MXPA98008002A - New derivatives of oxazolidine, production processes and pharmaceutical agents containing these compues - Google Patents

Abstract

The present invention relates to new oxazolidine derivatives, processes for their production in addition to pharmaceutical agents containing these substances. The present invention relates to the compounds of the general formula I (see formula I), in which the symbols have the meaning as listed in the claims.

Description

New oxazolidine derivatives, processes for their production and pharmaceutical agents containing these compounds.

It is known that compounds carrying a basic or acid group are capable of inhibiting the aggregation of blood platelets when there is a very particular distance between the basic and acid group (Drugs of the Future 12. (2): 135-159 (1994)). Compounds with an antiagregatory effect on blood platelets are described in WO 93/14077, EP-AO 537-980, EP-AO 542 363, WO 94/22835 and EP 0623615A1.

The present invention relates to new oxazolidine derivatives, processes for their preparation in addition to pharmaceutical agents containing these substances.

It has now been found that oxazolidine derivatives effectively inhibit the aggregation of blood platelets and can thus be used to treat diseases that can be attributed to thromboembolic events such as stroke, myocardial infarction or arterial occlusive diseases as well as inflammations, osteoporosis or tumor diseases.

REF. : 028521 The present invention relates to the compounds of the general formula I in which it represents a residue of formula (a) or (b) (a) (b) M represents oxygen, sulfur or NR °°, X represents hydrogen or NR ^ *, W represents nitrogen or NH or CH or CH2, Q represents nitrogen or CH, And represents nitrogen or CH, Z represents nitrogen, CH or C-OH, A represents an alkylene chain - (CH2) p- which is optionally substituted, D represents a side chain of the form - (CHR ^ .- COO-Rβ or = CR3-COO-R ', n represents 1-3, m represents 0 or 1, p represents 0-3 R1, R1 independently represent each other hydrogen, lower alkyl, aryl, arylalkyl, hetaryl, acyl or an optionally substituted carbocyclic or heterocyclic ring or, together with the nitrogen to which they are attached, form an optionally substituted five- or six-membered ring which can contain the 3 additional heteroatoms, or represents a group (c) (c) -C = NH R1 represents hydrogen or a group -OR5 or -NR6R7 R 4 represents hydrogen, lower alkyl, aryl, arylalkyl, hetaryl or a group -0RS, R5 represents hydrogen, lower alkyl, aryl or arylalkyl, R6 represents hydrogen, lower alkyl, or arylalkyl, R7 represents hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl, R8 represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, phenyl or benzyl, in particular hydrogen, ethyl, phenyl or isopropyl, R10 represents hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl, arylsulfonyl or a group (c), R ° represents hydrogen, lower alkyl, arylalkyl or a group -NHR °°, R °° represents hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl, in addition to its pharmaceutically acceptable salts.

Lower alkyl should in all cases represent a straight or branched chain C_-C3 alkyl group such as p. ex. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl in particular methyl, ethyl, propyl, isobutyl and pentyl.

Aryl usually represents a phenyl residue optionally substituted one or several times.

Hetaryl usually represents a pyridyl, pyrimidyl, piperazyl, imidazolyl, pyrrolyl, furyl or thiophenyl residue, preferably a pyridyl, pyrimidyl, indolyl or imidazolyl residue unsubstituted or once or several times substituted.

Arylalkyl usually represents a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue, preferably a benzyl, phenethyl or phenylpentyl residue unsubstituted or once or several times substituted. C Res-Cß alkyl residues, preferably methyl, ethyl or isopropyl in addition to chloro, bromo, fluoro or hydroxy, methoxy, beciloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino are considered as substituents.

Acyl usually represents a formyl, acetyl, propionyl, butyryl or benzoyl residue, in particular an acetyl or benzoyl residue.

Alkylsulfonyl usually represents a methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl residue, in particular a butanesulfonyl residue.

Arylsulfonyl usually represents a residue of benzenesulfonic acid or toluenesulfonic acid.

A carbocyclic ring usually represents a saturated or unsaturated 5 or 6 membered ring optionally substituted once or twice by lower alkyl such as cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring.

A heterocyclic ring usually represents a saturated or unsaturated 5- or 6-membered ring optionally substituted once or twice by lower alkyl such as a pyrrolidine, piperidine, piperazine, morpholine, tetrahydro-pyrimidine, dihydropyridine or dihydroimidazole ring, preferably a piperidine ring or tetrahydropyrimidine.

In the case that the residues R1 and R2 together with the nitrogen to which they are bound form a ring of five or six members this is a saturated or unsaturated ring of 5 or 6 members optionally substituted once or twice by lower alkyl such as a ring of pyrrolidine, piperidine, piperazine, morpholine, tetrahydro-pyrimidine, dihydropyridine or dihydroimidazole, preferably a piperidine, pyrrolidine or tetrahydro-pyrimidine ring.

The heterocyclic ring of formula (a) usually represents a pyridine, pyridazine or pyrimidine ring in particular a pyridine or pyrimidine ring.

A heterocyclic ring of formula (a) usually represents a piperidine or hexahydropyrimidine ring, in particular a piperidine ring.

The compounds of the general formula I contain at least one asymmetric carbon atom and therefore the optically active compounds of the general formula I are also a related matter of the present application. The conformational isomers of the compounds of the general formula I which could be presented are an additional related matter of the present application.

Preferred compounds are compounds of the formula I in which n = l = 2, p = 0-1 and E, D, Y, Z and R4 have the given meanings.

The compounds of formula I are particularly preferred where D represents a group -COOR5, n = 2, p = 0 and Y = CH, Z represents nitrogen, M represents oxygen and E represents a substituted or unsubstituted pyridine, or pyrimidine ring or piperidine.

The compounds of the general formula I in which R8 represents hydrogen are produced by known processes of hydrolysis of an ester of the general formula I in which R8 H.

The compounds of the general formula I in which R 8 H can be produced according to the reaction route shown in scheme 1.

Scheme 1 cyclization symptom | "M-C" (III) Scheme i In the scheme I R *, A, D, E, M, Y, Z and n have the meanings mentioned above. As a rule cyclization symptom "M = CM 'represents phosgene, diphosgene, triphosgene, carbonyl-diimidazole, dimethyldiethyl or diphenyl ester of carbonic acid, methyl or ethyl ester of chloroformic acid, thiophosgene, iocarboniimididazole, carbon disulfide, alkyl nitrile, N, N dimethylformamide, bromocyanogen or chlorocyanogen, dimethyl ester of (N-acyl or N-sulfonyl) -dithiocarbamic acid, dialkylcarbonyl diimide, l-amidino-3, 5-pyrazole-nitrate in particular carbonyldiimidazole, diethyl ester of carbamic acid, ethyl ester of chloroformic acid, thiocarbonyl diimidazole or bromocyanogen MN3 represents a metal azide such as lithium azide, sodium, potassium tributyltin or magnesium, in particular lithium or sodium azide, TMSN3 is an abbreviation for trimethylsilylazide.

The compounds of the general formula IV in which E represents the formula (a) can be produced according to the reaction routes shown in scheme 2. c) hydr-lißi- from Italy-da. dt hydrogßpacidn of the »group» bßncilo; ß) reduction &n. of the nitroao group In the scheme 2 X, Q, W and Y have the meanings mentioned above; as a rule L represents a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, in particular chlorine or tosylate.

The compounds of the general formula IV in which E represents the formula (b) can be produced by hydrogenation of the ring of the compounds of the formula XVI or XVIII.

The compounds of the general formula V can be prepared by the reaction routes shown in scheme 3. a) epoxidation; b) metallo-organic reaction c) dehydroxylation Scheme 3 In scheme 3 R4, A, D, L and n have the meanings mentioned above.

Some of the compounds of the general formula VI are commercially available and can be obtained in special cases by the oxidation of an alcohol of the general formula XI in which D and R4 have the meanings mentioned above.

The compounds of the general formula VII can be produced by the reaction of a compound of the general formula VI with an organometallic compound of the general formula XX prepared from a compound of the general formula VIII in which A and n have the meanings mentioned above and M represents a metal such as lithium, magnesium or titanium.

The compounds of the general formula XXV (scheme 1) in which R 8 H, p = 0 and Z = N can also be prepared by the reaction routes shown in scheme 4.

Scheme 4 (XXX) a) potassium phthalimide; b) hydrolysis; c) acylation; d) peroxyacid; e) deacylation Scheme 4 In scheme 4 R4, D, MN3, TMSN3 and n have the meanings mentioned above, as a rule L1 represents a hydroxyl or acetyloxy group or has one of the meanings of L. As a rule R11 represents a residue methyl, ethyl, ter- butyl, phenyl or benzyl in particular a tert-butyl or benzyl residue.

In the case of the compounds of the general formula VIII, cycloalkenyl halides or alcohols are commercially available if p = 0. If p > The compounds of formula VIII are known in the literature or can be produced according to the processes described therein (Brinker UH, Tetrahedron Lett., 1991, 4461-4464, Atkinson PH, J. Chem. Soc. Perkin Trans 1, 1977 , 230-238, Müller E., Chem. Ber. 108, 1401-1412 (1975), Walton JC, J. Chem. Soc. Perkin Trans 2, 1986, 1641-1646, BalmeG., Tetrahedron 48, 3891-3902 (1992), Fieser et al., J. Amer. Chem. Soc. 70, 3174-3196 (1948), Lee GM, J. Oerg. Chem., 55, 1281-1285 (1990)).

The compounds of the general formula XII are, as a rule, commercially available pipecolic carboxylic acid derivatives; in special cases the compounds of the general formula XII can be produced by the reaction of a commercially available 3-piperidone or 4-piperidone of the formula XXI with a commercially available acetic acid ester of the general formula XXII, R, OOC-CH2-R3 (XXII) wherein R1 and R8 have the meanings mentioned above with a Wittig reagent of the general formula XXIII Rp.) OC (CHR 3) - P R 9 (XXIII) _ 9 in which R 3, R 8 and m have the meanings mentioned above, R 9 represents butyl, phenyl or p-tolyl and Hal "represents chloride, bromide or iodide.

