonyl derivative or unprotected, preferably the amino acid fragments 3,4-dehydroproline, 4,5-dehydropipecolinic acid, azetidine, proline, pipecolinic acid, a dipeptide fragment which is unsubstituted or mono- or polysubstituted at the N-terminus, consisting of natural amino acids, the corresponding D-amino acids or amino acids in the L or D form, which are very similar to natural amino acids, preferably 5 combinations of the amino acids 3,4-dehydroproline, 4,5-dehydropipecolinic acid, azetidine, proline, pipecolinic acid, phenylalanine, phenylglycine, cyclohexylalanine, cyclohexylglycine, alanine, valine, glycine, particularly preferably combinations of the amino acids azetidine, proline, 10 3,4-dehydroproline, cyclohexylalanine, cyclohexylglycine, phenylglycine and phenylalanine, other radicals for R are given in the published integrin receptor antagonist and serine protease inhibitor applications, where R in 15 each case corresponds to the molecular fragment which is attached to the heterocyclic alkylamino-substituted amidine radical.
To this end, carboxamide oximes of the formula II
\ NHZ ( II ) R-N
n in which n and R are as defined in formula I are reacted with Zn in the presence of carboxylic acids, such as formic acid, acetic acid and propionic acid, preferably acetic acid, to the corresponding amidines of the formula I.
Compounds of the formula I may contain one or more centers of asymmetry. According to the process according to the invention, it is possible to prepare both pure enantiomers or diastereomers and mixtures of the enantiomers or diastereomers. In the reaction of the process according to the invention, the configuration at the centers of asymmetry is retained.
Thus, the process for preparing compounds of the formula I
provides simple access to the thrombin inhibitors of WO 98/06741, represented therein by the formula III
NH
'4-'B-E-~~ H ( III ) where D is S
.H
-N
The structural elements A, B, E in the meanings of WO 98/06741 correspond to particularly preferred compounds of the formula I
in which the unit A-B-E is represented by the radical R.
The carboxamide oximes required for carrying out the process according to the invention are prepared by known methods (F. Eloy et al., Chem. Rev. ~. (1962), 155) by reacting the corresponding nitriles with hydroxylamine or, preferably, its salts, particularly preferably hydroxylamine-hydrochloride. The corresponding hydroxylamine derivative is preferably employed in a 1- to 3-fold excess. The reaction is carried out in an inert solvent. Preferred solvents are alcohols, such as methanol, ethanol, n-propanol, iso-propanol or n-butanol, if appropriate in a mixture with methylene chloride, toluene or else water. If salts of the hydroxylamine are employed, at least one equivalent of a base which is stronger than hydroxylamine itself has to be added to liberate the hydroxylamine. It is also possible to employ an excess of base, based on the hydroxylamine salt.
Suitable bases are both inorganic bases, such as sodium carbonate (F. Tiemann, Chem. Ber. ~, (1884), 126), and metal alkoxides, such as sodium methoxide or potassium tert-butoxide (B. D.
Judkins, Synth. Commun. 2~ (1996), 4351), but particularly preferably also tertiary amines, such as triethylamine (H.
Jendralla et al., Tetrahedron ~, (1995), 12047) or diisopropylethylamine. The reaction takes place at a temperature as low as room temperature; however, to accelerate the reaction it is possible to heat the reaction mixture up to the boiling point of the reaction solution, but generally not to more than 80°C.
The isolation of the carboxamide oximes varies. In the case of crystallization from the reaction solution, the products are isolated by filtration. In other cases, the reaction mixture is concentrated and taken up in a water-immiscible solvent in which the products are readily soluble. This solution is washed with water which, if appropriate, has been acidified with mineral acid to pH 2, and is concentrated. The residues can be crystallized in a customary manner in a suitable solvent. However, it is generally also possible to subject the products to further reactions without further purification.
