Method for production of acetylamidiniophenylalanylcyclohexylglycilpypidinioalanin amides

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of acetylamidiniophenylalanylcyclohexylglycilpypidinioalanin amides of formula I , wherein X anions are physiologically acceptable anions, and analogous thereof. Said compounds are effective inhibitors of fibrillation factor Xa and are useful, for example, in prevention of thrombosis. Claimed method includes coupling of 2-[2-acetylamino-3-(4-amidinophenyl)-propionylamino]-2-cyclohexylacetic acid, obtained from 2-[2-acetylamino-3-(4-cyanophenyl)acryloylamino]-2-cyclohexylacetic acid by assimetric hydration and converting of cyano group to amidine, or salt thereof with 3-(2-amino-2-carbamoylethyl)-1-methylpyridinic acid or salt thereof. Also are disclosed starting materials and intermediated used in this method, process for production the same and acetyl-(S)-4-amidiniophenylalanyl-(S)- cyclohexylglycil-(S)-(1-methyl-3-pypidinio)alanin amide in form of ditosylate.

EFFECT: simplified method; increased commercial availability of compounds with applicable anion.

14 cl, 16 ex

 

The present invention relates to a method for acetylgalactosaminyltransferase formula (I):

in which the anion X is a physiologically acceptable anion, and their analogues, which are effective inhibitors of factor XA clotting and which can be used, for example, to prevent thrombosis. The method according to the invention includes the combination of 2-[2-acetylamino-3-(4-amidinophenoxy)propionamido]-2-cyclohexyloxy acid, which is obtained from 2-[2-acetylamino-3-(4-cyanophenyl)acrylamido]-2-cyclohexyloxy acids by asymmetric hydrogenation and conversion of ceanography in amedieval group, or a salt thereof, 3-(2-amino-2-carbamoylethyl)-1-methylpyridinium salt, or its salt. In addition, the invention relates to the original materials and intermediate products for this method, processes for their preparation and acetyl-(S)-4-amidino-i.e. phenylalanyl-(S)-cyclohexylglycine-(S)-(1-methyl-3-pyridinio) alaninemia in the form of ditosylate.

In the case of some clinical conditions, such as, for example, a strong vein thrombosis, high risk of myocardial infarction or stable or unstable angina, impaired blood clotting system and the occurrence of thrombosis, the result can be fatal. Od is ako, in the case of prevention of thrombosis, it is undesirable excessively or even completely inhibit the blood clotting system, as this may result in life-threatening bleeding. Commonly used inhibitors of coagulation, such as heparin, aspirin or hirudin, do not have an optimal property profile, as they can lead to complications such as bleeding and, in the case of some of these clinical conditions, unable to prevent occlusion of the vessel. In experimental animals has shown that the specific inhibitors of factor XA enzyme coagulation reliably prevent the formation of thrombin without the occurrence of bleeding, which see, when using direct thrombin inhibitors. The compounds of formula (I) and their analogues are specific and potent inhibitors of factor XA, which is effective for intravenous, subcutaneous and oral administration.

The compounds of formula (I) and their analogues are described in International application WO-A-95/29189 and the appropriate application for U.S. patent US-A-5849510. According to WO-A-95/29189, they are obtained by solid-phase synthesis when using methods with the use of protective groups, where 3-pyridylamine associated with resin using Knorr linker and then injected into the reaction mix with cyclohexylglycine, the nitrogen atom of the pyridine quaternized, Deepti is injected into the reaction mix with acetyl-4-amidinopropane, obtained from 4-cyanophenyl-alanine, and the product, after removal from the resin, purified by chromatography. This solid-phase method is unsuitable for obtaining multi-kg quantities required for Toxicological and clinical studies, or even for synthesis on an industrial scale.

Pharmaceutically active compound is acceptable as a product for research and for future use for patients only if it may be carried out in the required scale and with adequate purity, purity, if have centers of asymmetry compounds include, in particular, also stereochemical purity. The compounds of formula (I) contain peptide dication having positive charges in ameinias group and N-methylpyridinium group. Among the compounds of formula (I) with different anions X-such as acetate, chloride, fumarate, benzoate, tartrate, maleate, triptorelin, tosylate, sulfate or pamoate-anion, found that only salt triperoxonane acid (compound of formula (I), X-=CF3FROM

-
2
) is crystalline. However, thermostability of salt triperoxonane acid is insufficient, its shelf life, neodol the instrumental and from a physiological point of view, salt less preferred for long-term use. According to powder x-ray all other salts of compounds of formula (I) found that they are amorphous. The amorphous nature of the salts is a significant problem in obtaining the compounds of formula (I) in a relatively large scale, as it makes it impossible for the recrystallization, fractional deposition is the only possible method for cleaning when used in large scale. However, the effectiveness of treatment by precipitation, of course, much lower than that by crystallization, and therefore, it is necessary to obtain the crude compound of formula (I) with the corresponding anion X in a reaction, which proceeds smoothly as possible, so that in the end it was possible to obtain a product clinically acceptable purity by fractional precipitation. However, the method of obtaining, of course, must also be acceptable in terms of factors such as, for example, the output, the number of stages or the availability and cost of raw materials.

The method of obtaining compounds of formula (I), which is carried out not in the solid phase, described in the International application WO-A-97/22712. According to this method, three amino acid structural units contained in the compounds of formula (I)bind in the same comparada, as in the method according to WO-A-96/29189. (S)-3-Pyridylamine protected on the amino group with tertbutoxycarbonyl group (BOC), is first converted into amide, which is then, after removal of the protective group is introduced into the reaction mix with (S)-N-Boc-cyclohexylglycine, the protective group is removed, the dipeptide is introduced into the reaction mix with acetyl-(S)-4-cyanopyrrolidine and cyano in the received result of the Tripeptide turn, by reaction with hydrogen sulfide, methyliodide and ammonia, in amedieval group and the nitrogen atom of the pyridine quaternized. The product is isolated in the form of a salt triperoxonane acid by evaporation obtained at the last stage of the reaction the reaction solution, dissolution of the residue, add triperoxonane acid, filtration and freeze-drying. However, it is found that the purity obtained using this method product, including stereochemical purity, does not meet the requirements for complex chromatographic purification, which includes large losses and unacceptable when the method is carried out in large scale. In order to avoid possible objections from a physiological point of view regarding trifurcation, in addition, it is necessary to turn the product into a different salt, using ionoobmennoi chromatography. Moreover, the method has considerable technology is not the kami, as, for example, the use of solvents, such as diethyl ether or hexane, or working at low temperatures, and the use of expensive starting materials (minor number three enantiomerically pure non-natural α -amino acids (S)-3-pyridylamine, (S)-cyclohexylglycine and (S)-4-amidinothiourea (or (3)-4-cyanopyrrolidine; amidinopropane can be obtained from ceanography)contained as a block design in the compounds of formula (I), commercially available, but these compounds are very expensive). Therefore, there is still a need for an easily implemented method of obtaining large-scale compounds of formula (I) with a suitable anion X.

This goal is achieved through the method of obtaining compounds of formula (I) according to the present invention, which includes the transformation of the compounds of formula (II), by catalytic hydrogenation and conversion of ceanography in amidinopropane, in the compound of formula (III)or its salt with the acid HX, followed by reaction of the compound of formula (III)or its salt with the compound of the formula (IV)or its salt with the acid HX to obtain the compounds of formula (I), where the anions X are physiologically acceptable anions.

Whereas in the known methods, the molecule of formula (I) is designed by combining a C-terminal dipeptide from pyridylamine and cyclohexylglycine with N-terminal amino acid of amidinohydrolase (or cyanovinylene), in the method according to the invention a molecule synthesized by a combination of N-terminal dipeptide of amidinothiourea and cyclohexylglycine with the C-terminal amino acid by pyridinylamino. In addition, under proposed in the invention method, the dipeptide, which is used for this combination, a structural unit CH-CO-NH-CH-CO, which has two centers of chirality-sensitive epimerization, is not formed by the reaction of a combination of two chiral α -amino acids, as in the known methods, and is obtained by asymmetric hydrogenation. In the method according to the invention the peptide combination of proceeds smoothly and quantitatively using inexpensive reagents. The epimerization is very low. The compounds of formula (I) are obtained with high yield and high chemical and stereochemical purity by fractional precipitation. To achieve the desired purity there is no need for chromatographic ochistka or expensive and complex technologies, such as drying, freezing.

The present invention therefore relates to a method, which is similar to the above method whereby, when using the original materials of different configurations, get the stereoisomers of compounds of formula (I), as, for example, compounds in which the center of chirality in amidinopropane strukturnoi unit has the configuration (R), and/or the center of chirality in cyclohexylglycine structural unit has the configuration (R), and/or a center of chirality in pyridylamino structural unit has the configuration (R), or compounds in which one or more centers of chirality in the form of mixtures (RS). In addition, the invention relates to methods, which are similar to the above methods whereby, when using the appropriate starting materials, receive similar compounds of formula (I) and their stereoisomers), for example, compounds that instead of a metal of the group in acetaminophe in amidinopropane structural unit containing (C1-C4)-alkyl group and/or instead of a methyl group from the Quaternary nitrogen atom of the pyridine contain (C1-C4)-alkyl group, and examples of such a (C1-C4)-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

Physiologically acceptable anions X in the compounds of formulas (I) and (IV) and the acid HX can be, for example, chloride, bromide, iodide, methanesulfonate, toluene-4-sulfonate, acetate, benzoate, and others. In the case of a polyvalent anion, such as sulfate anion, x is the equivalent of the anion. X preferably represents an anion, in respect of which there is no objection from a physiological point of view, even if the compounds of formula (I) are used in relatively high doses and over a relatively long period of time, and/or which gives the compounds of formula (I) useful properties for pharmaceutical processing and pharmacological actions, such as suitable solubility in water, and/or which gives the compounds of formulas (I) and (IV) favorable properties in relation to the implementation of the method according to the invention, such as the simplicity of the method, suitable solubility in the solvents, the fact that they are easily deposited and/or easily filtered out, etc. According to a preferred variant implementation of the present invention X is toluene-4-sulfonate(=4-methylbenzenesulfonate=4-CH3-C6H4-SO

-
3
= toilet = TosO-or iodide; according to a particularly preferred variant of the invention, X is toluene-4-sulfonate.

Thus, according to this particularly preferred variant implementation of the invention relates to a method for obtaining compounds of formula (I) in the form of ditosylate, i.e. the compounds of formula (Ia):

which includes the transformation of the compounds of formula (II), by catalytic hydrogenation and conversion of ceanography in amidinopropane, in the compound of formula (III) or the th salt of toluene-4-sulfonic acids and the reaction of the compound of formula (III) or its salt of toluenesulfonic acid with the compound of the formula (IVa) or its salt of toluene-4-sulfonic acids to obtain the compounds of formula (Ia). From a physiological point of view there are no objections against tosylate anion contained in the compound of formula (Ia)and the compound of formula (Ia) is, in particular, is especially good properties in the process according to the invention. The compound of formula (Ia) are easily deposited and easily filtered and receive it with a particularly high yield and high purity. The present invention therefore also relates to the compound of formula (Ia) as such and its solvate as, for example, adducts with water or alcohols, to the use of compounds of formula (Ia) as an inhibitor of factor XA or for the treatment, including therapy and prophylaxis of thromboembolic complications, such as thrombosis, myocardial infarction or angina, and to the use of compounds of formula (Ia) to obtain medicines for these medical applications, and to pharmaceutical preparations (or pharmaceutical compositions)comprising an effective amount of the compounds of formula (Ia) and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable excipients and/or additives. More detailed information about the use of compounds of formula (I), including the compound of formula (Ia)and pharmaceutical preparations comprising them, are contained in the International application WO-A-95/29189 and the application for U.S. patent US-A-5849510, is the quiet specifically included in the present description by reference.