Some of the compounds of the general formula XI are commercially available and can be obtained in special cases according to the known methods by hydrogenation of the ring of an arylcarboxylic acid of the general formula XXIV in which R4 and D have the meanings stated above.

The compounds of the general formula XX can be synthesized in situ according to the general methods for the production of organometallic compounds.

Some Wittig reagents of the formula XXIII are commercially available and can be prepared from the corresponding commercial halogen and thiophosphin compounds.

The hydrolysis of an ester of the general formula I to form the corresponding carboxylic acid of the general formula I is usually carried out according to standard methods in which a carboxylic acid ester of the general formula I in water or a mixture of water, tetrahydrofuran, dioxane, methanol or ethanol preferably in a water / tetrahydrofuran mixture is treated at temperatures between room temperature and 80 ° C, preferably at room temperature with a hydroxide such as sodium, potassium or lithium hydroxide preferably sodium hydroxide or lithium or with an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid.

As a rule the reaction of a compound of the general formula XIII with l-benzylpiperazine or 4-hydroxy-piperidine or 4-oxopiperidine (scheme 2) or the reaction of a compound of the formula IX with a compound of the formula XII (scheme 3) is carried out in an aprotic solvent such as toluene, tetrahydrofuran, diethyl ether, dimethylformamide or methylene chloride preferably dimethylformamide or tetrahydrofuran using a base such as potassium hydride, sodium hydride, potassium carbonate or sodium acid carbonate preferably Sodium hydride or potassium carbonate and at a temperature between room temperature and 180 ° C preferably at 120 ° C or room temperature.

The reaction between 3-piperidone or 4-piperidone of formula XXI and an ester of formula XXII is usually carried out under the conditions of an aldol reaction in a solvent such as methanol, ethanol, toluene, tetrahydrofuran, diethyl ether or dimethylformamide, preferably tetrahydrofuran or dimethylformamide using a base such as sodium methylate or potassium methylate or potassium ethylate, sodium hydride, potassium hydride, lithium diisopropylamide, potassium hexamethyldisilazide preferably sodium hydride or lithium diisopropylamide and at a temperature between - 78 ° C and 90 ° C preferably, however, at -78 ° C and room temperature.

The benzyl protecting groups are removed if necessary by catalytic hydrogenation such as p. ex. by palladium / carbon / hydrogen.

The reaction of Mitsunobu between a compound of formula XVIII and the phthalimide is carried out according to the methods known in the literature. { Mitsunobu 0., Synthesis, page 1 (1981)).

The reductive amination of a ketone of formula XVI with dibenzylamine or an amine of formula XXV is carried out according to methods known in the literature by the reaction of the ketone and amine component in a solvent such as methanol or ethanol in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride triacetate with the addition of a Brónsted or Lewis acid such as hydrochloric acid, acetic acid, titanium tetrachloride or titanium tetraisopropylate and at a temperature between 0 ° C and 100 ° C preferably at room temperature or in the presence of a hydrogenation catalyst such as platinum dioxide and a hydrogen atmosphere (Borch RF, Org Synth, Coll. Vol.6, 499 (1988); Heinzelman RVZ Chem. 8, 270 (1968); Mattson RJJ Org. Chem. 5_j¿, 2552 (1990); Barney CL Tetr. Letters JH, 5547 (1990); Hutchins RO, J. Org. Chem.! £, 3571 (1981)).

Nitration of a compound of general formula XIV to form a compound of formula XV is usually carried out with sodium nitrite or isoamyl nitrite in water or ethanol with the addition of an acid such as hydrochloric acid or acetic acid and at a temperature between -20 ° C and 80 ° C preferably at room temperature.

A nitroso compound of the general formula XV is reduced according to known methods by the reaction of a compound of the formula XV in a solvent such as water, acetic acid, ethanol, tetrahydrofuran or diethyl ether preferably acetic acid or tetrahydrofuran with a reducing agent such as elemental zinc, lithium aluminum hydride or sodium aluminum hydride preferably elemental zinc or lithium aluminum hydride and at a temperature between room temperature and 120 ° C preferably, however, at 70 ° C. A compound of the general formula XV can also be converted to a compound of the formula IV by a hydrogenolytic process using a catalyst such as palladium / carbon (Hatt, HH, Org Synth, Coll. Vol.2, 211 (1943); FW, J. Amer. Chem. Soc. H, 4996 (1951).

Oxidation of an alcohol of the general formula XI to form a ketone of the general formula VI is carried out according to known methods such as the oxidation of Jones (Jones ERH, J. Chem. Soc. £ (1946) ), the oxidation of Swern (Swern D. Tetrahedron _ 1651 (1978), the oxidation of Dess-Martin (Dess DB, Martin JC, Org. Chem. _U 4155 (1983) or using a bromo-urotropin complex as the agent of oxidation (Yavari I., J. Chem. Res. (S) 274 (1994).

The Wittig reagents used are optionally produced analogously to the methods known in the literature (Buddras J., "Angew. Chem." £ j.}., 535 (1968); Bestmann H.J.

"Angew, Chem. 77, 620, 651 (1965); Wittig G. Ber. Deutsch.

Chem. Ges. , 1654 (1955)).

The Wittig reaction is carried out according to known methods by refluxing the reagents in an aprotic solvent such as benzene, toluene or xylene, preferably toluene.

As a rule the hydrolysis of phthalimide is carried out according to the known methods by treating the phthalimide with hydrazine hydrate or a semi-concentrated mineral acid such as hydrochloric acid or sulfuric acid preferably with hydrazine hydrate or hydrochloric acid at room temperature.

The acylation of amines with an acylating agent is carried out as a rule in a solvent such as methylene chloride, dimethylformamide or pyridine, preferably methylene chloride or pyridine with the addition of an auxiliary base such as triethylamine or 4-dimethylamino-pyridine. at a temperature between -10 ° C and 50 ° C preferably, however, at room temperature. Halides of carboxylic acids such as acetyl chloride, propionide bromide or benzyloxycarbonyl chloride or carboxylic acid anhydride such as acetic anhydride or di-tert-butyl dicarbonate come into consideration as an acylating agent, but the anhydride is preferably used acetic acid, benzyloxycarbonyl chloride or di-tert-butyl dicarbonate.

The epoxidation of an olefin of formula VII or of formula X or of formula VIII or of formula XXVIII is carried out according to the methods known in the literature by reacting them with a peracid such as m-chloroperbenzoic acid, peracetic acid or trifluoroperacetic acid preferably m-chloroperbenzoic acid in an aprotic solvent such as methylene chloride and at a temperature between -30 ° C and 50 ° C preferably at room temperature; in addition, the olefins listed above can be converted into the corresponding epoxides by means of the Sharpless epoxidation (Sharpless K.B., Org. Synthesis, Vol. 63, 66 (1985)).

As a rule the organometallic reaction in scheme 3 is a Grignard reaction which is carried out according to the methods known in the literature. However, the magnesium reagent of formula XX can optionally be converted to a lithium or titanium reagent before it reacts with a carbonyl compound of formula VI (Reetz M.T., Chem. Ber. HA, 1421 (1985)).

The conversion of an aminoalcohol of the formula III into a compound of the formula I (scheme I) is carried out according to the methods known in the literature by reacting an aminoalcohol of the formula III with diethylcarbonate (Evans DA, Org. Synthesis, Vol. 68 77 (1989)) or carbonyldiimidazole (Chadwick DI, J. Chem. Soc. Perkin Trans 481 (1984); Geffken D. Arch. Pharm. 313. 817 (1980) or phosgene (Newman WS, J. Am. Chem. Soc. 12, 4199 (1951)) or diphosgene or triphosgene (Hassner A., Synth Commun. 21, 2839 (1993)) p methyl, ethyl or benzyl ester of chloroformic acid (Kanoshinzo, J. Org Chem. 52., 3865 (1988) or thiophosgene (Dubey SK, Can. J. Chem., 6: 1 565, (1983)) or thiocarbonyldiimidazole (Goering BK, Tetrahedron Lett 25. (38), 6997, (1994 )) or carbon disulfide (Zinner H., J. Prakt. Chem., 15, 72 (1962) or bromocyanogen (Mousseron, Bull. Soc. Chim. Fr., 737 (1953)) or alkyl nitrile (ItoY., J Organomet, Chem. 131 121 (1977)) or dimethyl ester of acid ( N-acyl or N-sulfonyl) -dithiocarbamic acid (Bretschneider H., Monatsh. Chem. 103. 1377 (1972); Evers R., J. Prakt. Chem., 333, 699 (1991)) or l-amidino-3,5-pyrazole-nitrate (Fotsch CH, Tetrahedron Lett., 15, 2481 (1994) in a solvent such as methylene chloride, dimethylformamide, toluene, xylene. , ethanol, dioxane, tetrahydrofuran, water or diethylether, preferably dimethylformamide, methylene chloride, ethanol or tetrahydrofuran optionally with the addition of an auxiliary base such as triethylamine or pyridine and at a temperature between -50 ° C and 80 ° C preferably at room temperature .

Catalytic hydrogenation of a compound of formula XXIV is carried out in a solvent such as methanol or ethanol with the addition of a catalyst such as ruthenium oxide, rhodium oxide or palladium / strontium carbonate preferably rhodium oxide in an atmosphere of hydrogen at a pressure of 1-200 bar preferably at 200 bar and at a temperature between room temperature and 200 ° C (Rastin RH, I. Chem. Soc. 1855 (1949)).

The opening of an epoxide of an epoxide of formula V with an amine of formula IV (scheme 1) or of an epoxide of formula IX with an amine of formula XII (scheme 4) is usually carried out in a solvent such as methanol , ethanol, dimethylformamide or toluene preferably ethanol or toluene and at a temperature between 0 ° C and 120 ° C preferably 80 ° C.