Some of the compounds of the formula II prepared in this manner are novel compounds and accordingly also form part of the subject matter of the present invention. Particular preference is given to the following compounds:
2-N-Boc-aminomethyl-(4-amidoximo)thiophene 2-N-Cbz-aminomethyl-(4-amidoximo)thiophene N-Boc-Pro-2-(4-amidoximo)thienylmethylamide N-Cbz-Pro-2-(4-amidoximo)thienylmethylamide N-Boc-Aze-2-(4-amidoximo)thienylmethylamide N-Boc-Dhp-2-(4-amidoximo)thienylmethylamide N-Boc-Dep-2-(4-amidoximo)thienylmethylamide Pro-2-(4-amidoximo)thienylmethylamide Aze-2-(4-amidoximo)thienylmethylamide Dhp-2-(4-amidoximo)thienylmethylamide Dep-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-N-Boc-D-Chg-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-N-Boc-D-Cha-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CHZ)-N-Boc-D-Phe-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CHz)-N-Boc-D-Phg-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Chg-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Cha-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Phe-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Phg-Dhp-2-(4-amidoximo)thienylmethylamide List of abbreviations:
Aze: Azetidinecarboxylic acid Boc: tert-butoxycarbonyl t-Bu: tert-butyl Cbz: benzyloxycarbonyl Cha: cyclohexylalanine Chg: cyclohexylglycine Dep: 4,5-dehydropipecolinic acid Dhp: 3,4-dehydroproline Phe: phenylalanine Phg: phenylglycine Pro: proline The synthesis of the amidines according to the process according to the invention is preferably carried out by transferring the carboxamide oximes into a solution of acetic acid, where they are reacted by addition of metallic zinc, which is usually employed as a fine powder. The reaction is usually carried out in a solution of pure acetic acid. However, it is also possible to carry out the reaction in, for example, a solution of propionic acid or in a solvent mixture. Suitable solvents are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol and n-butanol. The zinc is employed in an excess of up to 10 equivalents. The reaction can be carried out in a temperature range of from -10°C to 70°C, and preference is given to a temperature range of from 20 to 50°C. The conversion can be monitored by thin-layer chromatography. A reaction time of from 2 to 5 hours is customary. However, it is also possible to stir the reaction mixture at 20°C for a relatively long period of time.
Work-up is simple. Excess zinc and the zinc salts formed are l0 filtered off, and the reaction mixture is concentrated, The reaction products can either be isolated and characterized at this stage or directly reacted further. In particular, the removal of any protective groups, such as tert-butyl ester or N-tert-butoxycarbonyl groups, can be carried out advantageously without intermediate isolation after the solid Zn residues have been removed.
Reductions of carboxamide oximes with Zn to give amidines have hitherto not been described. With respect to the known reduction of carbaldoximes with Zn to aminomethylene compaunds (G. D. Pandey et al., Indian J. Chem. Sect. B .~~. (1980), 160; E. Testa et al., Chimia ~ (1957), 310; S. Negi et al., Synthesis, (1996), 991), it is surprising that the process according to the invention permits the cleavage of a N,O bond without a C,N double bond present in the same structural element being reduced.
The examples below serve to illustrate the process according to the invention.
2-N-Boc-aminomethyl-(4-amidoximo)thiophene 2-N-Cbz-aminomethyl-(4-amidoximo)thiophene N-Boc-Pro-2-(4-amidoximo)thienylmethylamide N-Cbz-Pro-2-(4-amidoximo)thienylmethylamide N-Boc-Aze-2-(4-amidoximo)thienylmethylamide N-Boc-Dhp-2-(4-amidoximo)thienylmethylamide N-Boc-Dep-2-(4-amidoximo)thienylmethylamide Pro-2-(4-amidoximo)thienylmethylamide Aze-2-(4-amidoximo)thienylmethylamide Dhp-2-(4-amidoximo)thienylmethylamide Dep-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-N-Boc-D-Chg-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-N-Boc-D-Cha-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CHZ)-N-Boc-D-Phe-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CHz)-N-Boc-D-Phg-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Chg-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Cha-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Phe-Dhp-2-(4-amidoximo)thienylmethylamide N-(t-Bu00C-CH2)-NH-D-Phg-Dhp-2-(4-amidoximo)thienylmethylamide List of abbreviations:
Aze: Azetidinecarboxylic acid Boc: tert-butoxycarbonyl t-Bu: tert-butyl Cbz: benzyloxycarbonyl Cha: cyclohexylalanine Chg: cyclohexylglycine Dep: 4,5-dehydropipecolinic acid Dhp: 3,4-dehydroproline Phe: phenylalanine Phg: phenylglycine Pro: proline The synthesis of the amidines according to the process according to the invention is preferably carried out by transferring the carboxamide oximes into a solution of acetic acid, where they are reacted by addition of metallic zinc, which is usually employed as a fine powder. The reaction is usually carried out in a solution of pure acetic acid. However, it is also possible to carry out the reaction in, for example, a solution of propionic acid or in a solvent mixture. Suitable solvents are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol and n-butanol. The zinc is employed in an excess of up to 10 equivalents. The reaction can be carried out in a temperature range of from -10°C to 70°C, and preference is given to a temperature range of from 20 to 50°C. The conversion can be monitored by thin-layer chromatography. A reaction time of from 2 to 5 hours is customary. However, it is also possible to stir the reaction mixture at 20°C for a relatively long period of time.
