SK298A3 - New oxazolidinone derivatives, process for preparing the same and medicaments that contain these compounds - Google Patents

Abstract

New oxazolidinone derivatives are disclosed, as well as a process for preparing the same and medicaments that contain these substances. The disclosed compounds have general formula (I), in which X, Y and Q independently represent nitrogen or CH; W stands for hydrogen or NR<0>R<00>; Z stands for nitrogen, CH or C-OH; A, E and G independently represent the valence dash or an alkylene chain -(CH2)n-; B stands for a valence dash and, when Z equals N, it may also stand for a carbonyl group; D stands for a side chain having the form -(CHR<3>)m-COO- or =CR<3>-COO-; n equals 1 to 5; m equals 0.1; R<1>, R<2> independently represent hydrogen, lower alkyl or aryl, or form together a carbocyclic five- or six-membered ring; R<3> stands for hydrogen or a group -OR<5> or -NR<6>R<7>; R<4> stands for hydrogen or a group -OR<5>; R<5> stands for hydrogen, lower alkyl, aryl or arylalkyl; R<6> stands for hydrogen, lower alkyl or arylalkyl; R<7> stands for hydrogen, lower alkyl, arylalkyl, acyl, alkylsulphonyl or arylsulphonyl.

Description

Technical field

The present invention relates to novel oxazolidinone derivatives, to a process for their preparation, and to medicaments containing them.

BACKGROUND OF THE INVENTION

It is known that compounds carrying one basic and one acidic group are capable of inhibiting platelet aggregation when the basic and acidic groups in these compounds occupy a certain distance (Drugs of the Future 19 (2): 135159 (1994)). WO 93/1477, EP-A-0 537980, EP-A-0 542 363, WO 94/22834, WO 94/22835 and EP 0623615A1 disclose compounds having an antiplatelet effect on platelets.

It has now been found that oxazolidinone derivatives effectively inhibit platelet aggregation and therefore can be used to treat diseases that can lead to thromboembolic events such as apoplexy, myocardial infarction or arterial obstructive disease, as well as inflammation, osteoporosis or cancer.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

-A-

In which

X, Y and Q independently of one another are nitrogen or CH,

W represents hydrogen or NR ° R ⁰⁰ ,

Z is nitrogen, CH or C-OH,

A, E and G independently of one another denote a valency dash or an alkylene chain - _{(CH2) n} B denotes a valency dash, and where Z is equal to N, is the carbonyl,

D is a side chain of the form - (CHR ³ ) _m -COO-r or = CR ³ -COO-, n is 1-5, m is 0, 1,

R ¹ , R ² independently of one another are hydrogen, lower alkyl or aryl, or together form a carbocyclic five- or six-membered ring,

R ³ is hydrogen or a radical -OR ⁵ or -NR ⁶ R ^7,

R ⁴ is hydrogen or -OR ^5,

R ⁵ is hydrogen, lower alkyl, aryl or arylalkyl,

R ⁶ is hydrogen, lower alkyl or arylalkyl,

R ⁷ is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl.

R 0, R ⁰⁰ are, independently of one another, hydrogen, lower alkyl, aryl, arylalkyl, heteroaryl, 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 it may still contain 1 to 3 additional heteroatoms, or represent a pOOO skupinu group

-C-NH

R ⁰⁰⁰ represents hydrogen, lower alkyl, arylalkyl or a group

NHR ⁰⁰⁰⁰ ,

R ⁰⁰⁰⁰ represents hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl, as well as their pharmacologically acceptable salts.

Lower alkyl is in each case a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, pollen, isobutyl and pentyl.

Aryl generally means optionally substituted one or more substituted phenyl.

Arylalkyl generally means unsubstituted or mono- or poly-substituted benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl, in particular benzyl, phenethyl or phenylpentyl. Suitable substituents are C1 -C6 alkyls, in particular methyl, ethyl or isopropyl, as well as chlorine, bromine, fluorine or hydroxy, methoxy, benzyloxy, acetyloxy, carboxyl, ethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, dimethylamino-carbonyl, dimethylaminocarbonyl, , cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino.