The epoxide opening of an epoxide of formula V (scheme 1) with a metal azide is carried out according to the methods known in the literature by the reaction of an epoxide of formula V with a metal azide such as azide of lithium, sodium, potassium, tributyltin or magnesium, preferably sodium azide, in a solvent such as methanol, ethanol, 1,4-dioxane, water, dimethylformamide, tetrahydrofuran, acetonitrile or hexamethylphosphorotriamide or in mixtures of the mentioned solvents, but preferably in methanol, dimethylformamide or mixtures of 1,4-dioxane-water and at a reaction temperature between -10 ° C and 120 ° C, preferably 80 ° C (Vanderverf CA, J. Am. Chem. Soc. 7 £, 1231 (1954) Saito S., Tetrahedron Lett., 4153 (1989), Hudlicky T., J. Chem. Soc. Perkin Trans. I, 2907 (1991)). As a rule an epoxide of formula V is reacted with trimethylsilyl azide in a solvent such as methanol, tetrahydrofuran, methylene chloride, chloroform, dichloroethane or benzene, preferably tetrahydrofuran or methylene chloride, without additional additives or the use of additives such as titanium tetraisopropylate, aluminum triisopropylate, dichlorotitanium diisopropylate or diethylaluminum fluoride, preferably titanium tetraisopropylate aluminum triisopropylate, and at a temperature between 0 ° C and 100 ° C but preferably at room temperature (Emziane M., Synthesis, p.541) (1988); Saito S., Tetrahedron Lett. 2 £, 5309 (1985); Blandy C, Tetrahedron Lett. 24, 4189 (1983); JungM.E., J. Org. Chem., 53., 2614 (1991)).

The reaction of a compound of formula XXXI with a metal azide to form a compound of formula XXVI (scheme 4) is a nucleophilic substitution in the case that L1 has the meaning of L, which is carried out according to the standard methods of organic synthesis.

Deacylation of a compound of formula XXX to form a compound of formula XXV is carried out according to standard methods in which a compound of formula XXX in water or a mixture of water, tetrahydrofuran, dioxane, methanol or ethanol, preferably in a water / tetrahydrofuran mixture, is treated with a hydroxide such as sodium, potassium or lithium hydroxide, preferably sodium or lithium hydroxide, or with an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid, or with palladium / carbon / hydrogen at a temperature between room temperature and 80 ° C preferably at room temperature.

The conversion of an azide of formula XXVI into an amine of formula XXV is carried out according to known methods: Suami T., Bull. Chem. Soc. Jpn., 51, 855 (1978); (Boullanger P., Bull. Soc. Chem. Pr., P.2149 (1973); Ackerman K., Can. J. Chem., 5O, 3886 (1972); Hannesian S., Chem. Ind., P. 1296 (1965), Horner L., Liebigs Ann. Chem., 5.21, 117 (1955), Koziara A. Synthesis, pp. 487 (1987), Vogel E., Ang. Chem. Int. Ed. Engl., 1 &;, 962 (1979); Purwono B., Synlett, 1, 231 (1992).

The compounds of formula I contain one or more chiral centers and therefore may be present in a racemic or optically active form. The racemates can be resolved mechanically or chemically by known methods in the enantiomers. Preferably the diastereomers are formed from the racemic mixture by reaction with an optically active acid such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various camphor sulfonic acids optically. active agents such as ß-camforsulfonic acid.

Of course it is also possible to obtain optically active compounds of the formula I using the methods described above using the initiator materials (eg those of the formula V or VIII) which are already optically active.

Within the meaning of the present invention all the prodrug forms of the compounds of the general formula I are also claimed, but especially the carboxylic acid esters of the general formula I in which Rβ represents a methyl, ethyl, n-propyl residue , isopropyl, butyl, phenyl or benzyl, in particular a methyl, ethyl or benzyl residue.

The alkali metal salts, the ammonium salts, the trifluoroacetates or the hydrochlorides are previously used as pharmacologically acceptable salts which are produced in the usual manner p. ex. by tritration of the compounds with organic or inorganic acids or bases such as p. ex. Sodium carbonate or potassium acid carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous ammonia or amines such as p. ex. trimethylamine or triethylamine, trifluoroacetic acid or hydrochloric acid. As a rule the salts are purified by precipitation from water / acetone.

The new substances of the formula I according to the invention and the salts thereof can be administered enterally or parenterally in a liquid or solid form.

All the usual forms of application come into consideration, such as tablets, capsules, dragees, syrups, solutions, suspensions, etc. The water is preferably used as an injection medium which contains the usual additives such as stabilizing agents, solubilizers, buffers for the injection solutions.

Such additives are p. ex. , tartrate and citrate buffer, ethanol, complexing agents (such as ethylenediamine tacetic acid and non-toxic salts thereof), high molecular weight polymers (such as liquid polyethylene oxide) to regulate viscosity. The liquid carrier substances for the injection solutions have to be sterile and are preferably filled in ampoules. Solid carrier substances are p. ex. starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, vegetable and animal fats, solid polymers of high molecular weight (such as polyethylene glycols); Suitable preparations for oral application may optionally contain flavors and sweeteners.

The dose may depend on several factors such as the form of application, species, age and / or individual status.

The daily doses to be administered are approximately 1-1000 mg / human, preferably 100-500 mg / human, and can be taken individually or divided into several administrations.