Work-up is simple. Excess zinc and the zinc salts formed are l0 filtered off, and the reaction mixture is concentrated, The reaction products can either be isolated and characterized at this stage or directly reacted further. In particular, the removal of any protective groups, such as tert-butyl ester or N-tert-butoxycarbonyl groups, can be carried out advantageously without intermediate isolation after the solid Zn residues have been removed.
Reductions of carboxamide oximes with Zn to give amidines have hitherto not been described. With respect to the known reduction of carbaldoximes with Zn to aminomethylene compaunds (G. D. Pandey et al., Indian J. Chem. Sect. B .~~. (1980), 160; E. Testa et al., Chimia ~ (1957), 310; S. Negi et al., Synthesis, (1996), 991), it is surprising that the process according to the invention permits the cleavage of a N,O bond without a C,N double bond present in the same structural element being reduced.
The examples below serve to illustrate the process according to the invention.
Example 1 Synthesis of 2-N-Boc-aminomethyl-(4-amidino)thiophene a) 2-N-Boc-aminomethyl-(4-amidoximo)thiophene 70 g (294 mmol) of 2-N-Boc-aminomethyl-(4-cyano)thiophene together with 51.1 g (735 mmol) of hydroxylammonium chloride were initially charged in 700 ml of ethanol. At 20°C - 30°C, 113.8 g (882 mmol) of diisopropylethylamine were then added, and the reaction mixture was stirred at 20°C - 30°C for 12 h.
For work-up, the ethanol was distilled off under reduced pressure. The residue was taken up in 1000 ml of methylene chloride (CHZC12). The organic phase was washed once with 500 ml and a second time with 250 ml of water. The organic phase was concentrated and the product was then precipitated out by addition of methyl tert-butyl ether (MTBE).
Yield: 78 g 1sC NMR (DMSO; ppm): 148.3 (amidoxime) C11H17N303S (271.34); calculated: (M+H)+ = 272; found: (M+H)+
b) 2-N-Boc-aminomethyl-(4-amidino)thiophene At 20°C, 5 g (18.4 mmol) of the carboxamide oxime prepared according to a) were dissolved in a mixture of 25 ml of acetic acid and 25 ml of methanol. A little at a time, 2.4 g (36.9 mmol) of zinc powder were then added, the internal temperature increasing to 30 - 35°C. After 12 h of stirring at 25 - 40°C, TLC (CH2C12/Methanol 9:1) showed that there was no starting material left. The solids were filtered off and the filter residue was then washed with methanol. The combined filtrates were concentrated at about 50°C under reduced pressure. The residue was dissolved in CH2Clz The CH2C12 phase was washed with water which had been adjusted to pH 12 with aqueous sodium hydroxide solution. The aqueous phase was, after phase separation, reextracted with CH2C12.
The combined CH2C12 -phases were washed until neutral and then concentrated.
Yield: 2.4 g of a solidified foam 13C-NMR (DMSO; ppm): 158.8 (broadened, amidine) C11H17N302S (255.34); calculated (M)+ = 255; found: (M)+ = 255 Example 2 Synthesis of N-Boc-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide a) N-Boc-3,4-dehydroprolyl-2-(4-amidoximo)thienylmethylamide 50 g (177 mmol) of N-Boc-3,4-dehydroprolyl-2-(4-cyano)thienylmethylamide together with 30.8 g (442.5 mmol) of hydroxylammonium chloride were initially charged in 590 ml of ethanol. At 20°C
- 30°C, 113.8 g (882 mmol) of diisopropylethylamine were then added, and the mixture was stirred at 20°C - 30°C for 12 h, after which, according to TLC (CH2C12/methanol 9:1), the reaction had gone to completion. For work-up, most of the ethanol was distilled off under reduced pressure. The residue was taken up in 120 ml of CH2C12. The organic phase was washed with 180 ml of water. The aqueous phase was reextracted once with 60 ml of CHZC12 The combined CH2C12 phases were washed once more with 30 ml of water, filtered and concentrated.