In addition to the above described methods for producing compounds of formula (I) and obtain the compounds of formula (Ia) of the compounds of formulas (II) and (IV) or their salts, the present invention relates to a method for obtaining compounds of formula (Ia), which involves the reaction of the compounds of formula (III) or its salt with toluene-4-acid with the compound of the formula (IVa) or its salt with toluene-4-acid to obtain the compounds of formula (Ia). In the case of this method, which allows to obtain the compound of formula (I) in specific ditosylate form with unexpectedly good yield and good purity and which is characterized by the fact that its implementation proceeds particularly smoothly and it can be implemented in a simple way, all of the above and the following explanations in the context of the method described above refer, respectively, to the reaction of compounds of formulas (III) and (IV) or their salts, i.e., to phase peptide combinations.

The compounds of formula (I) can also be represented by the formula (V), which shows that they can be formally regarded as additive salts with an acid HX and substituted one cation of amidinopropane pyridinium salts, falling under the formula (V) (available free amidinopropane (= carbamimidoyl group = aminoiminomethyl group-C(=NH)-NH2instead, the proton is trated, positively charged amidinopropane-C(=NH

+
2
)-NH2in the formula (I)).

Accordingly, the connection can also be variously named, for example, as Picatinny pyridinium salts, which contain positively charged amidinopropane as Deputy and two negatively charged anion X as counterions, or as an additive salt with the acid HX monocationic pyridinium salts, which contain free amidinopropane as Deputy and negatively charged anion X as counterion. Depending on the respective cases can be suitable other names, such as name, produced from peptide nomenclature, according to which positively charged amidine group (= amidinopropane) or free amedieval group and positively charged pyridinium group (= pyridinium) is considered as alternates. The compound of formula (Ia), for example, can be called as 3-{(S)-2-[(S)-2-((S)-2-acetylamino-3-(4-amidinophenoxy)propionamido-2-cyclohexylethylamine]-2-carbamoylethyl} -1-methylpyridinesuccinate or as 3-{(S)-2-[(S)-2-((S)-2-acetylamino-3-(4-amidinophenoxy)propionamido)-2-cyclohexyl) - Rev. ethylamino]-2-carbamoylethyl}-1-metilprednisolona salt of toluene-4-sulfonic acids or N-acetyl-4-(aminoiminomethyl)-L-i.e. phenylalanyl-L-2-cyclohexylethyl-3-(1-methylpyridine-3-yl)-]-L-aluminometasilicate salt of toluene-4-sulfonic acids.

In the process according to the invention the compound of formula (II) can be converted into a compound of formula (III) by first stereoselective hydrogenation of the compounds of formula (II) for obtaining the compounds of formula (VI), followed by transformation of ceanography in amidinopropane, or first by turning ceanography in amidinopropane, then by stereoselective hydrogenation.

Preferably, first conduct the hydrogenation to obtain a compound of formula (VI), then perform the transformation of ceanography in amidinopropane.

Stereocontrolled hydrogenation of the double bond C=C in dehydropeptides formula (II) can be carried out through the use of selective heterogeneous catalysts or chiral transition metal complexes. It is preferably carried out using chiral metal complexes based on rhodium(I) or ruthenium-(II), particularly preferably rhodium(I). The catalyst based on transition metal may be cationic or neutral and can be used in a dedicated form or can be formed in situ in the medium for the hydrogenation of chiral ligand and catalyst precursor, for example salts of rhodium, such as [Rh(COD)Cl]2or [Rh(COD)2]+Y-(COD means cycloocta-1,5-diene, Y means, for example, those who reverberat). The hydrogenation catalyst may be in the environment for homogeneous hydrogenation in dissolved form or it can be turned into a heterogeneous form by binding to a solid carrier, therefore it can be easily removed by filtration after completion of the hydrogenation and reused in the next boot for hydrogenation. As chiral ligands for transition metal fit many different connections. Overview in respect of such chiral ligands can be found, for example, in book I. Ojima "Catalytic Asymmetric Synthesis", pages 445-447, VCH, new York, 1993. According to a preferred variant implementation of the present invention, for the asymmetric hydrogenation of compounds of formula (II) to obtain the compounds of formula (VI) use the complex of rhodium(I) with chiral phosphine as ligand. Particular preference is given to catalyst Rh (I)-(+)-VRRM, that is, the catalyst based on rhodium(I), which includes as a chiral ligand (+)-(2R, 4R)-1-tert-butyloxycarbonyl-4-diphenylphosphino-2- (diphenylphosphinomethyl) pyrrolidine (in a molar ratio of rhodium: ligand = 1:1). The catalyst preferably receive in situ from a salt of rhodium and ligand.

Suitable solvents for the stereoselective hydrogenation of the compounds of formula (II) to obtain the compounds of formula (VI) are, for example the EP, ethers, particularly miscible with water, ethers, or lower alcohols, such as methanol, ethanol or isopropanol. Hydrogenation is particularly preferably carried out in methanol. The hydrogenation preferably carried out at temperatures in the range from about 20° With up to about 60° S, especially preferably from about 30° With up to about 50° With, for example, at about 40° C. Set pressure of hydrogen depends on used equipment; preferably create a hydrogen pressure from about 1 bar to about 20 bar, particularly preferably from about 5 bar to about 15 bar, for example about 10 bar. To improve the efficiency of the hydrogenation reaction is carried out with the exclusion largely of oxygen and with very vigorous stirring. The hydrogenation product can be isolated in a simple way by adding water and filtering or separation by centrifugation of the resulting precipitate. Asymmetric hydrogenation proceeds with very high stereoselectivity and yield and leads to the production of the compounds of formula (VI) with diastereomeric excess (d.e.) 98,4% d.e. (S,S)-isomer in the crude product and diastereoisomerism excess of 99.5% in the selected product, when it does so the output is 97%. In addition, these excellent results were recip who are at very high ratios of substrate/catalyst from about 2000:1 to about 5000:1.

The present invention also relates to the compound of formula (VI) as such, that is, (S)-2-[(S)-2-acetylamino-3-(4-cyanophenyl)propionamido]-2-cyclohexyloxy acid and its salts, for example salts of alkali or alkaline earth metals such as sodium or potassium, the above method of production thereof and their use as an intermediate product, in particular, as an intermediate product for pharmaceutically active substances.

Cyano in the compound of formula (VI) can be converted into amedieval group by various methods known to the expert, for example, using the method described in International application WO-A-97/22712, which, however, has some shortcomings in the implementation on an industrial scale, as, for example, the use of hydrogen sulfide. The transformation is preferably carried out by first joining the hydroxylamine to the cyano in the compound of formula (VI) with the formation of the intermediate N-hydroxyamides formula (VII). The compound of formula (VII) then make a simple manner by means of hydrogenolysis, i.e. by reaction with hydrogen in the presence of a hydrogenation catalyst, in amidin formula (III). The principle of this sequence of reactions is described, for example, N. Jendralla, etc.. Tetrahedron, 51, 12047 (1995).

The required hydroxylamine is preferably receive in situ from a salt g is doxylamine, for example hydroxylaminopurine or hydroxylammonium, and bases, such as sodium or potassium basic compound or tertiary amine. Used for the reaction of compounds of formula (VI) with the salt of hydroxylamine base is preferably sodium bicarbonate. Hydroxylamine or a salt of hydroxylamine preferably used in excess, for example, in amounts of from about 1 mol to about 2 mol per mol of compound of formula (VI). Suitable solvents for the reaction with hydroxylamine or a salt of hydroxylamine are, for example, lower alcohols. Especially preferred solvent is methanol. The compound of formula (VII) is preferably obtained at temperatures from about 20° up to about 65° C, particularly preferably at temperatures from about 40° With up to about 60° C. If using salt of hydroxylamine added the base also makes carboxyl group in the compound of formula (VI) or that the compound of formula (VII) to the corresponding salt. If it is desirable intermediate excretion of N-hydroxyamides formula (VII), then this connection can be selected preferably in the form of a salt with a carboxyl group, that is, if your base is a sodium compound, in the form of a sodium salt of carboxylic acid, which can the be precipitated by concentrating the reaction mixture and/or blending in a relatively nonpolar solvent and removal by filtration or centrifugation.

The hydrogenolysis of compounds of formula (VII) or its salt to obtain the compounds of formula (III) can be carried out in conditions that are normally used for catalytic hydrogenation reactions, for example, in the presence of a conventional catalyst based on a noble metal such as palladium on coal. The reaction conditions depend on the used hardware. The pressure of hydrogen, for example, may be in the range of from about 1 bar to about 30 bar, mainly from about 5 bar to about 25 bar, and the reaction temperature may be from about 20° With up to about 70° mainly from about 40° With up to about 60° C. the Hydrogenolysis is preferably carried out in an acidic environment. Preferred solvents for hydrogenolysis are, in particular, if use N-hydroxyamide in the form of salts, polar solvents, such as lower alcohols or acetic acid. Especially preferred solvent is acetic acid. The resulting amidinov compound of formula (III) may be isolated as such or in the form of additive salts with acid (amidinov compound of formula (III) as such is not in the form that has free amidinopropane and carboxyl group, which is represented by formula (III), a is a tautomeric form of the formula (IIIa), i.e. the ideal of betaine or zwitterion, in which the carboxyl group is dissociative to carboxylation and medinova structural unit protonated to ameeneemagu cation).

In the presence of acid, which can be even during the hydrogenolysis, for example, if the solvent used is acetic acid, or may be added during processing, the compound of formula (III) are obtained in the form of additive salts with an acid. So, when using an acid of formula HX is formed salt of the formula (VIII), in which the anion X is preferably a physiologically acceptable anion, for example, iodine - or tosylation. The compounds of formula (VIII) are above the salt of the acid HX and the compounds of formula (III). If the compound of formula (III) must be allocated in the form of additive salts with an acid, the acid HX is preferably chosen so that the compound of formula (VIII) contain the same anion as the resulting compound of formula (I). So, if must be received ditosylate salt of the formula (Ia) and the compound of formula (III) must be allocated in the form of salts, preference is given to obtaining midinotate formula (VIII), where X=TosO-for example, by adding toluene-4-sulfonic acids during processing. As already indicated, for the peptide combination with the compound of the formula (IV) may use the either the compounds of formula (III) as such, that is, betaine (or zwitterion) of the formula (IIIa)or ameinias salt of the formula (VIII) (= Sol NC and the compounds of formula (III)), and in both cases, are similar purity and yield. The compound of formula (III) is preferably isolated in the form of betaine (or zwitterion) of the formula (IIIa) and used as such for peptide binding. If the hydrogenolysis is carried out in acetic acid, the initially formed salt of acetic acid compounds of the formula (III) (= compound of the formula (VIII), where X-=cetatenie) can be converted to betaine by recrystallization from water.

The present invention also relates to compounds of the formula (III) and their salts and compounds of formulas (IIIa) and (VIII) as such, that is, (S)-2-[(S)-2-acetylamino-3-(4-amidinophenoxy)propionamido]-2-cyclohexyloxy acid in the form of betaine (zwitterion), and in the form of their salts, the above method of production thereof and their use as intermediate products, in particular as intermediates for pharmaceutically active compounds.

The peptide combination of amidine formula (III) (in salt form or preferably in the form of a betaine of the formula (IIIa)) pyridinesulfonamide formula (IV) or its salt to obtain the compounds of formula (I) can be carried out by conventional methods, combinations, known to the specialist.

Pyridinylamino preference is sustained fashion used in the form of a salt with the acid HX, that is, in the form dicationic salts of the formula (IX), in which the anions X means preferably physiologically acceptable anions.

The anion X in the compound of formula (IV) or the compound of formula (IX) and, if the compound of formula (III) use as a salt of the formula (VIII), therefore, the anion in the compound of formula (VIII)is preferably the anion of the resulting compounds of formula (I), that is, in the case of obtaining the compounds of formula (Ia), tosylation. If neither compound of formula (III)or the compound of formula (IV) for peptide binding is not used in the form of a salt with the acid HX, the second equivalent of the anion X, which is required for obtaining the compounds of formula (I), in addition to the equivalent of the anion X, entered using the compounds of formula (IV)may be attached in the form of equivalent acid HX or salt of the acid HX during processing of the reaction mixture peptide combinations.