Within the meaning of the present invention the following oxazolidininone derivatives are preferred in addition to the compounds mentioned in the examples and compounds that can be derived by combining all the meanings for the substituents mentioned in the claims. 1) 1- [2-0x0-3- (l-pyrimidin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid 2) Acid 1-. { 2-OXO-3- [1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid 3) Acid. { l- [2-OXO-3- (l-pyrimidin-4-yl) -piperidin-4-yl) -octahydro-benzooxazol-7-yl] -piperidin-4-yl} -acetic 4) Acid (l-. {3- [1- (2-Amino-pyrimidin-4-yl) -piperidin-4-yl] -2 -oxo-octahydro-benzooxazol-7-yl}. -piperidin- 4-yl.) -acetic 5) Acid (l-. {3- [1- (2-methylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazole-7) -yl.}. -piperidin-4-yl.}. -acetic 6) Acid (1- {2-oxo-3- [1- (2-phenylamino-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-benzooxazol-7-yl}. -piperidin- 4-il.}. -acetic 7) 2-methanesulfonyl amino-3- acid. { l- [2-Oxo-3- (1-pyrimidin-4-yl-piperadin-4-yl) -octahydro-benzooxazol-7-yl] -piperidin-4-yl} -propionic 8) 1- [2-OXO-3- (l-pyrimidin-4-yl-piperadin-4-yl) -octahydro-benzooxazol-7-ylmethyl] -piperidine-4-carboxylic acid 9) 1- [2-OXO-3- (3, 4, 5, 6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-ylmethyl] -piperidin-4 acid - carboxylic ) Acid l-. { 3- [1- (2-Amino-pyrimidin-4-yl) -piperidin-4-yl] -2 -oxo-octahydro-benzooxazol-7-ylmethyl} -piperidine-4-carboxylic acid 11) Acid l-. { 2-oxo-3- [1- (2-piperadin-l-yl-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-benzooxazol-7-ylmethyl} • piperidin- 4 -carboxylic 12) Acid l-. { 3- [1- (2-amino-pyrimidin-4-yl) -piperidin-4-yl] -2 -oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid 13) Acid l-. { 3- [1- (2-benzylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-ylmethyl} -piperidin-4-carboxylic acid 14) Acid 4-. { 3- [1- (2-Benzylamino-pyrimidin-4-yl) -piperidin-4-yl] -2 -oxo-octahydro-benzooxazole-7-ylmethyl} -cyclohexanecarboxylic ) Acid 4-. { 3- [1- (2-benzylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-ylmethyl} -4-hydroxy-cyclohexanecarboxylic 16) 4- [2-0x0-3- (3, 4, 5, 6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -cyclohexane-carboxylic acid 17) Acid 4-. { 3- [1- (2-amino-pyrimidin-4-yl) -piperidin-2-oxo-octahydro-benzooxazol-7-yl} -cyclohexanecarboxylic acid 18) 4-Hydroxy-4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyl-4-yl) -octahydro-benzooxazole-7- acid il] -cyclohexanecarboxylic 19) 4-hydroxy-4- acid. { 2-Oxo-3- [1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperadin-4-yl] -octahydro-benzooxazol-7-yl} -cyclohexanecarboxylic ) Acid. { l- [2-OXO-3- (3,4,5,6-tetrahydro-2H- [1, '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidin-4-yl} -acetic 21) 2- (Butan-1-sulfonylamino) -3- acid. { l- [2-OXO-3- (3,4,5,6-tetrahydro-2 H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidin-4-yl} -propionic 22) Acid l-. { 2- [2-OXO-3- (3,4,5,6-tetrahydro-2 H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -ethyl} -piperidine-4-carboxylic acid 23) Acid l-. { 3- [1- (2-methylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -piperidin-4-carboxylic acid 24) l-. { 3- [2-OXO-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -propyl} -piperidine-4-carboxylic acid ) Acid l-. { 3- [2-OXO-3- (l-pyrimidin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-yl] -propyl} -piperidine-4-carboxylic acid 26) 1- (3- {3- [1- (2-Amino-pyrimidin-4-yl) -2-oxo-octahydro-benzooxazol-7-yl} -propyl) -piperidin-4-acid carboxylic 27) 1- [2-OXO-3- (l-pyridazin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid 28) Acid. { l- [2-OXO-3- (l-pyridazin-4-yl) -octahydro-benzooxazol-7-yl] -piperidin-4-yl} -acetic 29) 1- [2-OXO-3- (l-pyridazin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-ylme] -piperidine-4-carboxylic acid ) 4- [2-OXO-3- (l-pyridazin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-yl] -cyclohexanecarboxylic acid 31) Acid l-. { 3- [2-OXO-3- (l-pyridazin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-yl] -propyl} -piperidine-4-carboxylic acid 32) 1- [2-OXO-3- (4-pyrimidin-4-yl-piperidin-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid 33) 4- [2-OXO-3- (4-pyrimidin-4-yl-piperidin-1-yl) -octahydro-benzooxazol-7-yl] -cyclohexanecarboxylic acid 34) Acid (±) - (3 '? Í, 7'ß, 7c.) - l-. { 3- [1- (2-Benzylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid ) Acid l-. { 2- [2-oxo-3- (4-pyrimidin-4-yl-piperazin-1-yl) -octahydro-benzooxazol-7-yl] -ethyl} -piperidine-4-carboxylic acid 36) 1- [2-Oxo-3- (4-pyrimidin-4-yl-piperidin-4-yl) -hexahydro-cyclopentaoxazol-6-yl] -piperidin-4-carboxylic acid 37) 1- [2-OXO-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -hexahydro-cyclopentaoxazol-6-yl] -piperidine-4 acid -carboxylic 38) Acid l-. { 3- [1- (2-amino-pyrimidin-4-yl) -piperidin-4-yl] -2 -oxo-hexahydro-cyclopentaoxazol-6-yl} -piper idin-4-carboxylic acid 39) Acid (l- { 2-oxo-3- [1- (2-phenylamino-pyrimidin-4-yl) -piperidin-4-yl] -hexahydro-cyclopentaoxazole-6- il.}. -piperidin-4-yl) -acetic 40) Acid l-. { 2- [2-OXO-3- (3,4,5,6-tetrahydro-2 H- [1,4 '] bipyridinyl-4-yl) -hexahydro-cyclopentaoxazol-6-yl] -ethyl} -piperidine-4-carboxylic acid 41) 1- [2-Oxo-3- (l-pyridazin-4-yl-piperidin-4-yl) -hexahydro-cyclopentaoxazol-6-yl] -piperidine-4-carboxylic acid 42) 1- [2-OXO-3- (4-pyridin-4-yl-piperazin-1-yl) -hexahydro-cyclopentaoxazol-6-yl] -piperidine-4-carboxylic acid 43) 4-Hydroxy-4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -hexahydro-cyclopentaoxazol-6-yl] acid] -ethyl} -cyclohexanecarboxylic 44) 1- [2-Oxo-3- (l-pyrimidin-4-yl-piperidin-l-yl) -octahydro-cyclopentaoxazol-8-yl] -piperidine-4-carboxylic acid 45) Acid l-. { 2-Oxo-3- (1- (2-phenylamino-pyrimidin-4-yl) -piperidin-4-yl) -octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid 46) 1- [2-OXO-3- (3, 4, 5, 6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -octahydro-cycloheptaoxazole-8- acid il] -piperidin-4-carboxy 1 ico 47) Acid l-. { 3- [1- (2-amino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-cycloheptaoxazol-8-yl} -piperidine-4-carboxylic acid 48) Acid (l-. {3- [1- (2-amino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-cycloheptaoxazol-8-yl}. -piperidine- 4-il) -acetic 49) Acid l-. { 2-Oxo-3- [1- (2-piperidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-cycloheptaoxazol-8-ylmethyl} -piper idin- 4 - carboxí 1 i co 50) 1- (2-Oxo-3- { L- [2- (pyridin-4-ylamino) -pyrimidin-4-yl}. -octahydro-benzooxazol-7-yl) -piperidin-4 acid carboxylic 51) 1- (2-Oxo-3- { L- [2- (pyrimidin-2-ylamino) -pyrimidin-4-yl] -piperidin-4-yl}. -octahydro-benzooxazole-7- acid il) -piperidin-4-carboxylic acid 52) 1- (2-Oxo-3-. {l- [2- (1, 4, 5,6,6-tetrahydros-pyrimidin-4-yl] -piperidin-4-acid il.} - octahydro-benzooxazol-7-yl) -piperidin-4-carboxylic acid 53) Acid l-. { 3- [1- (2-Cyclohexylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -piperidin-4-carboxylic acid 54) Acid l-. { 3- [1- (2-pyrrolidin-l-yl-pyrimidin-4-yl) -piperidin-4-yl] -2- i oxo-octahydro-benzooxazol-7-yl} -piperidin- 4 -carboxylic 55) Acid l-. { 2-Oxo-3- [1- (2-pyrrolidin-1-yl-hexahydro-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-benzooxazol-7-yl} -piperidin-4-carboxylic acid 56) Acid l-. { 2-Oxo-3- [1- (2-pyrrolidin-1-yl-l, 4,5,6-tetrahydro-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-benzooxazol-7-yl} -piperidin-4-carboxylic acid 57) 1- [3- (1'-Benzyl- [1,4 *] bipiperidinyl-4-yl-2-thioxo-octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid 58) 1- [2-Acetylamino-3- (3,4,5,6-tetrahydro-2-H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine acid -4-carboxylic 59) 1- [2-imino-3- (3, 4, 5, 6-tetrahydro-2-H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine acid - 4-carboxylic 60) 4- (lH-Indol-3-ylmethyl) -1- [oxo-3- (3,4,5,6-tetrahydro-2-H- [1,4 '] bipyridinyl-4-yl) - octahydro-benzooxazol-7-yl] -piperidin-4-carboxylic acid 61) 4-Butyl-l- [2-OXO-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyl-4-yl) -octahydro-benzooxazole-7- acid il] -piperidine-4-carboxylic acid 62) 1- [2-OXO-3- (3, 4, 5, 6-tetrahydro-2-H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -4 acid -phenethyl-piperidin-4-carboxylic acid 63) (-) - (3'S, 7'S, 7R) -l- [2-oxo-3- (3,4,5,6-tetrahydro-2-H- [1, 4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid [c_] aoD = -17.4 ° (c = 1.18; CHC13) 64) (+) - (3'R, 7'R, 7S) -1- [2-oxo-3- (3,, 5, 6-tetrahydro-2-H- [1,4 '] bipyridinyl-4 -yl) -octahydro-benzooxazol-7-yl] -piperidin-4-carboxylic acid [a] 20D = -18.7 ° (c = 1.2; CHC13) The following examples show some of the variants of the process that can be used to synthesize the compounds according to the invention. However, it is not intended to represent a limitation of the related matter of the invention. The structure of the compounds was confirmed by LH and optionally by 13 C-NMR spectroscopy in addition to by mass spectroscopy. The plurality of substances was determined by means of C, H, N in addition to thin layer chromatography.

Ejetppl? - Acid (+) - ('a. 7' S.7o?) -1- r2-oxo-3- (3.4.5 .6-tetrahydro-2-H- n. 4 'l bipyridinyl-4-yl) - octahydro-benzooxazol-7-yl-l-piperidin-4-carboxylic acid a) A solution of 46 g (0.4 mol) of 4-chloropyridine and 123.5 g (0.86 mol) of 4-piperidone-ethylene ketal is heated in 400 ml of p-xylene for 48 h at reflux. Subsequently, the reaction mixture is cooled, the precipitate is removed by filtration, the mother liquor is concentrated to dryness and the residue is purified by column chromatography on silica gel (ethyl acetate / alkaline methanol saturated with 9/1 ammonia). In this manner 79.7 g (90%) 8-pyridin-4-yl-1,4-dioxa-8-aza-spiro- [4.5] decane is obtained as a white powder, m / e = 200; Fp = 65 ° C. b) A solution of 79.7 g of the ketal produced in a) in 2 1 of tetrahydrofuran is mixed with 1 1 of 6 N hydrochloric acid and the reaction mixture is stirred for 2 h at room temperature. Subsequently the tetrahydrofuran is removed under vacuum in a rotary evaporator, the hydrochloric acid solution is made alkaline with semiconcentrated ammonium hydroxide solution and extracted four times with 100 ml of methylene chloride each time. After drying the combined organic extracts with sodium sulfate and removing the solvent, the residue is purified by column chromatography on silica gel. In this manner, 6.42 g (100% yield) of 2, 3, 5, 6-tetrahydro- [1,4 '] bipyridinyl-4-one is obtained as a gray powder, m / e = 176; Fp = 102 ° C. c) A solution of 41.6 g of cis-2, 3-epoxycyclohexanol (Svante T., J. Org. Chem., 3J 1380 (1973)) and 54 g of imidazole in 650 ml of dimethylformamide (DMF) are mixed at 0 ° C with 67.7 g of tert-butyl dimethylchlorosilane. After this, the reaction mixture is stirred for an additional 4 hours at 0 ° C, then it is mixed with 600 ml of water and the aqueous solution is extracted four times with 100 ml of ethyl acetate. After drying the combined organic phases with sodium sulfate and removing the solvent under reduced pressure, the residue is distilled in vacuo. 50 g of cis-1-tert-butyl-dimethyl-silyloxy-2,3-epoxycyclohexane are obtained. bp0.os = 74 ° C. 'H-NMR (CDC13): d = 3.90 ppm (m, ÍH); 3.10 (width S, ÍH); 3.0 (width s, ÍH); 1.65 (ra, 2H); 1.40 (m, 3H); 1.15 (m, ÍH); 1.82 (s, 9H); 0.01 (s, 6H). d) A mixture of 20 g of epoxide le) and 34 ml of ethyl ester of 4-piperidine carboxylic acid in 160 ml of ethanol is heated for 48 h under reflux.

Subsequently, the reaction mixture is evaporated to dryness and the residue is purified by column chromatography on silica gel (ethyl acetate / isohexane = 1/2). 22.2 g of ethyl ester of (±) - (le., 2ß, 3ß) -1- [3- (tert-butyl-dimethylsilanyloxy) -2-hydroxy-cyclohexyl] -piperidine-4-carboxylic acid are obtained as a powder white, m / e = 385.