Acyl generally means formyl, acetyl, propionyl, butyryl or benzoyl, in particular acetyl or benzoyl.

Alkylsulfonyl generally means methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl, especially butanesulfonyl.

Arylsulfonyl generally means a residue of benzenesulfonic acid or toluenesulfonic acid.

When R ^{@ 1} and R @ ² together form a carbocyclic five- or six-membered ring, it is a saturated or unsaturated, optionally lower alkyl, mono- or six-membered five- to six-membered ring, such as a cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring.

The compounds of the formula I contain at least one asymmetric carbon atom and therefore the optically active compounds of the formula I are also the subject of the present application. The present invention further relates to conformational isomers of the compounds of formula I which may optionally exist.

Preferred compounds are those compounds of formula I wherein AB is (CH ₂ ) _1-3 or (CH ₂ ) 1-3 CO and E, G, Q, W, X, Y, Z, D, R ¹ , R 2. ² and R ⁴ are as defined above.

by known methods by ester hydrolysis II

Particularly preferred are compounds of formula I wherein A-B is a methylene, ethylene, carbonyl or methylenecarbonyl group and E, G, Q, W, X, Y and Z are nitrogen.

The compounds of the formula I are otherwise prepared by the general formula _x ^ (CHR ³⁾ _m -COOR ⁸

The

X ,. Y, Z and m are as defined above and R ⁸ is methyl, ethyl, tert-butyl, phenyl or benzyl. ...

Compounds of formula II are prepared according to the reaction path outlined in Scheme 1.

(II) wherein R ¹ , R ² , R ³ , R ⁴ , A, B, E, G, Q, W,

SCHEME 1 λο ¹

, -H λ_ _ε _ _ν -τ

V ^E N Y_ _G - _N

Λα '

-A-B

Å 2

carbonyl

Synthon

D — R ⁸ (III)

A — B-Z (II)

Scheme 1

In Scheme 1, R ¹ , R ² , R ⁴ , R ⁸ , A, B, D, E, G, Q, W, X, and Z have the meanings given above. Carbonyl-Synthon means in general phosgene, diphosgene, triphosgene, carbonyldiimidazole, dimethyl, diethyl or diphenyl carbonate, methyl or ethyl chloroformate, in particular carbonyldiimide azole, diethyl carbonate or ethyl chloroformate. MN ₃ means a metal azide such as lithium azide, sodium azide, potassium azide, tributylstanium azide or magnesium azide, in particular lithium azide or sodium azide. TMSN ₃ stands for trimethylsilyl azide.

Compounds of formula (IV) may be produced according to the reaction pathways reproduced in Scheme 2.

SCHEME 2 f ~ \

(XXXII) ^w

c) hydrolysis of phthalimide; d) hydrogenation of benzyl groups; e) reduction of the nitroso group; g) AcOH / 100 ° C / 3h; h) HCl / THF / H ₂ O

Scheme 2

In Scheme 2, E, G, Q, X and W have the meanings given above;

L is generally a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, in particular chlorine or tosylate.

The compounds of formula (V) may also be obtained by the reaction pathways shown in Scheme 3.

-A-B-L

R ¹ Ŕ ² (XI)

a) Wittig reaction; b) Pd / C / H ₂ ; c) ketal cleavage;

d) Wittig reaction; e) epoxidation; d) reaction of organometallic compounds

Scheme 3

In Scheme 3, R ¹ , R ² , R ³ , R ⁴ , A, B and L have the meanings given above, and when B is a carbonyl group, L can also be a hydroxy group; p is 1 or 2.

Compounds of formula (VI) are partially commercially available and in special cases can be obtained by oxidation of an alcohol of formula (XX)

wherein D, R ⁴ and R ⁸ are as defined above.