Examples of agents peptide combinations, suitable for the activation of carboxyl or carboxylate groups in the compound of formula (III) (or (IIIa) or (VIII)), which can be specified are carbodiimide, such as, for example, dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC), or oranjevyi salts, such as O-[(lanoitanretni)amino]-N,N,N’,N’-tetramethylpropylenediamine TOTU) or O-(7-AZ is benzotriazol-1-yl)-N,N,N’,N’-tetramethylpropylenediamine (HATU). Carbodiimide preferably used in the presence of hydroxybenzotriazole or hydroxybenzotriazole reagents, such as 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazin (=3-hydroxy-1,2,3-benzotriazin-4(3H)-he=HOObt), or 1-hydroxy-1H-benzotriazole (HObt). Preferred activating agents and reaction conditions, in which case the epimerization at the chiral carbon atoms, in particular α -position to a carbonyl group in the compound of formula (III)are minimal, so diastereomeric impurities are formed only in small amounts, if any, are formed. Activating agents that are particularly preferred in this regard are HATU, DCC/HOObt and DCC/HObt. In particular, when using HATU or DCC/HOObt, the reaction mix leads to a product that contains only 0.7-1.5% diastereoisomer in the crude product. Especially preferred, because of its significantly lower cost, is DCC/HOObt. For security reasons, HOObt preferably used in the media, such as Dicalite®.

The reaction mix is preferably carried out in a polar solvent or a mixed solvent). Suitable solvents are proton solvents such as lower alcohols, e.g. methanol, ethanol or isopropanol, and from among these alcohols, preferred isopropano is, because the danger of turning the C-terminal amide group in the ester group is lower than when using methanol or ethanol. Especially preferably the combination is carried out in aprotic polar solvents in which the reaction mix is fast and smooth, for example in Amidah, such as N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP)or dimethyl sulfoxide (DMSO). However, it is also possible to use solvents, such as, for example, ethyl acetate, tetrahydrofuran (THF) or dichloromethane, in particular, also in a mixture with other solvents. In particularly preferred cases, the reaction mix is carried out in DMF or NMP, which give excellent results combination and the output of the compounds of formula (I) are 85-95% (after two sediment product). Particularly preferably, the binding is carried out in DMF, as it is more easily can be removed from the product. The reaction mix is preferably carried out at temperatures from about 0° With up to about 30° S, especially preferably from approximately 0° With up to about 25° With, for example, by first stirring the reaction mixture at a temperature of about 10° and then leaving it to warm to room temperature. If, according to the preferred option stage combination, the connection fo the formula (III) in the form zwitterion formula (IIIa) being in communication with dicationic salt of the formula (IX), favorable pH (from about 3.3 to 4.2, if X in the compound of formula (IX) means toilet) usually present during the entire reaction combinations without adding any additional necessary Foundation. Optional pH value can be set accordingly by adding bases, such as tertiary amine. If the compound of formula (III)and the compound of formula (IV) used for the reaction combinations in the form of a salt with the acid HX, for the reaction of the peptide combination requires adding at least one equivalent of a base, e.g. a tertiary amine such as triethylamine or, preferably, N-ethyldiethanolamine.

According to a preferred variant implementation stage combinations, where used as an activating agent is carbodiimide together with N-hydroxybenzotriazole or N-hydroxybenzotriazole reagent, such as, for example, HOObt, this reagent may be present in quantities above the stoichiometric or catalytic amounts, as N-hydroxy-reagent is regenerated during the reaction of compounds of formula (IV) with the activated complex ester intermediate formed from the compounds of formula (III) and N-hydroxy-reagent. If, for example, the reaction mix carried out using DCC/HOObt, HOObt preferably IP is result in the amount of from about 0.15 mol to about 1 mol per mol of compound of formula (III), particularly preferably in amounts of from about 0.2 mol to about 0.3 mol, for example, about 0.25 mole, per mole of the compounds of formula (III). Carbodiimide preferably used in slight excess. If the reaction mix carried out using DCC/HOObt use, for example, preferably in an amount of from about 1.1 moles to about 1.4 mol per mol of compound of formula (III), particularly preferably in amounts of from about 1.2 mol to about 1.3 mol, for example, approximately 1.25 mol, per mol of compound of formula (III). The order in which you add the reagents, is mutable. Preferably, first get the download of the compounds of the formula (III) and formula (IV) or their salts, any substrate that can be added, and N-hydroxy-reagent and dispense into carbodiimide, for example, in the form of a solution in a solvent such as. DMF or NMP, in a few hours, for example, from about 5 to about 10 hours. According to this method, the reaction mix at a temperature of reaction is about 10° C, followed by stirring at room temperature, usually ends quickly, runs virtually quantitatively and get a product of high purity.

For processing, the reaction mixture is preferably first filtered and the product is then precipitated by adding a suitable organic solvent. E. what does the reaction mix is carried out in DMF or NMP, the deposition is preferably carried out using an excess of a lower ketone, such as acetone or methyl ethyl ketone, and particularly preferably a solution in DMF or NMP is added dropwise or by pumping the excess acetone or methyl ethyl ketone. The precipitated product produce by filtration or centrifugation, washed and, if it is desirable to increase the purity, precipitated a second time or even third time in a similar way (for example, by dissolving the product in DMF and sedimentation by injection of a solution in acetone or methyl ethyl ketone). Using this technique, the greatest number of by-products remain in solution and after two deposition processes, for example, the compound of formula (Ia) (ditosylate) get with the release of approximately 91% and a purity of approximately 97% (+ approximately 2.4% of diastereoisomer).

The initial products of formulas (II) and (IV) or their salts, which are used in the above method according to the invention can be obtained, for example, by the following methods. In a preferred variant of the method described above according to the invention, the initial product of the formula (II) and/or the initial product of the formula (IV) or their salts, which are used, are obtained by the following methods or partially receive the following ways.

The compound of formula (II) can be is obtained by reaction of azlactone formula (XI) with (S)-cyclohexylglycine (formula (XII)). Aslacton formula (XI), which essentially is in the form of Z-isomer is obtained in standard conditions of synthesis azlactone on Erlenmeyer of 4-formylbenzoate (formula (X)) and N-acetylglycine, for example, by heating with sodium acetate and acetic anhydride in a solvent, preferably by boiling under reflux in acetone. The reaction of compounds of formulas (XI) and (XII) to obtain dehydropeptides formula (II) is preferably carried out in an alkaline solution, for example, adding one equivalent (based on cyclohexylglycine) bases, such as sodium hydroxide or potassium hydroxide, in a mixture of water and miscible with water solvent, e.g. a ketone, such as acetone, or a simple ester, particularly preferably in a mixture of acetone and water, at temperatures from about 30° With up to about 50° With, for example, about 40° C. To identify the product, the reaction mixture is acidified, for example with hydrochloric acid, to a pH of about 2.3 and diluted with water and the precipitate is filtered or separated by centrifugation. Using this technique, the resulting compound of the formula (II) is mainly in the form of a Z-isomer, the content of the E-isomer is <2%. The present invention also relates to compounds of formulas (II) and (XI) and salts of compounds of formula (II) is such, in particular in the form of Z-forms of the above methods for their preparation and their use as intermediate products, in particular, as intermediates for pharmaceutically active compounds. Salts of compounds of formula (II)which may be mentioned are, for example, salts of alkali and alkaline earth metals such as sodium salt or potassium salt.

Required, optional pure (S)-cyclohexylglycine (formula (XII) is preferably receive one of the following three ways. According to the first way of obtaining used the original product is racemic phenylglycine (formula (XIII)), which by hydrogenation of the aromatic rings in standard conditions is transformed into the racemic cyclohexylglycine (formula (XIV)), for example, by hydrogenation in the presence of a catalyst based on a noble metal such as rhodium on charcoal, in hydrochloric acid at a temperature of from about 80° C to about 120° With, for example, at about 100° and when the hydrogen pressure from about 10 bar to about 30 bar. The racemic cyclohexylglycine then acetimidoyl in standard conditions according to the amino group using, for example, acetic anhydride in the presence of a base such as sodium hydroxide, in water, at a temperature of from about 0° With up to about 30° and when the pH value is at least 11 of Racemic N-acetylcyclohexanone (formula (XV)is then subjected to the operation of splitting the enzymatic racemate by using acylase (L-specific aminoacylase, ES) to obtain optically pure (S)-cyclohexylglycine (formula (XII)) and N-acetylcyclohexanone containing a large excess of (R)-antipode (formula (XVI)) (see, for example, K. Drauz, etc.. Enzyme Catalysis in Organic Synthesis, VCH, Weinheim, 1995; M.A. Verkhovskaya, etc., Russ. Chem. Rev., 60, 1163 (1991); H.K. Chenault, etc., J. Am. Chem. Soc., 111, 6354 (1989)). Selective enzymatic of deacetylation (S)-N-acetylcyclohexanone (RS)-mixture can be carried out, for example, when using acylase "Amano" 30000 in the presence of chloride cobalt(II) in water at a pH value of approximately 7.8 and at a temperature of about 38-40° C. Usageprice cyclohexylglycine is essentially enantiomerically pure (S)-isomer. (R)-N-Acetylcyclohexanone, which remains in the filtrate, after racemization, for example, by heating with acetic acid and acetic anhydride at about 115° again it may be subjected to enzymatic deacetylation, so in the end, essentially the entire quantity of racemic N-acetylcyclohexanone turn optically pure (S)-cyclohexylglycine.

The second possible way of obtaining (S)-cyclohexylglycine is to obtain racemic N-acetylcyclohexanone (formula (XV)by one-step method catalyzed by palladium aminocarbonylmethyl based on cyclohexanecarbonyl the IDA, of carbon monoxide and ndimethylacetamide, then described by the splitting of the racemate using acylase (see M. Beller and others, Chem. Eur. J., 4, 935 (1998)).

According to a third method of obtaining (S)-cyclohexylglycine (formula (XII)), the phenyl group in enantiomerically pure (S)-phenylglycine (formula (XVII)) hydronaut to tsiklogeksilnogo group do not result in racemization conditions. Suitable catalysts are the catalysts based on noble metals, such as, for example, rhodium-on-coal. The hydrogenation is preferably carried out in an acidic medium, for example in a carboxylic acid, such as glacial acetic acid, particularly preferably a strong acid, such as, for example, 2 n hydrochloric acid or sulfuric acid. In such strong acid hydrogenation proceeds quickly and without significant racemization at a temperature of from about 60° C to about 80° and the pressure of hydrogen, for example, about 20 bar. The resulting product has a quality similar to that of the product obtained from racemic phenylglycine above described method. The original product (S)-phenylglycine is more expensive than the original product (RS)-phenylglycine, however, due to the low cost of production, the way in which using (S)-phenylglycine as the source material is more preferably the M.

Enantiomerically pure original product of the formula (IV) or its salt of the formula (IX) preferably receive, based on pyridine-3-carbaldehyde (formula (XVIII)), which in conditions similar to those mentioned above for the conversion of compounds of formula (X) in the compound of formula (XI)into aslacton formula (XIX), for example, by heating N-acetylglycine and acetic anhydride in acetone. Aslacton formula (XIX) may be subjected to solvolysis with water to obtain N-acetyldihydrocodeine, that is, carboxylic acid, or a lower alcohol, for example, (C1-C3-alkanols, such as methanol or ethanol, to obtain the ester of carboxylic acid, preferably methanol, with the aim of obtaining complex methyl ester (compare with formula (XX)). As the subsequent asymmetric hydrogenation carried out particularly preferably in alcohol under acidic conditions, where the greatest number of or all of the carboxyl groups are converted to ester groups, and because the solvolysis of azlactone formula (XIX) with alcohols runs more smoothly than that with water, the compound of formula (XIX) is preferably subjected to solvolysis using a lower alcohol, particularly preferably methanol. Alcoholysis is preferably carried out in the presence of weak bases, for example tertiary amines, such as triethyl is min, at temperatures from about 50° up to about 65° C. methyl ester preferably isolated in the form of additive salts with a strong acid, i.e. in the form of compounds of formula (XX), where the anion Y is an anion of a strong acid, such as, for example, tetrafluoroborate or toilet-anion. Particularly preferably, the product of the methanolysis of azlactone formula (XIX) are precipitated in the form of tetrafluoroborate by adding terraforming acid, for example, an aqueous solution terraforming acid, until a pH from about 1.5 to about 2, for example, about 1.9, and the product, after deposition, bring it to fullness by adding a nonpolar solvent, for example, a simple ester, such as methyl tert-butyl ether, filtered or allocate by centrifugation. The compound of formula (XX), where Y=BF4, is obtained in high yield (90%) and very high degree of purity (>99.5%pure).