A solution of 18.7 g of the alcohol ld) and 12 ml of triethylamine in 200 ml of methylene chloride is mixed at the internal temperature of 5-10aC with 5.4 ml of methanesulfonic acid chloride. The reaction mixture is allowed to stir for one hour at room temperature, subsequently 50 ml of sodium acid carbonate solution is added, the phases are separated, the organic phase is washed with 100 ml of water and dried with sodium sulfate. After removing the solvent in a rotary evaporator, the residue is purified by column chromatography on silica gel (ethyl acetate / isohexane = 1/3). 21 g of ethyl ester of (±) - (la, 2ß, 3ß) -1- [3- (tert-butyl-dimethylsilanyloxy) -2-methanesulphonyl-cyclohexyl] -piperidine-4-carboxylic acid ester is obtained as a slightly yellow oil. 'H-NMR (d6-DMSO): d = 4.45 ppm (d, ÍH); 4.20 (width s, ÍH); 3.95 (q, 2H); 3.10 (s, 3H); 2.88-263 (m, 2H); 2.50 (m, ÍH); 2.20-2.00 (m, 2H); 1.75-1.62 (m, ÍH); 1.58-1.18 (m, 7H); 1.10 (t, 3H); 0.80 (s, 9H); 0.01 (S, 6H). f) A solution of 21 g of the silyl derivative le) in 200 ml of tetrahydrofuran is mixed with 63 ml of a 1.1 molar tetrabutylammonium fluoride solution in tetrahydrofuran. The reaction mixture is allowed to stir for 30 hours at room temperature, then it is concentrated to dryness and the residue is chromatographed on silica gel (ethyl acetate / isohexane = 95/5). 6.3 g of ethyl ester of (±) - (1, 2β, 3β) -1- (3-hydroxy-2-methanesulfonyl-cyclohexyl) -piperidine-4-carboxylic acid is obtained as a white powder, m / e = 349 g) A mixture of 5.48 g of hydroxymethylate lf) and 550 mg of sodium hydride is stirred for one hour at ° C in 200 ml of tetrahydrofuran (THP) and after the subsequent addition of 50 ml of water is stirred for 15 hours at 50 ° C. After this the THF is removed in a rotary evaporator and the aqueous mixture is extracted three times with 30 ml of methylene chloride each time. After drying the combined organic phases with sodium sulfate and removing the solvent in vacuo, 3.9 g of ethyl ester of (±) -trans-1- (2,3-epoxy-cyclohexyl) -piperidine-4-carboxylic acid are obtained as a yellow oil which is reacted without further purification. h) A solution of 3.4 g of the epoxide produced in lg), 5.3 g of sodium azide and 4.3 g of ammonium chloride is heated for 24 hours at 70 ° C in 50 ml of an ethanol / water mixture (80/20 ).

Subsequently the ethanol is removed in vacuo, the residue is diluted with 10 ml of water and the aqueous solution is extracted three times with 15 ml of methylene chloride each time. After drying the combined organic phases with sodium sulfate and removing After the solvent in a rotary evaporator, the crude product is chromatographed on silica gel (ethyl acetate / isohexane: 4/1). In this way 2.74 g of ethyl ester of (±) - (lc_, 2ß, 3ß) -1- (3-azido-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid is obtained. as an orange oil, which solidifies slowly. 'H-NMR (d6-DMSO): d = 4.53 ppm (width S, 1H, OH); 4.05 (q, 2H); 3.30 (width d, 2H); 2.80 (quasi d, ÍH); 2.65 (quasi d, ÍH); 2.50 (m, ÍH); 2.25 (m, 3H); 1.90-1.40 (m, 7H); 1.30-1.02 (m + t, 6H). i) A solution of azide produced in lh) in 20 ml of ethanol is mixed with 0.8 g palladium / 10% carbon and the mixture is hydrogenated for 6 h / 40 mbar at room temperature. Subsequently the catalyst is removed by filtration and the solution is concentrated in a rotary evaporator. In this manner, 2.4 g of (±) - (lo, 2β, 3β) -1- (3-amino-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester is obtained. FAB 271 j) A solution of 2.4 g of amine li), 1.6 g of ketone lb) and 3.75 g of sodium borohydride triacetate in 40 ml of methylene chloride is stirred for 48 h at room temperature. Subsequently, the reaction mixture is mixed with 10 ml of water and acidified with 1N hydrochloric acid. After separating the phases, the aqueous acid phase is extracted again with 10 ml of methylene chloride and then alkalinized with hydroxide solution. sodium 1 N. After extracting the alkaline mixture three times with 15 ml of methylene chloride each time and drying the combined organic phases with sodium sulfate, the solvent is removed in a rotary evaporator. The crude product is then purified by means of preparative HPLC (RP 18, methanol / buffer (pH = 7.5) 70/30). In this way, 2.5 g of ethyl ester of (±) - (la, 2ß, 3ß) -1- [2-hydroxy-3- (3,4,5,6-tetrahydro-2H- [1,4]) is obtained. '] bipyridinyl-4-ylamino) -cyclohexyl] -piperidine-4-carboxylic acid. LH-NMR (d6-DMS0): d = 8.20 ppm (d, 2H); 6.85 (d, 2H); 4.15 (m, ÍH); 4.12 (q, 2H); 3.85 (width d, 2H); 3.10 (t, ÍH); 3.0-2.8 (m, 4H); 2.70 (d, ÍH); 2.55 (m, 2H); 2.30 (width t, 3H); 2.0 (d, ÍH); 1.88 (m, 4H); 1.80-1.50 (m, 5H); 1.38-0.88 (m, 5H); 1.25 (t, 3H).

A solution of 2.5 g of the amino alcohol of lj) and 1.9 g of carbonyldiimidazole in 20 ml of dimethyl formamide is stirred for 15 h at room temperature.

Subsequently the reaction solution is evaporated to dryness and the residue is purified by means of Preparative HPLC (Merck, Select B, methanol / buffer (pH = 7.5) 65/35). In this way, 2.78 g of (±) - (3 'a, 7' ß, la) -1- [2-OXO-3- (3, 4, 5, 6-tetrahydro-2H-) ethyl ester is obtained. [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid as a yellow oil, m / e = 456. 1) A solution of 1.85 g of the ethyl ester lk) and 4.60 ml of IN sodium hydroxide solution in 30 ml of methanol is stirred for 1 h at room temperature. Subsequently, the methanol is removed in vacuo and the product is purified by means of an ion exchange (Dowex 50, form H). In this manner 0.95 g of the titled compound is obtained as a white powder Fp. > 200 ° C. m / e (El spectrum) = 500 as a trimethylsilyl derivative).

Example-the Acid (-) - (3'S, 7'S, 7R) -1- r2-oxo-3- (.4.5.6-tetrahydro-2H-fl.4 '1-bipyridinyl-4-yl) -octahydro-benzooxazole -7- ill- piper idin- - carboxy 1 ico and Oft * After carrying out the substitution reaction steps 2a) -2c) of the racemic cis-2, 3-epoxycyclohexanol in example 2a) by (IR, 2R, 3S) -l-hydroxy-2, 3- epoxycyclohexane gives the optically active compound ethyl ester of (ÍS, 2S, 3R) -l-azido-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid ([a] D20 = -41.4 ° C (C 1.2; CHC13 )) from which the titled compound is obtained analogously to example li) -11). [a] D = -17.4 ° (C1.18; CHC13).

(IR, 2R, 3S) -l-hydroxy-2,3-epoxycyclohexanes obtained according to Svante T. (J. Org. Chem. 22., 1380 (1973)) epoxidizing (R) -cyclohex-2-enol known in the literature (Fukazawa et al., Tetrahydron Asymmetry 4, 2323 (1993)) by means of meta-chloroperbenzoic acid.

Example 2 Additional processes for the production of ethyl ester of (+) - (la 2 & 2 a) -1- -3-azido-2-hydroxy-? I? Leexyl) piperidin-4-car? O? ? ) a) A solution of 119.65 g of cis-2, 3-epoxycyclohexanol (see example le) and 188 ml of triethylamine in 400 ml of methylene chloride is mixed at 0 ° C with a solution of 240 g of p-acid chloride. toluenesulfonic in 500 ml of methylene chloride. Subsequently the reaction mixture is stirred for 15 hours at room temperature, the precipitated salt is then removed by filtration and the filtrate is washed with 100 ml of saturated sodium hydrogen carbonate solution. After drying the methylene chloride phase with sodium sulfate and removing the solvent, the crude product is purified by column chromatography on silica gel (ethyl acetate / isohexane = 1/1). In this way 211 g (75%) of cis-2, 3-epoxycyclohexyl tosylate is obtained as yellow oil, which solidifies slowly. 1-NMR (CDC13): d = 7.85 ppm (d, 2H); 7.35 (d, 2H); 4.90 (m, ÍH); 3.27 (width S, ÍH); 3.17 (width S, ÍH); 2.45 (S, 3H); 1.80 (m, 2H); 1.65 (m, 3H); 1.22 (m, ÍH).

A mixture of 112 g of the epoxide 2a) and 110 ml of ethyl ether of 4-piperidinecarboxylic acid in 250 ml of ethanol is irradiated for 2.75 hours in a microwave oven with an energy of 500 W so that the reaction temperature is of 65 ° C. Subsequently the reaction solution is cooled to 0 ° C, the product is filtered by suction, washed twice with 50 ml of cold ethanol each time and washed three times with 50 ml of diethyl ether each time and dried under vacuum at 30 ° C. In this manner, 96 g (54%) of ethyl ester of (2 a, 3ß) -1- (3-p-toluenesulfonyloxy-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester is obtained. Fp = 135 - 137 ° C. m / e = 425.'-RMN (CDC13): d = 7.75 ppm (d, 2H); 7.22 (d, 2H); 4.85 (width s, ÍH); 4.05 (q, 2H); 2.50 (t, ÍH); 2.35 (s, 3H); 2.18 (m, ÍH); 2.05 (t, 2H); 1.75 (m, 3H); 1.55 (m, 4H); 1.32 (m, ÍH); 1. 15 (t, 3H); 1.10 (m, ÍH).

A mixture of 37 g of tosylate 2b) and 34.3 g of sodium azide in 250 ml of dimethylformamide is irradiated in a microwave oven for 20 min with an energy of 500 W in such a way that the reaction temperature is 90CC. Subsequently the reaction solution is cooled to room temperature, the sodium salt is filtered, the filtrate is evaporated to dryness under vacuum at 50 ° C, the residue is placed in 50 ml of water and the aqueous mixture is extracted three times with 50 ml of water. my diethyl ether each time. After drying the combined organic phases with sodium sulfate and removing the solvent, the product is purified by column chromatography on silica gel (ethyl acetate / isohexane = 6/4). In this way, 21.8 g (84%) of the compound titled as a slightly gray powder is obtained. Fp. : 61-63 ° C. The titled compound is obtained according to this process in a better yield and higher purity than the process of lh).