Yield: 66.3 g of a solidified foam.
13C_~ (DMSO; ppm): 147.9 (amidoxime) C16H22N4O4S (366.44); calculated: (M+H)+ = 367; found: (M+H)+ _ b) N-Boc-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide At 40°C, 41.4 g (113 mmol) of the carboxamide oxime prepared according to a) were dissolved in 400 ml of acetic acid. 41.1 g (630 mmol) of zinc powder were then added a little at a time such that the internal temperature did not exceed 50°C.
The mixture was stirred at 25 - 40°C for 2.5 h, after which no more starting material was detected by TLC (CH2C12/methanol 9:1). The solids were filtered off and the filter residue was then washed with acetic acid. The combined filtrates were concentrated at about 50°C under reduced pressure and partitioned between 180 ml of MTBE and 370 ml of water. The aqueous phase was adjusted to pH 7 using aqueous sodium hydroxide solution. The MTBE phase was separated off, and 180 ml of CH2C12 were then added and the aqueous phase was adjusted to pH 12 using aqueous sodium hydroxide solution.
The CHzCl2 phase was separated off and the aqueous phase was then reextracted twice with 150 ml of CH2C12. The combined CHzCl2 phases were washed once with water and concentrated.
Yield: 34.6 g of a solidified foam.
13CNMR (DMSO; ppm): 159.9 (amidine) C16H22N4~3S (350.44); calculated: (M+H)+ = 351; found: (M+H)+
Example 3 5 Synthesis of N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide a) N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-10 2-(4-amidoximo)thienylmethylamide 365.8 g (0.623 mol) of N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-cyano)thienylmethylamide together with 108.3 g (1.559 mol) of hydroxylammoniumchloride were initially charged in 1.83 1 of ethanol. At 20°C - 30°C, 241.3 g (1.870 mol) of diisopropylethylamine were then added, and the mixture was stirred at 20°C - 30°C for 12 h, after which, according to TLC
(CH2C12/methanol 9:1), conversion was complete. For work-up, most of the ethanol was distilled off under reduced pressure.
The residue was taken up in 730 ml of MTBE. The MTBE phase was washed once with 1.1 1 of water and the aqueous phase was reextracted once with 370 ml of MTBE. The combined MTBE
phases were once more washed with 180 ml of water and then dried at 0.5 bar by azeotropic distillation and concentrated to a volume of 730 ml. The product is precipitated out by dropwise addition of the MTBE solution to 2.2 1 of petroleum ether (60/40) and dried in a drying cabinet at 50°C for 12 h.
Yield: 371.5 g of a slightly yellow to colorless powder 13C NMR (DMSO; ppm): 147.9 (amidoxime) C30H45N5~7S (619.79); calculated: (M+H)+ = 620; found: (M+H)+ _ b) N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide, acetic acid salt At 30°C, 5 g (8.1 mmol) of the carboxamide oxime prepared according to a) were dissolved in 50 ml of acetic acid. At an internal temperature of 50 - 55°C, 2.9 g (44,4 mmol) of zinc powder were then added a little at a time. The mixture was stirred at about 50°C for 2 h, after which no more starting material could be detected by TLC (CH2C12/methanol 9:1). The solids were filtered off and the filter residue was then washed with acetic acid. The combined filtrates were concentrated at about 50°C under reduced pressure.
Yield: 4.3 g of a slightly yellow to colorless powder 13C ~ (DMSO; ppm): 159 (broadened, amidine),1H NMR (DMSO;
PPm) : 1. 87 (CH3C02-) C30H45N5~6S (603.79); calculated: (M+H)+ = 604; found: (M+H)+ _ c) N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide, base At 35°C, 62 g (100 mmol) of the carboxamide oxime prepared according to a) were dissolved in 620 ml of acetic acid. At an internal temperature of 35 - 40°C, 36 g (550 mmol) of zinc powder were then added a little at a time. After the mixture had been stirred at about 40°C for 4 h, no more starting material could be detected by TLC (CH2C12/methanol 9:1). The solids were filtered off and the filter residue was then washed with acetic acid. The combined filtrates were concentrated at about 50°C under reduced pressure and partitioned between 200 ml of MTBE and 410 ml of water. The aqueous phase was adjusted to pH 7 using aqueous sodium hydroxide solution. The aqueous phase was separated off, and the MTBE phase was then reextracted twice with 200 ml of water and discarded. The combined aqueous phases were subsequently adjusted to pH 12 using aqueous sodium hydroxide solution and extracted twice with 330 ml of MTBE each time.