The next stage is asymmetric catalytic hydrogenation dehydrophenylalanine derivative of the formula (XX) with the aim of obtaining optically active derivative of the amino acid of formula (XXI). As mentioned, in order to achieve high yield and short reaction time, this hydrogenation is preferably carried out under acidic conditions, for example in acetic acid, in particular the military, preferably in the presence of a strong acid, for example toluene-4-sulfonic acids or terraforming acid, which is used in at least stoichiometric amount, for example, 1-2-fold molar amount, to becoming fully pyridine group in the pyridinium salt. In the case of hydrogenation is preferred to use pyridinium salts of the formula (XX) and, if necessary, additional acid. Especially preferably the hydrogenation of pyridinium salts of the formula (XX), in particular, salts, where Y=BF4carried out in lower alcohol, particularly methanol, in the presence of about 15 mol.% a strong acid. Preferred acids, in the presence of which carry out the hydrogenation of the salt of formula (XX)are tetraphobia acid, and toluene-4-acid, especially tetraphobia acid, which can be used in aqueous solution.

As catalyst for the asymmetric hydrogenation of compounds of formula (XX) to those of formula (XXI), respectively, acceptable explanations given above with respect to catalysts for the hydrogenation of compounds of formula (II) to the compounds of formula (VI). Thus, stereocontrolled hydrogenation of the double bond C=C in the compound of formula (XX) may be carried out in a similar way when using selective heterogeneous catalysts or the use of chiral complexes is the basis of transition metals. This hydrogenation is preferably carried out using chiral metal complexes based on rhodium(I) or ruthenium-(II), in particular rhodium-(I). The catalyst based on transition metal can be used in a dedicated form or can be obtained in situ in the medium for the hydrogenation of chiral ligand and catalyst precursor, such as a salt of rhodium, such as [Rh(COD)Cl]2. The catalyst preferably receive in situ. As chiral ligands for the complex based on the transition metal, also suitable many different connections. According to a preferred variant implementation of the present invention the catalyst used for the asymmetric hydrogenation of compounds of formula (XX) to compounds of formula (XXI)is a complex of rhodium(I), including chiral phosphine as a ligand, particularly preferably the catalyst Rh(I)-(+)-phenyl-SAR, that is, a catalyst based on rhodium(I), which contains as a chiral ligand (+)-(2R,4R)-1-phenylenecarbonyl-4-diphenylphosphino-2-(diphenylphosphinomethyl)-pyrrolidin (molar the ratio of rhodium:ligand = 1:1). However, suitable for use as ligands in catalytic complexes are, for example, above (+)-VRRM or aminomethylphosphonic (+)-PPP (= (+)-proprofs; see S. Döbler and others, Tetrahedon: Asymmetry, 7, 111 (1996)). In addition, the ligands for suitable catalytically active complexes on the basis of the transition metal are listed, for example, in book I. Ojima "Catalytic Asymmetric Synthesis", pages 445-447, VCH, new York, 1993.

Hydrogenation of the compounds of formula (XX) is preferably carried out at temperatures from about 20° With up to about 60° S, especially preferably from about 30° With up to about 50° With, for example, at about 40° C. in Addition, the pressure of hydrogen depends on used equipment; the preferred pressure of hydrogen is from about 0.2 bar to about 20 bar, particularly preferably from about 0.2 bar to about 10 bar, particularly preferably from about 0.5 bar to about 1 bar, for example, about 0.8 bar. In particular, when using a catalyst Rh(I)-phenyl-SAR, in order to improve the enantioselectivity of the hydrogenation is preferably carried out at a relatively low hydrogen pressure. As explained above in the case of hydrogenation of the compounds of formula (II), here also, in order to increase the efficiency of the hydrogenation, the reaction is carried out with the exclusion largely of oxygen and with very vigorous stirring. The hydrogenation product of the formula (XXI), in particular in the case of tetrafluoroborate, preferably allocate by crystallization, for example, alcohol such as isopropanol. Receive the config output ranges from about 86% to about 95%, enantiomeric purity, depending on certain conditions, is the enantiomeric excess of about 70% and the enantiomeric excess of about 95% (S)-isomer. In the case of hydrogenation of compounds of formula (XX) to those of formula (XXI) may use a very high ratio substrate/catalyst from about 5000:1 to about 10000:1, for example, about 8000:1.

At the next stage, the group of complex methyl ester in compounds of formula (XXI) hydrolyzing the purpose of obtaining a carboxyl group, acetyl group is removed from the amino group and the amino group protects this way so as to avoid any adverse reactions during the formation carboxamide group. The removal of acetyl groups and hydrolysis of complex methyl ester to the free carboxylic acid can be carried out simultaneously by treatment with acid, for example aqueous hydrochloric acid, such as 1 n hydrochloric acid or 4 n hydrochloric acid, at temperatures of, for example, from about 60° C to about 85° From or from about 85° With up to about 90° C. In order to facilitate the extraction of product from the aqueous reaction mixture, the free amino group is then preferably immediately turned into allmenalp, which later can be easily removed protective group, for example, in benzyloxycarbonylamino. The introduction of protective benzyl is ccarbonless group (Z group) is preferably carried out using N-benzyloxy-carbamidomethylated (=Z-OSu) in a solvent of water/tetrahydrofuran in the alkaline region, particularly preferably at pH values from about to 8.0 to about 8.5. Upon completion of the reaction, the organic solvent is distilled off, set slightly acidic pH, preferably a pH value of about 5, and saducees compound of formula (XXII) is filtered or allocate by centrifugation. If desirable, the purity of the compounds of formula (XXII) may be improved by recrystallization, for example, from water, to obtain the amide of formula (XXIII).

If the enantiomeric purity of compounds of formula (XXI) or the compounds of formula (XXII)obtained from them above described method is unsatisfactory, preferably acetyl group otscheplaut from the amino group in the compound of formula (XXI) than by using hydrochloric acid, and the enzyme and, thus, enantioselective. The enzymatic deacetylation is preferably carried out similarly enzymatic deacetylation of the above (R,S)-N-acetylcyclohexanone when using acylase "Amano" 30000. According to a particularly preferred method, the salt of the formula (XXI), selected after hydrogenation, is first dissolved in water and after addition of base, for example sodium hydroxide, stirred in an alkaline region, for example, at pH values from about 10 to about 11, for hydrolysis of complex methyl ester. After cobaltichloride cobalt(II) as socializaton, add acylase when the pH value is from about 7.8 to about 7,9 and at a temperature of from about 38° With up to about 40° With, for example, in amounts of from about 5 g to about 6 g per kg of the compounds of formula (XXI), and the mixture is stirred until deacetylation (S)-isomer. To turn deacetylating (S)-isomer in connection with the protected benzyloxycarbonylamino, then to the reaction mixture, preferably, as indicated above, add miscible with water, the solvent, such as tetrahydrofuran, the reaction with Z-OSu is carried out at a pH value of from about to 8.0 to about 8.5, the organic solvent is distilled off, the mixture is acidified to pH about 5, and then allocate usageprice enantiomerically pure product of the formula (XXII).

The transformation Z-sassenou amino acids of the formula (XXII) in the Z-substituted amide of the amino acids of the formula (XXIII) may be effected using methods which are customary for such reactions and are known to the specialist. According to a preferred method, the acid of formula (XXII) is activated by conversion into a mixed anhydride using alkylphosphonate, particularly preferably of isobutylacetate. This reaction is preferably carried out in the presence of a tertiary amine, for example N-ethyldiethanolamine, in a simple ether, such as tetrahydrofuran, as the races is varicela, at temperatures from about -10° With up to approximately 0° C, preferably from approximately -10° up to about -5° C.

Following this, the injected ammonia at a temperature of from about -10° With up to approximately 0° C, preferably from approximately -10° up to about -5° With, in the solution of the mixed anhydride. After conventional treatment and crystallization from solvent, such as, for example, ethyl acetate, get the connection formula (XXIII) with a yield of about 87%, with chemical and enantiomeric purity in each case is virtually 100%.

Methylation of the nitrogen atom of the pyridine in the compound of formula (XXIII) with the formation of the pyridinium salt of formula XXIV can be smoothly carried out with the help of numerous meteorous agents, as, for example, methyliodide, methyl bromide, methyl chloride or metalcolor-4-sulfonate, in a number of solvents, such as alcohols, such as isopropanol, amides, such as dimethylformamide, N,N,N’,N’-tetramethylrhodamine, ketones, such as acetone, or ethers, such as tetrahydrofuran, preferably at temperatures from about 40° With up to about 60° C. By the reaction of compounds of formula (XXIII) with methyl chloride in dimethylformamide at a temperature of 45° With, for example, obtain the connection formula (XXIV), where X=CL, with quantitative yield and purity of about 98.4%of. When methylation carry out the industrial scale, preferred is the use of less volatile meteorologi agent. As possible to avoid additional anyoneeven, for example, by ion-exchange chromatography, a further aspect of the choice meteorologi agent is the influence of the anion X, which is contained in the compounds of formula (IV), (IX) and (I) and derived from meteorologi agent on the properties of these compounds, for example, the solubility of the compounds of formula (IV) or its salt, which is important in the reaction of a combination of compounds of formulas (III) and (IV), or solubility properties in the precipitation and physiological compatibility of the compounds of formula (I). In General, it is found that the iodides and toluene-4-sulfonates on the basis of their properties particularly favorable, and, thus, the preferred mahilyouski agents are methyliodide and metalcolor-4-sulfonate (= metaltail). Toluene-4-sulfonates, in particular, in the case of the compounds of formula (IV) or its salt with toluene-4-acid, differ in that they can be easily separated, have a high solubility and have a high rate of peptide combinations, and in the case of the compounds of formula (I) are, in particular, are unusually good properties deposition, purity and yield. Particularly preferred meteorous agent for the conversion of compounds of formula (XXIII) with the Association of the formula (XXIV), thus, it is metalcolor-4-sulfonate.

Methylation of the compounds of formula (XXIII) with metalcolor-4-sulfonate is preferably carried out in a lower alcohol as a solvent, for example isopropanol, at a temperature of from about 40° With up to about 60° With, for example, at about 50° s Metalcolor-4-sulfonate is preferably used in a small excess, for example about 1-1,2-fold molar amount based on the compound of formula (XXIII). Methylation of the compounds of formula (XXIII), and then remove benzyloxycarbonyl protective group in the case of the compounds of formula (XXIV) by hydrogenolysis can be carried out separately. Preferably, the methylation and the hydrogenolysis is carried out by one-step reaction without intermediate highlight the compounds of formula (XXIV). To this end, the compound of formula (XXIV) is dissolved, for example, by adding water, if it is a precipitate from the reaction medium methylation, and then hydronaut in normal conditions, for example, in the presence of a conventional catalyst based on a noble metal such as palladium on charcoal, at temperatures from about 20° With up to about 40° C, preferably from about 20° With up to about 30° and when the hydrogen pressure from about 1 bar to about 20 bar, preferably from about 1 bar d is approximately 5 bar, particularly preferably at a pressure of approximately 1 bar, i.e. not at a gauge pressure of hydrogen. Monocationic salt comprising the cation of 3-((S)-2-amino-2-carbamoylethyl)-1-methylpyridine (containing a free amino group NH2in position 2) and the anion X, for example, tosylate-, iodine -, or chloranil, as counterion, i.e., the compound of formula (IV)may be isolated as such. The resulting pyridinylamino preferably isolated in the form of a salt with the acid HX, i.e. in the form dicationic salt of the formula (IX), and, to this end, the reaction mixture obtained by hydrogenolysis, mix approximately one equivalent of the acid HX, that is, approximately one equivalent of toluene-4-sulfonic if tosilata. The hydrogenation catalyst is filtered off, and the product can then be isolated by concentration and crystallization of the residue, for example, alcohol such as isopropanol.