Example? Acid (-.) - (3'R.7'R.7S) -l-r2-? Xo-3- (3.4.5.6-tetrahydro-2H-ri.4 'lbipyridinyl-4-yl) -octahydro-benzooxazole -7-ill -piperidine-4-carboxylic acid After carrying out the steps of substitution reaction 2a) -2c) of racemic cis-2, 3-epoxycyclohexanol in example 2a) by (ÍS, 2S, 3R) -l-hydroxy-2, 3-epoxycyclohexane occurs the optically active compound ethyl ester of (l, R, 2R, 3S) -l-azido-2-hydroxycyclohexyl) -piperidine-4-carboxylic acid ([a] D20 = + 42 ° (C1.23; CHC13)), from the titled compound is obtained analogously to example li) -11). [a] D = + 18.7 ° (C1.2; CHC13). (1S, 2S, 3R) -l-hydroxy-2,3-epoxycyclohexane is obtained according to Svante T. (J. Org. Chem.! £, 1380 (1973)) by epoxidation of (S) -cyclohex- 2-enol known in the literature (Sing VK, et al., Synth, Commun. 24, 375 (1994)) by means of meta-chloroperbenzoic acid.

Example 1 Acid (-.) - (3'Q_.7'ß.7g) -l-. { 3-n- (2-benzylamino-pyrimidin-4-yl) -piperidin-4-ip-2-oxo-octahydro-benzooxazol-7-yl} -piperidin-4-carboy?] rich a) A solution of 16 ml (0.12 mol) of 4-piperidone-ethylene ketal in 100 ml of ethanol is added dropwise to a solution of 18.5 g (0.12 mol) of 2,4-dichloro-pyrimidine and 17.5 ml of triethylamine in 150 ml of ethanol while cooling on ice.

Subsequently, the reaction mixture is stirred for 2.5 hours at room temperature and then evaporated to dryness. The residue is placed in 50 ml of water and the aqueous mixture is extracted three times with 200 ml of methylene chloride each time. After drying the combined organic phases with sodium sulfate and removing the solvent, the residue is recrystallized from ethyl acetate / isohexane. In this way 21.8 g of 8- (2-chloro-pyrimidin-4-yl) -l, 4-dioxa-8-aza-spiro- [4.5] decane is obtained as a white powder, m / e = 256. ' H-NMR (CDClj): d = 7.92 ppm (d, 1H; Ar-H); 6.35 (d, ÍH; Ar-H); 3.91 (S, 4H); Cetal-CH.); 3.65 (width s, 4H); 1.68 (t, 4H).

A mixture of 6 g of 2-chloropyrimidine 3a) and 7.2 ml of benzylamine is heated for 2 hours at 150 ° C. Subsequently the reaction mixture is cooled to room temperature, mixed with 30 ml of water, the aqueous solution is extracted three times with 20 ml of methylene chloride each time, the combined extracts are dried with sodium sulfate, the solvent is removed in a rotary evaporator and the residue is crystallized from ethyl acetate. In this way 7 g of 8- (2-benzylamino-pyrimidin-4-yl) -l, 4-dioxa-8-aza-spiro- [4.5] decane, m / e = 326 is obtained. 'H-NMR ( d6-DMSO): d = 7.88 ppm (d, 1H; Ar-H); 7.32 (m, 5H; Ar-H); 7.25 (width S, ÍH; NH); 6.12 (d, ÍH; Ar-H); 4.45 (d, 2H; pH-CH2-) 3.98 (s, 4H; ketal-CH2); 3.65 (width, s, 4H); 1.72 (width s, 4H). c) Analogously to example lb) 6.3 g of 1- (2-benzylamino-pyrimidin-4-yl) -piperidin-4-one is obtained as a brown oil of 7 g of ketal 3b) and 80 ml of 6N hydrochloric acid which is further reacted as a crude product. d) 0.77 g of ethyl ester of (±) - (la, 2ß, 3o.) -1- (2-hydroxy-3- [1- (2-benzylamino-pyrimidin-4-yl) -piperidin-4-) ilamino] -cyclohexyl.} -piperidine-4-carboxylic acid is obtained analogously to example 1j) of 0.42 g of amine li), 0.44 g of ketone 3c), 0.66 g of sodium triacetateborohydride and 0.3 ml of 100% acetic acid . m / e = 537. e) 0.54 g of ethyl ester of (±) - (3 'a, 7' ß, 7a) -1- acid. { 3- [1- (2-benzylamino-pyrimidin-4-yl) -piperidin-4-yl-2-oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid is obtained analogously to example lk) of 0.77 g of the aminoalcohol 3d) and 0.28 g carbonyl diimidazole. pos. FAB = 562. 'H-NMR (ds-DMS0): d = 7. 75 ppm (d, ÍH); 7.20 (m, 5H); 7.12 (width s, ÍH; NH); 6.03 (d, ÍH); 4.43 (d, 2H); 4.39 (width S, ÍH); 4.05 (q, 2H); 3.80 (t, ÍH); 3.69 (m, ÍH); 3.25 (width t, ÍH); 2.76 (m, 5H); 2.48 (m, 2H); 2.25 (m, 2H); 1.95-1.20 (m, 14H); 1.18 (t, 3H). f) 0.065 g of the titled compound is obtained analogously to example 11) of 0.1 g of ethyl ester 3e) and 0.4 ml of sodium hydroxide solution IN. m / e = 534. Fp = 180 ° C.

Example 4 Acid (+) - (3'a.7'ß.7o _) - l-. { 3-fl- (2-pyrrolidin-l-yl-pyrimidin-4-yl) -piperidin-4-ip-2-oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid < x a) A mixture of 7.7 g of chloropyrimidine derivative 3a) and 25 ml of pyrrolidine is irradiated in a microwave oven for 15 min with an energy of 500 W in such a way that the reaction temperature is 50 ° C.

Subsequently, the reaction solution is evaporated to dryness, the residue is placed in 20 ml of water and the aqueous mixture is extracted four times with 20 ml of methylene chloride each time. After drying the combined extracts with sodium sulfate and removing the solvent, the residue is purified by means of preparative HPLC (Merck, Select B, methanol / buffer (pH = 7.5) 75/25). In this manner, 7.8 g of 8- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -l, 4-dioxa-8-aza-spiro- [4.5] decane is obtained. m / e = 290. b) 5.9 g 1- (2-pyrrolidin-l-yl-pyrimidin-4-yl) -piperidin-4-one is obtained analogously to example lb) from 7.8 g of ketal 4a) and 72 ml of 6N hydrochloric acid which is further reacted as a crude product. c) 3.4 g of ethyl ester of acid (±) - (lo;, 2ß, 3a) -l-. { 2- hydroxy-3- [1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-ylamino] cyclohexyl} -piperidine-4-carboxylic acid is obtained as a yellow oil analogously to example 1j) of 2.46 g of ketone 4b), 2.7 g of the amine li), 3.2 g of sodium borohydride triacetate and 6 ml of 100% acetic acid. 'H-NMR (dβ-DMS0 + AcOH): d = 7.92 ppm (d, ÍH); 6.29 (d, ÍH); 4.52 (width d, 2H); 4.15 (q, 2H); 3.79 (t, ÍH); 3.53 (m, 4H); 3.20 (m, 3H); 3.00 (m, 3H); 2.55 (m, 2H); 2.20-1.70 (m, 3H); 3.00 (m, 3H); 2.55 (m, 2H); 2.20-1.70 (m, 13H); 1.62-1.35 (m, 5H); 1.25 (t, 3H). d) 2.5 g of ethyl ester of (±) - (3 'a, 7' ß, la) -l- acid. { 3- [1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid is obtained as a slightly gray powder analogously to example Ik) of 3.3 g of aminoalcohol 4c) and 1.6 g of carbonyldiimidazole. Fp = 140 ° C. m / e = 526. 'H-NMR (ds-DMSO): d = 8.01 ppm (d, ÍH); 6.21 (d, ÍH); 4.62 (width t, 2H); 4.20 (q, 2H); 3.99 (t, ÍH); 3.88 (m, ÍH); 3.55 (m, 5H); 2.98 (m, 5H); 2.65 (m, ÍH); 2.45 (m, 2H); 2.13 (m, ÍH); 2.08-1.40 (m, 18H); 1.33 (t, 3H). e) 0.16 g of the titled compound is obtained analogously to example 11) from 0.4 g of ethyl ester 4d) and 0.9 ml of IN sodium hydroxide solution. m / e = 498. 'H-NMR (d6-DMSO + AcOH): d = 7.60 ppm (d, ÍH); 6.25 (d, ÍH); 4.35 (width s, 2H); 3.78 (t, ÍH); 3.59 (width t, ÍH); 3.25 (m, 5H); 3.05-2.70 (m, 5H); 2.60 (width t, ÍH); 2.42 (width t, ÍH); 2.15 (m, ÍH); 1.80-1.38 (m, 14H); 1.20 (m, 4H).

Example 5 Acid (+) - (3 'a. 7' ß.7or) -1-. { 3- TI- (2-amino-pyrimidin-4-yl) -piperidin-4-yl-2-oxo-octahydro-benzooxazol-7-yl} -piperidin-4-carfrQXílJCQ a) A solution of 26 g of chloropyrimidine 3a) and 120 ml of liquid ammonia in 500 ml is maintained in an autoclave of 11 for 60 hours at 5 bar and 90 ° C. Subsequently the reaction mixture is evaporated to dryness, the residue is placed in 20 ml of water and the aqueous solution is extracted five times with 20 ml of methylene chloride each time. After drying the combined extracts with sodium sulfate and removing the solvent, the residue is stirred with 40 ml of ethyl acetate. In this way 5.7 g of 8- (2-amino-pyrimidin-4-yl) -l, 4-dioxa-8-aza-spiro- [4.5] decane is obtained as a yellow powder m / e = 236. b) 5.5 g of (2-amino-pyrimidin-4-yl) -piperidin-4-one is obtained analogously to example lb) as a yellow solid from 6 g of ketal 5a) and 65 ml of 6N hydrochloric acid. m / e = 192. c) 1.5 g of ethyl ester of acid (±) - (lo., 2ß, 3a) -l-. { 2- hydroxy-3- [1- (2-amino-pyrimidin-4-yl) -piperidin-4-yl) -piperidin-4-ylamino] -cyclohexyl} -piperidine-4-carboxylic acid is obtained as a yellow oil analogously to example lj) of 1 g of amine li), 0. 7 g of ketone li), 1.6 g of sodium borohydride triacetate and 0.8 ml of 100% acetic acid. m / e = 446. 'H-NMR (d6-DMSO): d = 7.80 ppm (d, ÍH); 6.08 (d, ÍH); 6.00 (s, ÍH; NH); 4.24 (d, 2H); 4.15 (m, 4H); 3.12 (t, 1H); 2.90 (m, 4H); 2.72 (width d, ÍH); 2.60 (m, 3H); 2.30 (width t, 3H); 1.88 (m, 5H); 1.70 (m, 5H); 1.25 (t, 3H); 1.15 (m, 3H). d) 0.3 g of ((±) - (3 * a, 7'ß, la) -1- { 3- [1- (2-amino-pyrimidin-4-yl) -piperidine- ethyl ester. 4-yl] -2-oxo-octahydro-benzooxazol-7-yl.}. -piperidine-4-carboxylic acid is obtained as a slightly gray powder analogously to example lk) of 1.1 g of aminoalcohol 5c) and 0.5 g of carbonyldiimidazole. m / e = 472. Fp = 120-122 ° C. e) 0.07 g of the titled compound is obtained analogously to example 11) from 0.11 g of ethyl ester 5d) and 0.25 ml of IN sodium hydroxide solution. m / e = 444. Fp > 200 ° C.