The combined MTBE phases were dried at about 0.7 bar by azeotropic distillation and concentrated to a volume of about 270 ml. The product is precipitated by dropwise addition of the MTBE solution to 740 ml of n-heptane and dried in a drying cabinet at 50°C for 12 h.
Yield: 57.2 g of a slightly yellow to colorless powder.
C30H45N5~6S (603.79); calculated: (M+H)+ = 604; found: (M+H)+ _
For work-up, the ethanol was distilled off under reduced pressure. The residue was taken up in 1000 ml of methylene chloride (CHZC12). The organic phase was washed once with 500 ml and a second time with 250 ml of water. The organic phase was concentrated and the product was then precipitated out by addition of methyl tert-butyl ether (MTBE).
Yield: 78 g 1sC NMR (DMSO; ppm): 148.3 (amidoxime) C11H17N303S (271.34); calculated: (M+H)+ = 272; found: (M+H)+
b) 2-N-Boc-aminomethyl-(4-amidino)thiophene At 20°C, 5 g (18.4 mmol) of the carboxamide oxime prepared according to a) were dissolved in a mixture of 25 ml of acetic acid and 25 ml of methanol. A little at a time, 2.4 g (36.9 mmol) of zinc powder were then added, the internal temperature increasing to 30 - 35°C. After 12 h of stirring at 25 - 40°C, TLC (CH2C12/Methanol 9:1) showed that there was no starting material left. The solids were filtered off and the filter residue was then washed with methanol. The combined filtrates were concentrated at about 50°C under reduced pressure. The residue was dissolved in CH2Clz The CH2C12 phase was washed with water which had been adjusted to pH 12 with aqueous sodium hydroxide solution. The aqueous phase was, after phase separation, reextracted with CH2C12.
The combined CH2C12 -phases were washed until neutral and then concentrated.
Yield: 2.4 g of a solidified foam 13C-NMR (DMSO; ppm): 158.8 (broadened, amidine) C11H17N302S (255.34); calculated (M)+ = 255; found: (M)+ = 255 Example 2 Synthesis of N-Boc-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide a) N-Boc-3,4-dehydroprolyl-2-(4-amidoximo)thienylmethylamide 50 g (177 mmol) of N-Boc-3,4-dehydroprolyl-2-(4-cyano)thienylmethylamide together with 30.8 g (442.5 mmol) of hydroxylammonium chloride were initially charged in 590 ml of ethanol. At 20°C
- 30°C, 113.8 g (882 mmol) of diisopropylethylamine were then added, and the mixture was stirred at 20°C - 30°C for 12 h, after which, according to TLC (CH2C12/methanol 9:1), the reaction had gone to completion. For work-up, most of the ethanol was distilled off under reduced pressure. The residue was taken up in 120 ml of CH2C12. The organic phase was washed with 180 ml of water. The aqueous phase was reextracted once with 60 ml of CHZC12 The combined CH2C12 phases were washed once more with 30 ml of water, filtered and concentrated.
Yield: 66.3 g of a solidified foam.
13C_~ (DMSO; ppm): 147.9 (amidoxime) C16H22N4O4S (366.44); calculated: (M+H)+ = 367; found: (M+H)+ _ b) N-Boc-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide At 40°C, 41.4 g (113 mmol) of the carboxamide oxime prepared according to a) were dissolved in 400 ml of acetic acid. 41.1 g (630 mmol) of zinc powder were then added a little at a time such that the internal temperature did not exceed 50°C.
The mixture was stirred at 25 - 40°C for 2.5 h, after which no more starting material was detected by TLC (CH2C12/methanol 9:1). The solids were filtered off and the filter residue was then washed with acetic acid. The combined filtrates were concentrated at about 50°C under reduced pressure and partitioned between 180 ml of MTBE and 370 ml of water. The aqueous phase was adjusted to pH 7 using aqueous sodium hydroxide solution. The MTBE phase was separated off, and 180 ml of CH2C12 were then added and the aqueous phase was adjusted to pH 12 using aqueous sodium hydroxide solution.