The present invention also relates to compounds of the formula (IV)in which X-means an anion or an equivalent of an anion, in particular a physiologically acceptable anion, such as chlorine-, bromine-, iodine -, or toluene-4-sulfonate anion, and their salts with an acid HX (= dication salt of the formula (IX)) as such, the above method of their production and the ways in which carry out one or more of the above stages, is for their use as intermediate products, in particular, as intermediates for pharmaceutically active compounds and to compounds of formula (XX), (XXI), (XXII) and (XXIV) as such.

The following examples serve to illustrate the present invention. However, the invention also includes modifications of the above and below embodiments, for example, the ways in which stage are combined in one process, or, on the contrary, the method is carried out in several separate stages, or where stage is carried out in a different order, or where the use of such reagents or solvents, or where modified processing methods.

Examples

Example 1

4-(2-Methyl-5-oxohexanoyl-4-ylidenemethyl)benzonitrile

The acetone in the number 80,0 l is introduced into the mixture of 15.0 kg (114,5 mol) of 4-formyl-benzonitrile, 19,2 kg (162,4 mol) of N-acetylglycine and 9.4 kg (114,5 mol) of anhydrous sodium acetate, followed by the introduction with stirring 35,0 l (370,5 mol) of acetic anhydride. The reaction mixture is stirred for 1 hour at boiling under reflux. The resulting thin yellow suspension is cooled to a temperature of 50° and as quickly as possible, with stirring and cooling, add 200 l of a mixture of water with ice. The mixture is stirred at a temperature of 20° C for one hour. To highlight a product, a suspension of yellow press in centrifuge washed with 75 l of deionized water, 40 l of isopropanol and 75 l of methyl tert-butyl ether. The product is dried under reduced pressure at a temperature of 40° C. Output: 18,17 kg (85,7 mol; and 75.2% of theory).

TPL: 192-193° C;

mass spectrometry (desorption chemical ionization (DCI)):

m/z=213 [M+H+];

1H-NMR (DMSO-d6): δ =2,42 (s, 3 H); 7,30 (s, 1 H); of 7.96 (d, 2 H); 8,33.(d, 2 H).

Example 2

(R,S)-Cyclohexylglycine

In nitrogen atmosphere, 10,0 kg (66,2 mol) of (R.S)-phenylglycine was added with stirring to 78.5 per l of water and 21.5 liters of 30%hydrochloric acid. Then, under stirring and in a nitrogen atmosphere add 209,6 g water-wetted rhodium coal (G 101 S/W 5%; Degussa AG). Create a hydrogen pressure of 18 bar and the mixture is heated to an internal temperature of 100° C and stirred for 72 hours. The mixture is then cooled to an internal temperature of 50° C. a sample is Taken for thin-layer chromatography (butanol/glacial acetic acid/water = 2/1/1; Rf[phenylglycine] = 0,60; Rf[cyclohexylglycine] = 0,68). After full conversion of the catalyst is filtered off at a temperature of 50° and the pH value of the filtrate at a temperature of 20° C, adjusted to 4 using approximately 15 l of concentrated aqueous sodium hydroxide solution. The mixture is stirred for 30 minutes and the precipitated precipitated product is filtered off, washed twice, each time in 35 l of water and drying the Ute at a temperature of 50° With under reduced pressure.

Output: 9.7 kg (93 % of theory).

TPL: >300° C;

mass spectrometry (DCI): m/z (%) = 158 ([M++H], 100);

1H-NMR (200 MHz, triperoxonane acid (TFUC)): δ =1,1-1,6 (m, 5 H); a 1.7-2.1 (m, 5 H); to 2.1-2.3 (m, 1 H); 4,3 (d, J=4 Hz, 1 H); 11,6 (s, 1 H);

X (CVG): ν =2927,7; 1583,9; 1508,8 cm-1.

Example 3

(R,S)-N-Acetylcyclohexanone

At room temperature, 9,41 kg (61,7 mol) of (R,S)-cyclohexylglycine with stirring to 30,2 l aqueous concentrated solution of sodium hydroxide in 134 l of water. The mixture is cooled to an internal temperature of 5-10° and when this internal temperature for two hours add metered 15,7 l (17 kg, 166 mol) acetic anhydride (exothermic reaction). Then check the pH value and, if required, is brought to a value equal to at least 11, when using an aqueous solution of sodium hydroxide. The mixture was stirred at an internal temperature of 5-10° C for 1 hour. Then the internal temperature was raised to approximately 23° and continue the stirring for the next two hours. Every hour is controlled so that the pH value constantly was 11. Upon completion of the reaction (thin layer chromatography; ethyl acetate/methanol/glacial acetic acid/water = 70/30/5/5; Rf[acetylcyclohexanone] = 0,83; Rf[cyclohexylglycine] = 0,55). the mixture ohla is to give an internal temperature of 5-10° C. the pH Value was adjusted to pH=3 by slowly adding approximately 36 l 30%hydrochloric acid at an internal temperature of 5-10° C. Stirring is continued for the next 15 minutes, and the mixture is then filtered. The resulting solid is washed twice, each time for 45 l of water and dried at a temperature of 60° With under reduced pressure. Output: to 11.52 kg (96, 7% of theory).

TPL: 195-197° C;

mass spectrometry (DCI): m/z (%) = 200,2 ([M++H], 100);

1H-NMR (200 MHz, DMSO-d6): δ =0,9-1,3 (m, 5 H); 1,5-1,8 (m, 6 H); to 1.86 (s, 3 H); to 4.1 (DD, J1=8 Hz, J2=6 Hz, 1 H); of 7.96 (d, J=8 Hz, 1 H); 12,47 (s, 1 H);

X (KBr): ν =3339,7; 2929,3; 1699,9; 1615,7; 1563,2 cm-1.

Example 4

(S)-Cyclohexylglycine obtained by enzymatic deacetylation (R,S)-N-acetylcyclohexanone

At room temperature and under stirring, 7,95 kg (39,.9 mol) of (R,S)-N-acetylcyclohexanone add to the 3.65 l 33%aqueous solution of sodium hydroxide in 143 liters of water. Under stirring establish a pH value equal to 7.8 using about 0.8 liters of 2 n hydrochloric acid. With stirring 13.8 g (0,058 mol) of uranyl chloride cobalt(II). The mixture is then heated to an internal temperature of 38-40° C. At a constant internal temperature and, with slow stirring, 40 g acylase "Amano" 30000 400 ml of water. The mixture is slow is stirred for 41 hours during which slowly precipitated (S)-cyclohexylglycine. When using 30%hydrochloric acid the pH carefully adjusted to 5.5 to 6.0. The mixture is cooled to an internal temperature of 2-5° C and stirred for 1 hour. Fallen in sediment (S)-cyclohexylglycine filtered off, washed with about 16 liters of water and dried under reduced pressure and at a temperature of 60° C. Output: 2,79 kg (44.5 percent).

TPL: >300°; [α ]D=32,1° (C=1; 1 n Hcl); the enantiomeric excess = efficiency of 99.78% (analysis by gas chromatography on Chirasil L-Val, followed by derivatization with propanol/Hcl and performatives anhydride);

mass spectrometry (DCI): m/z (%) = 158 ([M++H], 100);

1H-NMR (200 MHz, TFUC): δ =1,1-1,6 (m, 5 H); a 1.7-2.1 (m, 5 H); to 2.1-2.3 (m, 1 H); 4,3 (d, J=4 Hz, 1 H); 11,6 (s, 1 H);

X (KBr): ν =2927,7; 1583,9; 1508,8 cm-1.

For separation of unreacted (R)-N-acetylcyclohexanone, the mother solution at an internal temperature of 2-5° adjusted to pH 1 using approximately 4.3 liter of 30%hydrochloric acid and stirred at a temperature of 2-5° C for 1 hour. Precipitated in the sediment (R)-N-acetylcyclohexanone filtered off, washed with about 16 liters of water and dried under reduced pressure at a temperature of 60° C. Output: 3,76 kg (47,3%).

TPL: >210-212°; [α ]D=-23,5° (C=1; methanol); enantiomeric excess = 98,39% (analysis by gas chromatography on Chirasil L-Val, followed by derivatization with propanol/Hcl or methanol/Hcl).

Data1H-NMR, mass spectrometry and X correspond to the racemic original product 4.

Example 5

(R,3)-N-Acetylcyclohexanone obtained by racemization of (R)-N-acetylcyclohexanone

In nitrogen atmosphere and with stirring, 10,9 kg (54,7 mol) of (R)-N-acetylcyclohexanone mixed with 24,5 l glacial acetic acid and 1.7 l of acetic anhydride. The internal temperature was raised to 115° and the mixture is stirred at this temperature for 3.5 hours. The internal temperature is then reduced to about 20° and add 73 l of water. The pH value of the reaction mixture is 2. The mixture is stirred at a temperature of 0-3° C for 1 hour, the obtained solid is filtered off and washed twice, each time in 25 l of water and the substance is dried at a temperature of 60° With under reduced pressure. Output: 7,95 kg (73% of theory) of (R,3)-N-acetylcyclohexanone. TPL:195-196°; [α ]D=0° (C=1; methanol). Data1H-NMR, mass spectrometry and X correspond to the data of the product obtained in example 3. The mother liquor contains about 2 kg (R,S)-N-acetylcyclohexanone.

Example 6

(S)-Cyclohexylglycine obtained by hydrogenation without racemization of (S)-phenylglycine

In the apparatus for hydrogenation, covered with enamel, or Hastelloy, 90 g (of 0.53 mol) of (S)-phenylglycine (the content of R-and the Omer < 1%) at a temperature of 50° C, in nitrogen atmosphere and with stirring, are added to a solution of concentrated sulfuric acid (97%, 60 g) 0,70 l of deionized water. After dilution total number of phenylglycine (if required, add an additional amount of sulfuric acid (about 5 ml) is added 6.3 g of a 5%rhodium on charcoal, hydrated with water (50% water) (the company Engelhard, type 5% RH Carb Polcere Escat 30 M, Engelhard Code 8000). Apparatus for hydrogenation close and create an inert atmosphere using nitrogen. The mixture is heated to an internal temperature of 80° and create a hydrogen pressure of 20 bar. Full hydrogenation time is 5-6 hours, uptake of hydrogen is approximately 37 L. after the absorption of hydrogen, the mixture is left for further hydrogenation at a pressure of 20 bar for an additional 30-60 minutes. The mixture is then cooled to an internal temperature of 50° and the catalyst is filtered off at a temperature of 50° when using a pressure filter. The catalyst is washed with 0.30 liter of deionized water and the filtrate at a temperature of 20° set pH=4 by adding 90 ml of aqueous concentrated (33%) sodium hydroxide solution. Stirring is continued for 30 minutes and the precipitated precipitated product is filtered off by suction and washed deionizer the authorized water (generally about 0,85 l) as long until the washing water will not contain sulfation. The wet product in an amount of about 150 g dried at a temperature of 50° With under reduced pressure. Output: 80-84 g (86-90% of theory) of (S)-cyclohexylglycine. Optical purity: the enantiomeric excess of 99.3%.