Example 6 Acid (+) - (3'a.7'ß.7a _) - (l-r2-oxo-3- (3,4,5,6-tetrahydro-2H-ri.4 'lbipyridinyl-4-yl-octahydro-benzooxazol-7 -ip -piperidin-4-yl.} -acetic The titled compound is obtained analogously to examples 2b), 2c) and li) -ll) by substituting the ethyl ester of 4-piperidinecarboxylic acid in example 2b) for ethyl ester of 4-piperidineacetic acid. Fp = 135 ° C (decomposition). m / e = (El spectrum) = 514 (measured as trimethylsilyl derivative).

Example 7 Etil ást = r sie acid (+) - (2 'a. T & ia) -. { ? - .2-0x0-3-f 3.4. 5. 6-tetrahydro-2H-Fl. 4 '1 bipepyridinyl-4-yl-octahydro-benzooxazol-7-ill -4- (2-phenylethyl) -Pipeline-4-carboxylic acid The compound titled substituting the 4-piperidinecarboxylic acid ethyl ester in Example 2b) for 4- [4- (2-phenylethyl) piperidinecarboxylic acid ethyl ester analagously to examples 2b), 2c) and li) - lk) (Gilligan et al., J. Med., Chem. 17, 364 (1994)). m / e = 560. 'H-NMR (ds-DMSO): d = 8.13 ppm (d, 2H); 4.12 (q, 2H); 4.01 (m, 2H); 3.80 (t, ÍH); 3.70 (m, ÍH); 3.60 (m, 4H); 3.28 (m, ÍH); 2.80 (m, 5H); 2.45 (m, 2H); 2.32 (t, 3H); 2.05 (m, 2H); 1.95 (m, 2H); 1.70 (m, 9H); 1.35 (m, 5H); 1.20 (t, 3H).

Example 8 AcidO (+) - (3'0f.7'g.70f) -. { l- F2-thiooxo-3- (3,4,5,6-tetrahydro-2H-fl.4'-bipyridinyl-4-yl-octahydro-benzooxazol-7-ill-piperidine-4-carboxylic acid a) 0.2 g of ethyl ester of acid (±) - (3 * c_, 7'ß, 7c_) -1- [2-thiooxo) -3- (3, 4, 5, 6-tetrahydro-2H- [1 , 4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid is obtained analogously to example lk) from 0.3 g of aminoalcohol 1j) and 0.21 g of thiocarbonyldiimidazole. Pos. FAB = 472. b) 0.1 g of the product was obtained analogously to example 11) from 0.14 g of ethyl ester 8a) and 0.35 ml of IN sodium hydroxide solution from which 143 mg of the compound titled as an HCl salt was isolated. after the addition of 0.6 ml of IN hydrochloric acid. Pos. FAB = 472. Fp = 180 ° C.

Example 9 Acid ) - (3 'ff.7'8.7tt) -l- f3- (l-benzyl-fl.4'1bi? Iperidinyl-4-yl) -2-oxo-octahydro-benzooxazol-7-ip-piperidin-4 - carboxylic a) A mixture of 15 g of the pyridine derivative la) and 4 g of ruthenium oxide is hydrogenated until the incoming hydrogen is complete (30 hours). Subsequently, the catalyst is removed by filtration, the filtrate is concentrated in vacuo, the residue is placed in 120 ml of 1,4-dioxane and the solution obtained in this way is mixed with 18 ml of benzyl chloride and 15 g of sodium carbonate. potassium. The reaction mixture is then heated at reflux for 5 hours, after which it is cooled, the precipitate is removed by filtration and the filtrate is evaporated to dryness. The crude product is purified by column chromatography on silica gel (ethyl acetate + 10% saturated ammoniacal methanol). In this way, 3.4 g of 8- (1-benzyl-piperidin-4-yl) -1,4-dioxa-8-azaspiro [4.5] decane is obtained. 'H-NMR (ds-DMS0): d = 7.30 ppm (m, 5H); 3.85 (s, 4H); 3.45 (s, 2H); 2.84 (d, 2H); 2. 52 (m, 4H); 2.25 (m, ÍH); 1.88 (t, 2H); 1.63 (m, 6H); 1.42 (q with fine resolution, 2H). b) 1.2 g of 1 '-benzyl- [1,4'] bipiperidyl-4-one is obtained analogously to example lb) from 1.5 g of ketal 9a) and 10 ml of 6N hydrochloric acid. m / e = 272. 'H-NMR (ds-DMSO): d = 7.35 ppm (m, 5H); 4.01 (S, 2H); 3.22 (d, 2H); 3.01 (m, ÍH); 2.84 (d, 3H); 2.65 (q, 3H); 2.33 (t, 3H); 1.80 (m, 5H). c) 1.4 g of 1- [3- (1-benzyl- [1, 4 '] bipiperidinyl-4-amino) -2-hydroxy-cyclohexyl] -piperidin-4-carboxylic acid ethyl ester is obtained as a solid slightly gray analogously to example 1 j) from 1.2 g of the amine li), 1.2 g of ketone 9b) and 1.9 g of sodium borohydride triacetate. Fp = 92 ° C. d) 0.51 g of ethyl ester of (±) - (3 'a, 7 »ß, la) -1- [3- (1' benzyl- [1,4 '] bipiperidinyl-4-yl) -2- oxo-octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid is obtained as a white powder analogously to example lk) from 0.99 g of the aminoalcohol 9c) and 0.45 g of carbonyldiimidazole. Fp = 148-150 ° C. e) 0.12 g of the titled compound is obtained analogously to example 11) from 0.25 g of ethyl ester 9d) and 0.5 ml of sodium hydroxide solution. m / e = 524. 'H-NMR (Da0): d = 7.25 ppm (m, 5H); 3.92 (t, ÍH); 3.60 (s, 2H); 3.45 (m, 2H); 3.01 (d, 4H); 2.82 (ra, 3H); 2.48 (t, 2H); 2.38-2.00 (m, 7H); 1.95-1.60 (m, 10H); 1.35 (m, 7H).

Example IQ Acid (+) - (3'c..7'ß.7c_) -1- (3- fl.4'1bipiperidinyl-4-yl-2-oxo-octahydro-benzooxazol-7-yl) -piperidin-4- carboxylic a) A mixture of 0.74 g of the N-benzyl derivative 9d) and 0.3 g of 10% palladium / carbon in my ethanol is hydrogenated at 50 ° C / 4 bar until the inlet hydrogen is complete (2 hours) . After which the catalyst is removed by filtration and the filtrate is evaporated to dryness. In this way 0.355 g of ethyl ester of (±) - (3 * a, 7'ß, 7a_) -1- (3- [1,4 '] bipiperidinyl-4-yl-2-oxo-octahydro is obtained. -benzooxazol-7-yl) -piperidine-4-carboxylic acid. Pos. FAB = 524. Fp = 200 ° C. b) 0.13 g of the titled compound is obtained analogously to example 11) from 0.2 g of ethyl ester 10a) and 0.7 ml of IN sodium hydroxide solution. POS. FAB (MH *) = 435. Fp > 200 ° C.

Example 11 (+) - (3 'fi.7' a. La) -1- _2-oxo-3- (3,4,5,6-tetrahydro-2H-ri.4'-bipyridinyl-4-yl) -octahydro-benzooxazole-7 acid - ill -? iperidine-4-carboxylic acid a) A mixture of 1.77 g of trans-3-bromo-1,2-epoxycyclohexane (Lier E. et al., Helv. Chim. Acta, ¿2, 932 (1979)), 1.7 ml of ethyl ester of 4-piperidinecarboxylic acid and 1.8 g of potassium carbonate in 30 ml of dimethylformamide is stirred for 24 hours at room temperature. Subsequently, the reaction mixture is mixed with 400 ml of water and the aqueous solution is extracted three times with 40 ml of diethyl ether each time. After drying the combined organic phases with sodium sulfate and removing the solvent, the crude product is purified by column chromatography on silica gel (ethyl acetate + 1% ammoniacal methanol). In this way, 0.6 g of (±) -cis-1- (2,3-epoxy-cyclohexyl) -piperidine-4-carboxylic acid ester is obtained. 'H-NMR (CDC13): d = 4.05 ppm (q, 2H); 3.20 (d, ÍH); 3.05 (t, ÍH); 2.98 (m, ÍH); 2.82 (m, 2H); 2.40 (m, 12 lines, 2H); 2.18 (m ÍH); 1.85 (m, 2H); 1.70 (m, 6H); 1.50 (m, ÍH); 1.36 (m, ÍH); 1.19 (t, 3H). b) 0.6 g of (±) - (lc_, 2a, 3ß) -1- (3-azido-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester is obtained as a gray solid analogously to example 2c ) from 0.6 g of epoxide lia) and 0.23 g of sodium azide. m / e = 296. Fp = 90 ° C. c) 0.2 g of ethyl ester of (±) - (la, 2ar, 3ß) -1- (3-amino-2-hydroxy-cyclohexyl) -piperidin-4-carboxylic acid is obtained analogously to example li) from 0.44 g of azide llb). Pos. FAB = 270. 'H-NMR (CDC1,): d = 4.05 ppm (q, 2H); 3.60 (t, ÍH); 3.15 (q, ÍH); 3.00 (m, 2H); 2.50 (m, ÍH); 2.28-2.00 (m, 5H); 1.90-1.40 (m, 11H); 1.25 (m, ÍH); 1.18 (t, 3H). d) 0.12 g of ethyl ester of (±) - (la, 2a, 3ß) -1- (2-hydroxy-2H- [1,4 '] bipyridinyl-4-ylamino) -cyclohexyl] -piperidin- 4 - carboxylic acid is obtained analogously to example lj) from 0.2 g of amine 11c), 0.13 g of ketone lb) and 0.31 g of sodium borohydride triacetate. Pos. FAB = 430. e) 0.35 g of ethyl ester of (±) - (3 ', 7'a, 7a) -1- [2-OXO-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid is obtained analogously to example lk) from 0.42 g of aminoalcohol lid) and 0.24 g of carbonyl-diimidazole. m / e = 456. 'H-NMR (ds-DMS0): d = 8.20 ppm (d, 2H); 6.85 (d, 2H); 4.05 (q + m, 5H); 3.75 (m, ÍH); 3.20 (width d, ÍH); 2.90 (m, 3H); 2.30 (m, ÍH); 2.04 (m, 4H); 1.80 (m, 5H); 1.65-1.35 (m, 9H); 1.20 (t, 3H). f) 0.26 g of the titled compound is obtained analogously to example 11) from 0.3 g of the ethyl ester lie) and 1 ml of sodium hydroxide solution IN. Pos. FAB = 428.