The CHzCl2 phase was separated off and the aqueous phase was then reextracted twice with 150 ml of CH2C12. The combined CHzCl2 phases were washed once with water and concentrated.
Yield: 34.6 g of a solidified foam.
13CNMR (DMSO; ppm): 159.9 (amidine) C16H22N4~3S (350.44); calculated: (M+H)+ = 351; found: (M+H)+
Example 3 5 Synthesis of N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide a) N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-10 2-(4-amidoximo)thienylmethylamide 365.8 g (0.623 mol) of N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-cyano)thienylmethylamide together with 108.3 g (1.559 mol) of hydroxylammoniumchloride were initially charged in 1.83 1 of ethanol. At 20°C - 30°C, 241.3 g (1.870 mol) of diisopropylethylamine were then added, and the mixture was stirred at 20°C - 30°C for 12 h, after which, according to TLC
(CH2C12/methanol 9:1), conversion was complete. For work-up, most of the ethanol was distilled off under reduced pressure.
The residue was taken up in 730 ml of MTBE. The MTBE phase was washed once with 1.1 1 of water and the aqueous phase was reextracted once with 370 ml of MTBE. The combined MTBE
phases were once more washed with 180 ml of water and then dried at 0.5 bar by azeotropic distillation and concentrated to a volume of 730 ml. The product is precipitated out by dropwise addition of the MTBE solution to 2.2 1 of petroleum ether (60/40) and dried in a drying cabinet at 50°C for 12 h.
Yield: 371.5 g of a slightly yellow to colorless powder 13C NMR (DMSO; ppm): 147.9 (amidoxime) C30H45N5~7S (619.79); calculated: (M+H)+ = 620; found: (M+H)+ _ b) N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide, acetic acid salt At 30°C, 5 g (8.1 mmol) of the carboxamide oxime prepared according to a) were dissolved in 50 ml of acetic acid. At an internal temperature of 50 - 55°C, 2.9 g (44,4 mmol) of zinc powder were then added a little at a time. The mixture was stirred at about 50°C for 2 h, after which no more starting material could be detected by TLC (CH2C12/methanol 9:1). The solids were filtered off and the filter residue was then washed with acetic acid. The combined filtrates were concentrated at about 50°C under reduced pressure.
Yield: 4.3 g of a slightly yellow to colorless powder 13C ~ (DMSO; ppm): 159 (broadened, amidine),1H NMR (DMSO;
PPm) : 1. 87 (CH3C02-) C30H45N5~6S (603.79); calculated: (M+H)+ = 604; found: (M+H)+ _ c) N-(t-butoxycarbonylmethylene)-N-Boc-D-Chg-3,4-dehydroprolyl-2-(4-amidino)thienylmethylamide, base At 35°C, 62 g (100 mmol) of the carboxamide oxime prepared according to a) were dissolved in 620 ml of acetic acid. At an internal temperature of 35 - 40°C, 36 g (550 mmol) of zinc powder were then added a little at a time. After the mixture had been stirred at about 40°C for 4 h, no more starting material could be detected by TLC (CH2C12/methanol 9:1). The solids were filtered off and the filter residue was then washed with acetic acid. The combined filtrates were concentrated at about 50°C under reduced pressure and partitioned between 200 ml of MTBE and 410 ml of water. The aqueous phase was adjusted to pH 7 using aqueous sodium hydroxide solution. The aqueous phase was separated off, and the MTBE phase was then reextracted twice with 200 ml of water and discarded. The combined aqueous phases were subsequently adjusted to pH 12 using aqueous sodium hydroxide solution and extracted twice with 330 ml of MTBE each time.
The combined MTBE phases were dried at about 0.7 bar by azeotropic distillation and concentrated to a volume of about 270 ml. The product is precipitated by dropwise addition of the MTBE solution to 740 ml of n-heptane and dried in a drying cabinet at 50°C for 12 h.
Yield: 57.2 g of a slightly yellow to colorless powder.
C30H45N5~6S (603.79); calculated: (M+H)+ = 604; found: (M+H)+ _
Claims (6)
1. A process for preparing aryl- or hetarylamidines which are unsubstituted at the nitrogen and salts thereof with inorganic or organic acids, where appropriate carboxamide oximes are reacted with Zn in the presence of carboxylic acids at from -10°C to 50°C.