Example 7

(S)-2-[2-Acetylamino-3-(4-cyanophenyl)acrylamido]-2-cyclohexyloxy acid

(S)-Cyclohexylglycine in the number 3,14 kg (20 mol) in 70 l of acetone with stirring is heated to a temperature of 35° C. Then with stirring for 10 minutes, add 20 l of 1 n aqueous sodium hydroxide solution. The mixture is heated to a temperature of 40° and when the inner temperature of 40° add portions, with vigorous stirring, for 20 minutes 4,66 kg (22 mol) of solid 4-(2-methyl-5-oxohexanoyl-4-ylidenemethyl)benzonitrile. Upon completion of the addition, the reaction mixture is stirred at an internal temperature of 40° C for 1 hour. The reaction solution is then filtered through a pressure suction filter, covered with filter Seitz K1000 and activated charcoal (1 kg), and the filter residue is washed with 10 l of acetone. The filtrate is then cooled to a temperature of 14° C. then, with stirring for 10 minutes, add approximately 10 liters of 2 n hydrochloric acid until the pH value of 2.3. Stirring is continued for 15 minutes and the ova set the pH value when using 2 n Hcl. Within 20 minutes, then mixed under stirring with 160 l of deionized water, the resulting precipitates specified in the header connection. With stirring, the mixture is cooled to a temperature of 0° and at this temperature, stirred for 1 hour. To highlight, the product is pumped into a centrifuge, washed three times with water, using each time 10 l of water, dehydrated in a dryer and dried at a temperature of 40° With under reduced pressure. Output: 4,21 kg (11,4 mol; 57% of theory).

TPL: 196-198° C; mass spectrometry (ESI+[electronic ionization sputtering with the formation of positive ions]):

m/z=370,2 [M+H+];

1H-NMR (200 MHz, DMSO-d6): δ =0,98 and 1.35 (m, 5 H); 1,48-1,90 (m, 6 H); 1,99 (s, 3 H); 4,20 (DD, 1 H); 6,98 (s, 1 H); 7,72 (d, 2 H); 7,88 (d, 2 H); 8,02 (d, 1 H); 9,58 (s, 1 h); 12,65 (USS, 1 H).

Example 8

(S)-2-[(3)-2-Acetylamino-3-(4-cyanophenyl)propionamido]-2-cyclohexyloxy acid

In the first autoclave load 7,94 kg (21.5 mol) of (S)-2-[2-acetylamino-3-(4-cyanophenyl)acrylamido]-2-cyclohexyloxy acid in 100 l of methanol in an autoclave carefully create an inert atmosphere using nitrogen. The catalyst solution is prepared as follows: 3.0 liters of methanol are treated in an ultrasonic bath for 15 minutes, during which the injected argon. With the exclusion of oxygen then add 10.92 g (19,65 mmol who) (+)-VRRM and 4,88 g (of 9.75 mmol) [Rh(COD)Cl] 2and the mixture is left in an ultrasonic bath for 30 minutes. Then, with the exclusion of oxygen, the catalyst solution is yellow-orange color is injected in the autoclave.

Three times create a hydrogen pressure of about 3 bar and the autoclave immediately ventilate again. The reaction mixture is heated to an internal temperature of 40° To create a hydrogen pressure of 10 bar and the mixture is then hydronaut under stirring and at a temperature of 40° C for 20 hours. The autoclave is then blown off with nitrogen. After hydrogenation, the solution is filtered through a Seitz filter. The filtrate is heated to a temperature of 50° within 30 minutes add 110 l of deionized water and continue mixing at a temperature of 50° C for 1 hour. The mixture is then cooled to a temperature of 15° C and stirred at the temperature of 15° C for 1 hour. Phase precipitate the product produce by filtration through a pressure suction filter, washed with 20 l of deionized water and dried under reduced pressure at a temperature of 40° C. Output; 7,73 kg (20,81 mol; 96,7% of theory).

TPL: 209-211° C;

mass spectrometry (SI+): m/z=372,2 [M+H+];

1H-NMR (DMSO-d6): δ =0,95-to 1.38 (m, 5 H), 1,47 and 1.80 (m, 6 H), 1,72 (s, 3 H), 3,10 (HDD, 2 H), to 4.15 (DD, 1 H), 4,70 (m, 1 H), 7,47 (d, 2 H), 7,65(d, 2 H), 8,08 (d, 1 H)to 8.12 (d, 1 is), 12,60 (USS, 1 H).

Example 9

Betaine (S)-2-[(S)-2-acetylamino-3-(4-amidinophenoxy)propionamido]-2-cyclohexyloxy acid

Under stirring, to 3.77 kg (10.1 mol) of (S)-2-[(S)-2-acetylamino-3-(4-cyanophenyl)propionamido]-2-cyclohexyloxy acid and 1.06 kg (15,2 mol) of hydroxylaminopurine add 20 l of methanol. The mixture is stirred for 10 minutes and then add 2,52 kg (30 mol) of sodium bicarbonate. Within 1 hour the reaction mixture is slowly heated (emissions of carbon dioxide) until the internal temperature of 55° C, then stirred at a temperature of 55° C for 6 hours and at room temperature over night. Precipitated precipitated sodium chloride is filtered off by suction when using a Seitz filter and washed with 4 l of methanol. The methanol solution is concentrated to a volume of about 10 l when using a rotary evaporator with a bath temperature of about 40° and added dropwise, with vigorous stirring, to 60 l of isopropanol. The result is the precipitation of the sodium salt of N-hydroxyamides. For a complete precipitation of the mixture is concentrated under reduced pressure at a temperature of about 40° and with vigorous stirring, to a volume of about 50 liters Stirring is then continued for 1 hour at a temperature of 15° and the product is filtered through working p is the pressure on the suction filter. The precipitate is washed with 10 l of isopropanol and dried on a suction filter overnight in a stream of nitrogen.

The obtained sodium salt of N-hydroxyamides then directly used for subsequent hydrogenation. To this end, in the first autoclave load 26 l of glacial acetic acid and stirring portions add approximately 6.2 kg of sodium salt of N-hydroxyamides (wet crude product resulting from the above reaction). To the solution was added a suspension of 10%palladium-on-coal (50% water, and 0.40 kg) in 1 l of glacial acetic acid. The autoclave is first rinsed with nitrogen and then with hydrogen, and the mixture is then hydronaut at a temperature of 50° and a hydrogen pressure of 18 bar for 72 hours. The reaction mixture is allowed to cool to room temperature and filtered in a nitrogen atmosphere through a Seitz filter with a brightening layer coated with activated carbon, and the filter residue is washed with 2 liters of glacial acetic acid. The filtrate was concentrated in a rotary evaporator at a bath temperature of 50° until then, until there is no more to Athanasia glacial acetic acid and will not start crystallization. The mixture was then allowed to cool to a temperature of about 25° and while the mixture is still in a rotary evaporator flask rotary evaporator injected with 20 l of ethyl acetate, after which amidin precipitates as silikatnoi acid. After additional mixing time of 0.5 hours the precipitate is filtered by suction through a filter paper and carefully dried by sucking.

Crude midinotate, obtained as described above, with vigorous stirring injected in 20 l of deionized water heated to a temperature of 40° and the mixture is heated at a temperature of 80° until a clear solution is formed. Under vigorous stirring the mixture is cooled to a temperature of 15° C for 30 minutes, resulting in the deposition specified in the connection header (betaine). Stirring is continued at a temperature of 15° C for 1 hour, and precipitated precipitated product is filtered over a pressure suction filter. The filter cake is washed with 6 l of a mixture of ice water, carefully dried in a stream of nitrogen, transferred into the tank and together with 40 l of acetone was stirred at room temperature and under nitrogen atmosphere for 1 hour. Precipitated precipitated product is filtered over a pressure suction filter, washed with approximately 10 l of acetone and dried under reduced pressure and at a temperature of 40° C. Output: 2,58 kg (6,64 mol; and 65.7% of theory) specified in the connection header.

Mass spectrometry (ESI+): m/z=389,3 [M+H+];

1H-NMR (methane is l-d 4): δ =0,98-1, 38 (m, 5 H); 1,58-of 1.78 (m, 6 H); a 1.96 (s, 3 H); 3,10 (HDD, 2 H); was 4.02 (d, 1 H); br4.61 (DD, 1 H); 7,42 (d, 2 H); to 7.68 (d, 2 H).

Example 10

2-Methyl-4-[pyridin-3-yl-(Z)-methylene]-4H-oxazol-5-he

In nitrogen atmosphere, to 32.7 kg (280,0 mol) of N-acetylglycine and 15.3 kg (186,9 mol) of sodium acetate added to 40.0 l of acetone, then 20,0 kg (186,9 mol) pyridine-3-carbaldehyde. With stirring, add 40,0 l (429,0 mol) of acetic anhydride. Within 30 minutes the reaction mixture is heated to boiling point under reflux and then boiling under reflux is stirred for 1.5 hours. So get reddish thin slurry. The suspension is cooled to a temperature of 50° and then add 80,0 l methyl tert-butyl ether. As quickly as possible (<5 minutes), with stirring and cooling, add 200,0 l of a mixture of ice water (temperature <2° (C) and the mixture is then stirred for 1 hour at a temperature of 5-10° C. the beige Suspension is introduced into a centrifuge, which creates an inert atmosphere using nitrogen. The precipitate was separated by centrifugation, washed with 80,0 l deionized water and dried under reduced pressure and at a temperature of 40° C. Output; 24,8 kg (131,9 mol; 70,6% of theory).

TPL: 173° C; mass spectrometry (DCI): m/z (%) = 189 ([M+H+], 100);

1H-NMR (200 MHz, DMSO-d6): δ =2,40 (s, 3 who); 7,28 (s, 1 H); 7,53 (DD, 1 H); 8,61 (d, 2 H); 9,18 (USS, 1 H);

X (CVG): ν =1799,9; 1777/4; 898,0 cm-1.

Example 11

3-(2-Acetylamino-2-methoxycarbonylbenzyl)pyridinium tetrafluoroborate

In nitrogen atmosphere, a suspension of 12.0 kg (63,83 mol) of 2-methyl-4-[pyridin-3-yl-(Z)-methylene]-4H-oxazol-5-she 120,0 l of methanol are heated to a temperature of 60° C. Pump 0.5 l of triethylamine and the apparatus is washed with 0.5 l of methanol (pH value of the selected sample, measured using a glass electrode, is 8,15). Within 30 minutes the reaction solution is cooled to a temperature of 30° C. for 30 minutes, add 48%solution terraforming acid in water (11,8 kg; 64,5 mol). The mixture is cooled for 1 hour until internal temperature 10° and (if required, after the introduction of the seed), the suspension is then stirred at a temperature of 10° over the next three hours. Add 40,0 l methyl tert-butyl ether and the mixture was stirred at that temperature for 10° C for 1 hour. The suspension is introduced into a centrifuge, which creates an inert atmosphere using nitrogen, centrifuged and the product is washed with 20,0 l methyl tert-butyl ether and dried at a temperature of 40° With under reduced pressure. Output: 18.7 kg (60,71 mol; 95,1% of theory).

TPL: 179,4° C; mass spectrometry (ESI+): m/z (%) = 221 ([M+H+] the free base, 100);

p>  1H-NMR (200 MHz, DMSO-d6): δ =a 2.01 (s, 3 H); of 3.77 (s, 3 H); 7,21 (s, 1 H); 7,89 (DD, 1 H); 8,48 (d, 1 H); 8,76 (d, 1 H); 8,98 (s, 1 H); 9,92 (s, 1 H);

X (CVG):ν =1726,9; 1670,1; 1091,5 cm-1.