Example 12 Acid (+) - (3'ß.7'fi.7c_) -1- f2-oxo-3- (3,4,5,6-tetrahydro-2H-ri.4 '. Bipyridinyl-4-yl) -octahydro-benzooxazole - 7-ill -pipe jdip-4-carfrQ *; íli? O a) 0.9 g of ethyl ester of (±) - (la, 2ß, 3ß) -1- (3-benzyloxycarbonyl-amino-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid is obtained as a viscous oil analogous to example ld) from 0. 65 g of cis-3-benzyloxycarbonyl amino-1,2-epoxycyclohexane (Brouillette WJ et al., J. Org. Chem., 53., 4297 (1994)) and 0.6 ml of 4-piperidine-carboxylic acid ethyl ester , which is also processed as a raw product. b) A solution of 0.9 g of N-benzyloxycarbonylamine produced in 12a) in 15 ml of ethanol is mixed with 0.8 g of 10% palladium / carbon and the mixture is hydrogenated at normal pressure at room temperature until the incoming hydrogen complete (12 hours). Subsequently the catalyst is removed by filtration and the solution is concentrated in a rotary evaporator. In this way, 0.5 g of ethyl ester of (±) - (lc_, 2ß, 3ß) -1- (3-amino-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid ester is obtained. m / e = 270. 'H-NMR (dß-DMS0): d = 4.05 ppm (q, 2H); 3.48 (dd, ÍH); 3.20 (q, ÍH); 2.80 (dt, ÍH); 2.68 (dt, ÍH); 2.58 (t with fine resolution, ÍH); 2.42 (t with fine resolution, ÍH); 2.25 (m, ÍH); 2.13 (t with fine resolution, 1H); 1.78 (m, 2H); 1.63 (m, 2H); 1.55 (m, 4H); 1.38 (m, 3H); 1.15 (m, 2H). c) 0.33 g of ethyl ester of acid (±) - (lc_, 2ß, 3ß) -1- [2-hydroxy-3- (3,4,5,6-te rahydro-2H- [1,4-ylamino] ) - cyclohexyl] -piperidine-4-carboxylic acid is obtained analogously to example 1j) from 0.4 g of amine 12b), 0.26 g of ketone lb) and 0.42 g of sodium borohydride triacetate. The subsequent reaction of the aminoalcohol thus produced with 0.17 g of carbonyldiimidazole analogously to Example Ik) yields 0.22 g of ethyl ester of (±) - (3 '-, 7', β) -l- [2-oxo- 3- (3,4,5,6-tetrahydro-2H- [1,4] • bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-carboxylic acid saponification of which with 0.6 ml of hydroxide Sodium salt analogously to example 11) yielded 0.11 g of the titled compound. Fp = 150 ° C (decomposition). m / e = 428. 'H-NMR (d6-DMSO + AcOH): d = 4.05 ppm 8.15 (d, 2H); 7.10 (d, 2H); 4.65 (t, ÍH); 4.25 (width d, 2H); 3.98 (width d, ÍH); 3.61 (m, ÍH); 3.05 (m, 4H); 2.70 (m, 2H); 2.35 (m, ÍH); 2.10 (m, ÍH); 2.0-1.10 (m, 16).

Example 13 Test Microtitre plates were coated overnight with 2 μg / ml with the activated GpIIb / IIIa receptor isolated. After the unbound receptor had been removed during several washing steps, the surface of the plate was blocked with 1% casein and washed again. The test substance was added to the required concentrations, subsequently the plates were incubated for 10 minutes while being agitated on a linear stirrer. The natural ligand of the gpiib / llla receptor, fibrinogen, was added. After incubation for 1 hour the unbound fibrinogen was removed by several washing steps and bound fibrinogen was determined by measuring the change in optical density at 405 nm caused by a conjugated peroxidase monoclonal antibody in an ELISA marker. Inhibition of the Gp / IIb / IIla interaction of fibrinogen leads to lower optical densities. The IC50 value was determined on the basis of a concentration-effect curve.

Literature The fibrinogen GpIIb / IIIa ELISA is a modification of the test described in the following references: Nachman, R.L. & Leung, L.L.K. (1982): Complex formation of platelet membrane glycoproteins Ilb and Illa with fibrinogen. J. Clin. Invest. 69: 263-269.

Wright, P.S. et al. (1993): An echistatin C-terminal peptide activated GpIIblIIa binding to fibrinogen, fobronectin, vitronectin and collagen type Y and type IV, Biochem. J. 293: 263-267.

Pharmacological results: It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (1)

1. The compounds of the general formula I characterized because E represents a residue of formula (a) or (b) (a) '(b) M represents oxygen, sulfur or NR °°, X represents hydrogen or NR'R3, W represents nitrogen or NH or CH or CH2, Q represents nitrogen or CH, And represents nitrogen or CH, Z represents nitrogen, CH or C-OH, A represents an alkylene chain - (CH2) p- which is optionally substituted, D represents a side chain of the form - (CHR3) ,, - COO-R8 or = CR3-COO-R \ n represents 1-3, m represents 0 or 1, p represents 0-3 R ', R 2 represent independently of one another hydrogen, C -C6 alkyl, a phenyl residue which is optionally unsubstituted or substituted several times, a benzyl, phenethyl, phenyl-propyl, phenylbutyl or phenylpentyl residue, which is unsubstituted or substituted one or more times with C 1 -C 6 alkyl, chloro, bromo, fluoro, hydroxy, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, a pyridyl, pyrimidyl, piperazyl, imidazolyl, pyrrolyl, furyl or thiophenyl residue which is unsubstituted or substituted one or more times, a formyl, acetyl, propionyl, butyryl or benzoyl residue or a saturated carboxylic ring or unsaturated of 5 to 5 members which is optionally substituted or twice by alkyl C.-C3 or a saturated or unsaturated heterocyclic ring of 5 to 6 members which is optionally substituted once or twice by Cj.-Cß alkyl, or together with the nitrogen to which they are attached, form an optionally substituted five- or six-membered ring which may contain from 1 to 3 additional heteroatoms, or represent a group (c) R3 represents hydrogen or a group -OR5 or -NRSR7 R4 represents hydrogen, C.sub.C alkyl, a phenyl residue which is optionally unsubstituted or substituted several times, a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted one or more times by alkyl groups. Cß, chlorine, bromine, fluorine, hydroxy, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, a pyridyl residue, pyrimidyl, piperazyl, imidazolyl, pyrrolyl, furyl or thiophenyl which is unsubstituted or substituted one or more times, or a group -OR5, R5 represents hydrogen, C_-C3 alkyl, a phenyl residue which is optionally unsubstituted or substituted several times, a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted one or more times by Ci-Cg alkyl groups, chlorine, bromine, fluorine, hydroxy, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, Rβ represents hydrogen, C 1 -C 3 alkyl or a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted one or more times by C 1 -C 3 alkyl, chloro, bromo, fluoro, hydroxy, methoxy, benzyloxy, acetyloxy groups , carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, R7 represents hydrogen, C_-C3 alkenyl or a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted once or several times by C.sub.3-C, chloro, bromo, fluoro, hydroxy, methoxy, benzyloxy groups, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, a formyl, acetyl, propionyl, butyryl or benzoyl residue, a methanesulfonyl, ethanesulfonyl, propansulfonyl, butanesulfonyl or a benzenesulfonic acid or toluenesulfonic acid residue, R8 represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, phenyl or benzyl, in particular hydrogen, ethyl, phenyl or isopropyl, R 'represents hydrogen, Cj-Cg alkyl or a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted one or several times by C 1 -C 6 alkyl, chloro, bromo, fluoro, hydroxy, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino groups , acetylamino, benzoylamino and amidino, a formyl, acetyl, propionyl, butyryl or benzoyl residue, a methanesulfonyl, ethanesulfonyl, propansulfonyl, butanesulfonyl or a benzenesulfonic acid or toluenesulfonic acid residue or a group (O, R ° represents hydrogen, C_-C6 alkyl or a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted one or more times by C.sub.3 -C.sub.3, chloro, bromo, fluoro, hydroxy, methoxy, benzyloxy groups , acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, or a group - NHR °°, R °° represents hydrogen, represents hydrogen, alkyl C_-C6 or a benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl residue which is unsubstituted or substituted one or more times by alkyl groups C.-C6, chloro, bromo, fluoro, hydroxy, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino, a formyl residue, acetyl , propionyl, butyryl or benzoyl, a methanesulfonyl, ethanesulfonyl, propansulfonyl, butansul fonyl residue or a benzenesulphonic acid residue or toluensulonic acid.