2. ~A process as claimed in claim 1 for preparing substituted thienylamidines.
3. ~A process as claimed in claim 1 for preparing substituted thienylamidines, where the thienylamidine group is a structural fragment of a medicament.
4. ~A process as claimed in claim 1 for preparing substituted thienylamidines of the formula I
in which n = 1-3 and R can have the meanings below C1-C6-alkyl-CO, C1-C6-alkoxy-CO, benzyloxy, aryl or heteroaryl, where these aromatic compounds may be unsubstituted or further mono- or polysubstituted, an .alpha.-amino acid fragment in the R or S configuration whose N
atom is protected in the customary manner or unprotected, a dipeptide fragment which is unsubstituted or mono- or polysubstituted at the N terminus, which consists of natural amino acids, the corresponding D-amino acids or amino acids in the L or D form which are very similar to natural amino~
acids, which comprises reacting carboxamide oximes of the formula II
13~
in which n and R are as defined in formula I with Zn in the presence of a carboxylic acid.
in which n = 1-3 and R can have the meanings below C1-C6-alkyl-CO, C1-C6-alkoxy-CO, benzyloxy, aryl or heteroaryl, where these aromatic compounds may be unsubstituted or further mono- or polysubstituted, an .alpha.-amino acid fragment in the R or S configuration whose N
atom is protected in the customary manner or unprotected, a dipeptide fragment which is unsubstituted or mono- or polysubstituted at the N terminus, which consists of natural amino acids, the corresponding D-amino acids or amino acids in the L or D form which are very similar to natural amino~
acids, which comprises reacting carboxamide oximes of the formula II
13~
in which n and R are as defined in formula I with Zn in the presence of a carboxylic acid.
5. A process as claimed in any of claims 1 to 4, where the carboxylic acid is acetic acid.
6. A compound of the formula II as claimed in claim 4.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19915930.0 | 1999-04-09 | ||
| DE19915930 | 1999-04-09 | ||
| DE19933873 | 1999-07-23 | ||
| DE19933873.6 | 1999-07-23 | ||
| PCT/EP2000/003018 WO2000061574A2 (en) | 1999-04-09 | 2000-04-05 | Method for producing thiophenyl-amidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2369267A1 true CA2369267A1 (en) | 2000-10-19 |
Family
ID=26052817
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002369267A Abandoned CA2369267A1 (en) | 1999-04-09 | 2000-04-05 | Method for producing amidines |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1169315A2 (en) |
| JP (1) | JP2002541252A (en) |
| AU (1) | AU3559000A (en) |
| CA (1) | CA2369267A1 (en) |
| WO (1) | WO2000061574A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0302989A3 (en) * | 2001-01-29 | 2007-06-28 | Teijin Ltd | Benzamidine derivatives and process for production thereof |
| DE602006010834D1 (en) | 2005-03-16 | 2010-01-14 | Janssen Pharmaceutica Nv | NEW THIOPHENSULFOXIMINE FOR THE TREATMENT OF COMPLEMENTED DISEASES AND SUFFERING |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2375611A (en) * | 1941-08-19 | 1945-05-08 | May & Baker Ltd | Production of amidines |
| US2851490A (en) * | 1955-04-20 | 1958-09-09 | Monsanto Chemicals | Guanyl aliphatic mono-carboxylic acids |
| DE19632773A1 (en) * | 1996-08-14 | 1998-02-19 | Basf Ag | New thrombin inhibitors |
-
2000
- 2000-04-05 JP JP2000610848A patent/JP2002541252A/en not_active Withdrawn
- 2000-04-05 WO PCT/EP2000/003018 patent/WO2000061574A2/en not_active Application Discontinuation
- 2000-04-05 AU AU35590/00A patent/AU3559000A/en not_active Abandoned
- 2000-04-05 EP EP00914182A patent/EP1169315A2/en not_active Withdrawn
- 2000-04-05 CA CA002369267A patent/CA2369267A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002541252A (en) | 2002-12-03 |
| WO2000061574A2 (en) | 2000-10-19 |
| WO2000061574A3 (en) | 2001-04-26 |
| AU3559000A (en) | 2000-11-14 |
| EP1169315A2 (en) | 2002-01-09 |
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