Example 12

(S)-3-(2-Acetylamino-2-methoxycarbonylethyl)pyridinium tetrafluoroborate

In the autoclave, dissolve 10,3 kg (33.4 mol) of 3-(2-acetylamino-2-methoxycarbonylbenzyl)-pyridine of tetrafluoroborate in 120,0 l of methanol. Add 50%solution terraforming acid in water (1,018 kg, 5.8 mol) and the autoclave is closed and carefully create an inert atmosphere using nitrogen. The catalyst solution is prepared by treatment with 3.0 l of methanol in an ultrasonic bath for 15 minutes while introducing argon. With the exclusion of air, degassed thus methanol is mixed with 12.5 g (20,83 mmol) of (+)-phenyl-of SAR and 5.0 g (10,10 mmol) [Rh(COD)Cl]2and the solution of the catalyst yellow-orange color is subjected to ultrasonic treatment in an argon atmosphere for 30 minutes. With the exclusion of oxygen, the catalyst solution is introduced into the autoclave. The contents of the autoclave for 1 hour and heated at a temperature of 40° C. Three times create pressure hydrogen, in each case about 3 bars, and the autoclave immediately fully ventilated. Then create a hydrogen pressure of 1.5 bar and the mixture hydronaut at a temperature of 50° and under vigorous stirring. After 7 hours the hydrogenation is stopped. Analysis is by using HPLC (high performance liquid chromatography) of this sample shows at this point in time there was 99.1% specified in the connection header, and analysis by gas chromatography (capillary column made of quartz glass Chirasil Val length of 30 m, isothermal: 160° C; injector: 220° C; detector (flame ionization detector (FID)): 260°C; carrier gas: 0.8 bar hydrogen; tret(retention time) [(R)-enantiomer]:12, 64 minutes; tret[(S)-enantiomer]: 13,64 minutes) shows that the enantiomeric purity is the enantiomeric excess of 86% (S)-isomer. The autoclave is rinsed with nitrogen and the nitrogen atmosphere, the contents of the autoclave push through a Seitz filter in the tank, where the filtrate is kept at a temperature of +5° C in an atmosphere of nitrogen.

According to the above methods provide four further asymmetric hydrogenation (load size: 8,0 kg (25,97 mmol) and 10.3 kg (33,44 mol); the hydrogen pressure 2-10 bar; temperature 40°; time hydrogenation 4-6 hours; product content: 98,0-99,8% (HPLC); the enantiomeric purity of the crude product obtained in the hydrogenation solution: the enantiomeric excess 62,0 is 84.5% (S)-isomer (gas chromatography)).

The filtrates five downloads unite and the temperature of the jacket 40°subjected to concentration under reduced pressure to a residual volume of 150 L. Add 200 l of isopropanol and the mixture, at the temperature of the jacket 40° and under reduced Yes the tion, concentrated to a residual volume 250 HP two More times add isopropanol (in each case 100 l), and the mixture, at the temperature of the jacket 40° C, concentrated to a residual volume of 250 L. the result is the crystallization specified in the connection header. The white suspension is stirred at a temperature of 10° C in nitrogen atmosphere for 1 hour. The product is separated by centrifugation using a centrifuge, which creates an inert atmosphere using nitrogen, and washed with 100 l of isopropanol and 150 l of methyl tert-butyl ether. So get 45,0 kg (144,7 mol; 90,6% of theory) specified in the connection header with enantiomeric excess of 71% (S)-isomer (gas chromatography).

TPL: 126,2° With (according to differential scanning calorimetry (DSC));

mass spectrometry (ESI+): m/z (%) = 223([M+H+] the free base, 100);

1H-NMR (200 MHz, DMSO-d6): δ =1,78 (s, 3 H), is 3.08 (DD, J=9.5 and 7 Hz, 1 H), 3,29 (DD, J=9.5 and 4 Hz, 1 H), and 4.68 (m, 1 H), of 8.00 (DD, J=5.0 and 4.5 Hz, 1 H), 8,42 (t or 2 d, J approximately 6 Hz, 2 H), 8,80 (d, J approximately 5 Hz, 1 H), 8,82 (, 1 H), X (KBr): ν =1740,9; 1654,3 cm-1.

Example 13

(S)-2-Benzyloxycarbonylamino-3-(pyridin-3-yl)propionic acid

The solution 6,70 kg (21.6 mol) of (S)-3-(2-acetylamino-2-methoxycarbonylethyl)-pyridine of tetrafluoroborate (enantiomeric excess of 71%) in l water filtered through a pressure suction filter, covered with 0.5 kg of activated charcoal. When using about 3.0 liters of aqueous 33%sodium hydroxide solution the pH value of the filtrate is set to 10-11 and the solution is then stirred at a temperature of 20-25° C for two hours, during which the pH value constant support when using concentrated aqueous sodium hydroxide solution. Thin layer chromatography (mobile phase: ethyl acetate/methanol/water/acetic acid = 70/30/5/5) shows that the methyl ester completely hydrolyzed with the formation of carboxylic acids. The pH value was adjusted to 8.0 using approximately 150 ml of concentrated hydrochloric acid. Add to 11.7 g (0,049 mol) of uranyl chloride cobalt(II) and the reaction mixture is heated to an internal temperature of 40° C and stirred for hours at a constant temperature of 39° C. With very slow stirring and at a temperature of 39° With added 38.0 g acylase "Amano" 30000 400 ml deionized water and the mixture is then stirred at a constant value of pH of 7.9 and a constant temperature of 39° C for 40 hours. Thin layer chromatography (the mobile phase as specified above) confirms that the deacetylation subjected to approximately 85% of the carboxylic acid (corresponds to a content of (S)-isomer used in 3-(2-acetylamino-2-methoxycarbonylethyl)-Piri is ini tetrafluoroborate). In the tank to create an inert atmosphere using nitrogen, then add 22,0 l of tetrahydrofuran and the reaction mixture for 1 hour and cooled to an internal temperature of 10° C. for 45 minutes, add a solution 4,63 kg (18,6 mol) of N-(benzyloxycarbonyloxy)succinimide in 23,0 l of tetrahydrofuran, and during this time the pH value constant support when 8,0-8,5 by continuous addition of concentrated (33%) aqueous solution of sodium hydroxide. The mixture was then stirred for 1.5 hours at a temperature of 20° C. Thin layer chromatography (the mobile phase as specified above) shows the complete acylation of the free amino acids. To the reaction mixture are added to 60 l of ethyl acetate, and then the reaction mixture was intensively stirred for 15 minutes. After complete separation of the phases, an ethyl acetate phase is separated and discarded. In the aqueous phase set value pH 5.0, using approximately 3.7 liters of concentrated hydrochloric acid, add seed crystals of the enantiomeric pure, specified in the connection header and the suspension is then stirred overnight at a temperature of 5° C. In the atmosphere of nitrogen, the crystals are filtered when using a pressure suction filter, washed with 20 l of deionized water and dried at a temperature of 48° C under reduced pressure.

Output: 2.86 kg (9,52 mol; 51.9% of theory) specified in the connection header with enantiomeric excess of 100% (CSP Chiralpak AD 250× 4.6 mm Diacel; going forward phase: isopropanol/ethanol/n-hexane = 12/4/84+0.1% diethylamine; tret= 14,16 minutes); [α ]

20
D
=-9,95° (C=1.0; methanol).

TPL: 173-174° With (according to DSC);

mass spectrometry (ESI+): m/z (%) = 301 ([M+H+], 100);

1H-NMR (200 MHz, DMSO-d6): δ =2,85 (DD, J=9.5 and 7.5 Hz, 1 H), 3,10 (DD, J=9.5 and 3.5 Hz, 1 H)to 4.23 (m, 1 H), to 4.98 (s, 2 H), 7,15-7,40 (m, 6 H), 7,62 for 7.78 (m, 2 H), scored 8.38-of 8.50 (m, 2 H), 12,80 (USS, 1 H); X (KBr): ν =3369,7; 1707,4; 1504,7; 1046,9; 699,2 cm-1.

Example 14

Benzyl-(S)-[1-carbarnoyl-2-(pyridin-3-yl)ethyl]carbamate

Suspension 2,60 kg (8,65 mol) (3)-2-benzyloxycarbonylamino-3-(pyridin-3-yl)propionic acid in 60 l of tetrahydrofuran cooled to a temperature of -9° C. at this temperature for 5 minutes add 1,33 kg (10,29 mol) N-ethyl-Diisopropylamine. At a temperature of -9° then for 20 minutes add 1.36 kg (9,96 mol) of isobutylacetate, and the internal temperature at the end of the increase to -6° C. After vigorous stirring for 10 minutes the resulting thin slurry for 3 hours at a constant temperature of -5° -6° impose 2.1 kg (approximately mol) of gaseous ammonia. The first reaction is highly exothermic (originally need a slow introduction), later it is less exothermic. Within 30 minutes the reaction mixture is heated to a temperature of 16° that causes thick, but still mixed with the slurry of crystals. When the temperature of the jacket 30° the solvent is removed under reduced pressure. Bold white balance is suspended in 125 l of ethyl acetate. Add a solution of 3.0 kg of sodium bicarbonate in 50 l of water and the mixture is intensively stirred for 30 minutes, after which the solid is completely dissolved. The organic phase is separated and dried over 1.0 kg of sodium sulfate, the drying agent is filtered off and the filtrate is concentrated under reduced pressure with a bath temperature of 30° With up to a volume of about 6 liters of the Obtained precipitate is filtered off with suction, washed with 1.5 l of ethyl acetate and dried at a temperature of 30° With under reduced pressure. Output: 2.26 kg (at 7.55 mol; of 87.3% of theory). Chemical purity is 99.9% (HPLC: 125× 4.0 mm Purospher RP18, 40° C; detection at 210 nm) ; enantiomeric purity: the enantiomeric excess of 100% (HPLC: 250× 4.6 mm CSP Chiralpak Diacel AD; 40° C; detection at 248 nm; mobile phase: n-hexane/isopropanol/ethanol = 84/12/4+0.1% diethylamine; tret[(S)-isomer]: 14,93 minutes).

TPL: 152,8° With (according to DSC) ;

mass spectrometry (SI +): m/z (%) = 300 ([M+H+], 100);

1H-NMR (200 MHz, DMSO-d6): δ =2,77 (DD, J=9, 5 and 7.0 Hz, 1 H), to 3.02 (DD, J=9.5 and 3.5 Hz, 1 H), 4,19 (m, 1 H), 4,96 (s, 3 H), 7,00-7,40 (m, 7 H), 7,40-of 7.60 (m, 2 H), 7,60-7,76 (m, 1 H), at 8.36-8,53 (m, 2 H), X (KBr): ν =3306,8; 1674,9; 1537,7; 1424,0; 1271,6; 1251,3 cm-1.

Example 15

3-((S)-2-Ammonio-2-carbamoylethyl)-1-methylpyridine ditosylate

In the autoclave, 1.7 l of isopropanol is added to 1.00 kg of 3.33 mol) of benzyl-(S)-[1-carbarnoyl-2-(pyridin-3-yl)ethyl]carbamate and 0.67 kg (3.6 mol) metalcolor-4-sulfonate, allowed in the course of the stirrer and the reaction mixture was stirred in a closed autoclave at a temperature of 50° and in nitrogen atmosphere for 5 hours. The reaction mixture is left to stand at room temperature overnight, resulting in sedimentation of methylated N-benzyloxycarbonyl connection in the form of viscous mucus. The reaction solution is diluted with 0.33 l of deionized water and then added 10%palladium on coal (50% water, 50 g). The hydrogenation is carried out at atmospheric pressure by passing hydrogen (about 10 l/min) under continuous metered addition of a solution 0,63 kg of 3.33 mol) of monohydrate toluene-4-sulfonic acids in 1.0 l of deionized water at a temperature of 20-25° C for approximately three hours. Upon completion of the hydrogenation, the autoclave is rinsed with nitrogen and the solution after the hydrogenation is filtered through Phi is Tr Seitz and washed with 0.5 l of deionized water. The filtrate is transferred into a rotary evaporator and the concentrate in the steam-jet vacuum at a bath temperature of 40° With up to approximately 2.5 L. Then, with vigorous stirring, add 10 l of isopropanol and the mixture is concentrated under stirring and under reduced pressure with a bath temperature of 40° With up to a volume of about 5 liters, resulting specified in the header of the connection begins to crystallize. Under stirring, the suspension of crystals is cooled at a temperature of 15° C for 0.5 hour and the product is filtered with suction through a filter paper, washed with 1 l isopropanol, carefully dried by suction and dried. Output: 1.57 kg (3.0 mol; 90% of theory).

TPL: 219-220° C;

mass spectrometry (SI+): m/z (%) = 180,1 ([M+H+], 100);

1H-NMR (DMSO-d6): δ of 2.30 (s, 3 H), 3,10 is 3.40 (m, 2 H), 4,08 (DD, 1 H), 4,35 (s, 3 H), 7,12 (d, 4 H), of 7.48 (d, 4 H), of 7.70 (s, 1 H), of 7.90 (s, 1 H), 8,05 is 8.22 (m, 4 H), 8,42 (m, 1 H), of 8.95 (m, 1 H).

Example 16

3-{(S)-2-[(S)-2-Acetylamino-3-(4-amidinophenoxy)propionamido)-2-cyclohexylethylamine]-2-carbamoylethyl}-1-methylpyridine ditosylate

In nitrogen atmosphere, 1,306 kg (30,0%on Dicalite®; 2,40 mol) of 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine added to the suspension 5,43 kg (10,36 mol) of 3-((S)-2-ammonium-2-carbamoylethyl)-1-methyleneindoline and 4,00 kg (purity 93,15%; water content 6,85%; 9,591 mol) betaine (S)-2-(S)-2-acetylamino-3-(4-amidinophenoxy)propionamido]-2-cyclohexyloxy acid in 45,0 l N, N-dimethylformamide and the suspension is cooled to a temperature of 10° C. At this. temperature for 7 hours with constant velocity through the pump, add a solution of 2.56 kg (purity 98%; to 12.28 mol) dicyclohexylcarbodiimide 3.4 l of N, N-dimethylformamide, and the pump and pipe are then washed with 0.5 l of N, N-dimethylformamide. The mixture is stirred for 1 hour at a temperature of 10° and then, when heated to room temperature (23,5° (C)in the next 14 hours. The suspension is filtered through a layer Seitz and washed with a mixture of 2,2 l N, N-dimethylformamide and 0.2 l of toluene. Within 30 minutes, the filtrate pump in the tank that is loaded first 1200 l of acetone, which is intensively stirred in nitrogen atmosphere at a temperature of 18° C. the Mixture is stirred at room temperature for 10 minutes and the suspension is then filtered under nitrogen pressure through a pressure suction filter, which is covered with a polypropylene filter cloth and filter Seitz. The residue is washed 3 times in 100 liters of acetone, the solid substance on the pressure suction filter is dried overnight in a nitrogen atmosphere and then repeat the precipitation of the product from acetone. To this end, the solid is dissolved with stirring in 25 l of N,N-dimethylformamide and the solution is mixed with 2.5 l of toluene and within 15 minutes pump in the tank, downloadable sleep is Ala 1200 l of acetone, which is intensively stirred in nitrogen atmosphere at a temperature of 18° C. the Suspension is stirred at room temperature for 10 minutes and then passed through pressure with nitrogen gas through a pressure suction filter. The residue is washed 3 times in 100 l of acetone. The solid is thoroughly dried in a stream of nitrogen and then dried first at a temperature of 20° With under reduced pressure and then at a temperature of 43° C in high vacuum. Output: 7,83 kg (8,76 mol; for 91.3% of theory). The enantiomeric purity is ; the enantiomeric excess of >99% (HPLC: CSP Chiral AGP 100× 4.0 mm, 5 μm; 40° S; 0.7 ml/min 100 mm aqueous sodium acetate; tret= 6,20 minutes; tret[enantiomer] =4.26 deaths minute; tret[the diastereoisomer] = equal to 4.97 min);(C=1,0; water). Chemical purity is 97%, the content of diastereoisomer is 2.4 % (HPLC: Superspher 60 RPselect 250× 4.0 mm; 25° C; detection at 210 nm; 1.0 ml/min; mobile phase A; 950 ml water +50 ml of acetonitrile +7 ml of orthophosphoric acid, which is set to pH=3, with approximately 8 ml of triethylamine; mobile phase b: 600 ml of water and 400 ml of acetonitrile +7 ml of orthophosphoric acid, which is set to pH=3 with use approximately 8 ml of triethylamine; elution program: 15 min 100% mobile phase A; then for 10 minutes in the linear regime is - 50% mobile phase A + 50% mobile phase b; then, in the next 15 minutes in isocratic mode is a mixture of 50:50 mobile phases; tret[specified in the header of the cation] = 13,44 minutes; tret[toilet-anion] = 26,88 minutes).

Mass spectrometry (FAB, NBA): m/z(%)=722 ([M+] monotonicity, 15%); 550 ([M+] not containing tosilata of monocation (N-methylpyridine amidin), 100%);

1H-NMR (500 MHz, DMSO-d6): δ =0,80-1,25 (m, 6 H), 1,40-1,70 (m, 5 H), 1,72 (s, 3 H), to 2.29 (s, 6 H), 2,71 (d, 1 H), 2,98-of 3.07 (m, 3 H), 3,18 (DD, 1 H), of 4.05 (t, 1 H), 4,36 (s, 3 H), 4,55 with 4.65 (m, 2 H), 7,11 (d, 4 N), 7,27 (s, 1 H), 7,42 (s, 1 H), 7,47 (d, 4 H), 7,51 (d, 2 H), 7,73 (d, 2 H), 7,92 (d, 1 H), of 8.06 (DD, 1 H), 8,14 (d, 1 H), 8,21 (d, 1 H), 8,40 (d, 1 H), 8.88 (m, 4 H), the 9.25 (s, 2 H);

13C-NMR(75,43 MHz, AMCO-d6, {1H}-unleashed extended band): δ =20,67(2C), 22,31(1C), 25,51(2C), 25,65(1C), WEIGHING 28.32(1C), 28,89(1C), 34,21(1C), 36,95(1C), 47,79(1C), 52,19(1C), 53,30 (1C), 57,67(1C), 125,36(4C), 125,80(1C), 126,82(1C), 127,70 (1C), 128,03(4C), 129,59(1C), 137,74(2C), 138,13(1C), 143,36(1C), 144,68(1C), 145,25(2C), 145,37(1C), 145,63(1C), 165,16(1C), 169,26 (1C), 170,58(1C), 171,35(2C); X(CVG): ν =3286, 1663, 1184, 1124, 1035, 1011, 683, 569 cm-1.

1. The method of obtaining compounds of formula (I), including the conversion of the compounds of formula (II) by catalytic hydrogenation and conversion of ceanography in amidinopropane, in the compound of formula (III) or its salt with the acid HX and subsequent reaction with the compound of the formula (IV) or its salt with the acid HX order to obtain the connection form is s (I), where the anions X are physiologically acceptable anions.

2. The method according to claim 1, wherein the hydrogenation is carried out with the use of a chiral complex of rhodium(I) as a catalyst.

3. The method according to claim 1 and/or 2, in which the hydrogenation is carried out with the use of rhodium-(1)-(+)-(2R,4R)-1-tert-butyloxycarbonyl-4-diphenylphosphino-2-(diphenylphosphinomethyl) pyrolidine complex as a catalyst.

4. The method according to one or more of claims 1 to 3, in which the transformation of ceanography in amidinopropane carried out by reaction with hydroxylamine or a salt of hydroxylamine and hydrogenolysis, the resulting N-hydroxyamides.

5. The method according to one or more of claims 1 to 4, in which the reaction of the compounds of formulas (III) and (IV) or their salts is carried out in the presence of carbodiimide.

6. The method according to one or more of claims 1 to 5, in which the reaction of the compounds of formulas (III) and (IV) or their salts is carried out in the presence of dicyclohexylcarbodiimide and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine.

7. The method according to one or more of claims 1 to 6, in which the reaction of the compounds of formulas (III) and (IV) a compound of the formula (IV) is used in the form of a salt with the acid HX and the compound of formula (III) used as such, i.e. in the form of betaine.

8. The method according to one or more of claims 1 to 7, where the anion X-one is by toluene-4-sulfonate.

9. The compound of formula (Ia), in which the anion sO-is toluene-4-sulfonate.

10. The method of obtaining the compounds of formula (Ia), in which the anion TosO-is toluene-4-sulfonate-including the reaction of the compound of formula (III) or its salt with toluene-4-acid with the compound of the formula (IVa) or its salt with toluene-4-acid to obtain the compounds of formula (Ia).

11. The method according to claim 10, in which the compound of formula (IVa) is used in the form of its salt with toluene-4-acid and the compound of formula (III) used as such, i.e. in the form of betaine, and the reaction is carried out in the presence of dicyclohexylcarbodiimide and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine.

12. The compound of formula (II) and salts thereof.

13. The compound of formula (III) and its salts.

14. The compound of formula (IV) and its salt with the acid HX, where the anion X is a physiologically acceptable anion.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

The invention relates to compounds of the prodrugs of inhibitors dipeptidylpeptidase IV (DP IV) the General formula a-b-C, and And denotes the amino acid refers to a chemical bond between a and C or the amino acid and stable inhibitor of DP IV with the missing C-terminal phosphonate residue, which represents AMINOETHYLPIPERAZINE, aminoacetanilide or N-dipeptidyl, O-arylhydroxylamine

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

-interleukin" target="_blank">

The invention relates to compounds of General formulaand-

< / BR>
< / BR>
where n = 0, 1, or 2, m and m' = 1 or 2; R11is

< / BR>
or

< / BR>
R2'= R2= H, R3is-CH2Ar or 5-15 membered non-aromatic monocyclic group which may contain from 0 to 2 endocycles nitrogen atoms; R4is a branched (C1-5) alkyl group; R5choose from a group comprising-C(O)R7, -C(O)OR9, -C(O)C(O)R7; R7selected from the group: phenyl, naphthyl, isoquinoline, and phenyl may be substituted with halogen, (C1-6) alkoxy, 1,2-methylenedioxy or - N(H)C(O)(C1-6)-alkyl, R9independently selected from straight line (C1-5) alkyl group, optionally substituted by phenyl; R12and R13independently selected from the group comprising-R7-C(O)-R7and-C(O)-N(H)-R7or R12and R13together form a 4-8-membered saturated cyclic group, f is -interleukin (ICE), method of inhibiting ICE activity, methods of treating or preventing IL-mediated diseases

The invention relates to the compounds of formula I or formula II, where R1denotes N(R10)(R11); R2means thio-lower alkyl; each of R3and R5independently represents CH2or C(O); R4denotes a substituted or unsubstituted dionissia alkyl, where the Deputy is CH2NHC(O)R13and he added to the specified tighrope; R6denotes the residue synthetic heteroaromatic-amino acids; R7denotes a residue of natural or synthetic-amino acids; R8IT denotes or lower alkoxy, or together with R7forms homoserine; R9denotes H; each of R10and R11, independently, is H; R12denotes a substituted or unsubstituted fragment selected from aryl, allyssia of alkyl, where the substituents are one or more lower Akilov or halogen; R13denotes lower alkyl; R18denotes H; provided that if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2and R4can form a disulfide bond; or pharmaceutically acceptable salts

The invention relates to new compounds of General formula 1: R1- SO2- B - X - Z - C(O) - Y, where R1represents a (1-12C)alkyl, which optionally may be substituted CF3, (7-15C)aralkyl or Campari; represents a bond, an amino acid of formula-NH-CH[(CH2)pC(O)OH]-C(O)-, where R = 1, 2, or 3, D-3-Tiq, or L - or D-amino acid containing a hydrophobic or neutral side chain; X represents an amino acid with a hydrophobic side chain, glutamine, cyclic amino, -NR2-CH2-C(O) -, or a group:

< / BR>
where n = 2, 3 or 4, W represents CH; R3represents H, (1-6C)alkyl; Z represents a lysine or 4-aminocyclohexanol; Y represents-NH-(1-6C)alkylene-C6H5, -OR4where R4represents H, (2-6C)alkyl, or NR5R6and R5and R6independently represent H, (1-6C)alkoxy or (1-6C)alkyl, optionally substituted with halogen, or R5and R6together represent a (3-6C)alkylene, or R5and R6together with the nitrogen atom to which they are attached, represent< / BR>
where V carts is naphthyl-SO2-Asp-Pro-Lys[COCO]-OH,having anticoagulant activity; and the pharmaceutical composition having inhibitory by combinationally

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts
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