Compounds of formula VII can be prepared by reacting a compound of formula VI with an organometallic compound of formula XXI

(XXX) wherein R ¹ , R ² , A and B are as defined above and M is a metal such as lithium, magnesium or titanium.

Compounds of formula (VIII) are prepared according to known methods by reacting a compound of formula (VI) with a phosphoryl of formula (XXII).

A-B

(XXII) wherein R ² , A, B and p are as defined above, R ⁹ is butyl, phenyl or p-tolyl, and H a 1 is chloride, bromide or iodide.

Compounds of formula XI are commercially available and can be prepared in special cases by epoxidation of the alkene of formula XXIII

(XXIII) wherein R ¹ , R ² , A, B and L are as defined above.

Compounds of formula (XII) are generally commercially available pipecolinic acid derivatives; in special cases, compounds of formula XII can be prepared by reaction of commercially available 3- or 4-piperidone of formula XXIV / ^V · ⁰

HN &gt; ₃ (XXIV) with a commercially available acetic acid ester of formula XXV

R ⁸ OOC - _{CH 2} - _r 3 (XXV) wherein R ³ and R ⁸ are as defined above, or with a Wittig reagent of general formula XXVI r ⁸ ooc

(XXVI) wherein R ³ , R ⁸ , R ⁹ , m and IIa have the meanings given above.

Compounds of formula (XX) are partially commercially available and can be obtained in special cases according to known methods by hydrogenation of an arylcarboxylic acid core of formula (XXVII)

(XXVII) wherein R ⁴ , R ⁸ and D are as defined above.

Compounds of formula XXI are either commercially available or can be synthesized in situ according to the general procedure for the preparation of organometallic compounds.

Compounds of formula (X) by known procedures by reaction of a compound of formula (XXVIII)

According to IX, Wittig's reagent can be obtained

(XXVIII) wherein R ¹ , R ⁹ and Hal are as defined above.

The Wittig reagents of formula XXII or formula XXVI or formula XXVIII are partially commercially available and can be prepared from the corresponding commercial halogen compounds and triphosphines.

Hydrolysis of the ester of formula (II) to the corresponding carboxylic acid of formula (I) is accomplished by conventional methods by treating the carboxylic acid ester of formula (II) in water or in a mixture of water, tetrahydrofuran, dioxane, methanol or ethanol, especially water / tetrahydrofuran. , such as sodium, potassium or lithium hydroxide, in particular sodium or lithium hydroxide, or an acid such as hydrochloric, sulfuric or trifluoroacetic acid, in particular trifluoroacetic acid, and at temperatures between room temperature and 80 ° C, especially at room temperature.

, I

The reaction of a compound of formula XIII with 1-benzylpiperazine or 4-hydroxy- or 4-oxopiperidine (Scheme 2) or the reaction of a compound of formula XI with a compound of formula XII or a compound of formula XI with an amine of formula XII generally takes place in an aprotonic solvent such as toluene. , tetrahydrofuran, diethyl ether, dimethylformamide or methylene chloride, in particular dimethylformamide or tetrahydrofuran, using a base such as potassium hydride, sodium hydride, potassium carbonate or sodium bicarbonate, especially sodium hydride or potassium carbonate, and at temperatures between room temperature and 180 ° C, especially at 120 ° C or room temperature.

The reaction between the 3- or 4-piperidone of formula XXIV and the ester of formula XXV is carried out under aldol re14 conditions in a solvent such as methanol, ethanol, toluene, tetrahydrofuran, diethyl ether or dimethylformamide, especially tetrahydrofuran or dimethylformamide, using a base such as methanolate sodium or potassium or sodium or potassium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, potassium hexamethyldisilazide, in particular sodium hydride or lithium diisopropylamide, and at temperatures between -78 ° C and 90 ° C, preferably at -78 ° C and at room temperature.

Removal of the benzyl protecting groups occurs, if necessary, by catalytic hydrogenation such as palladium, carbon and hydrogen.

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

The reductive amination of a ketone of formula XVI with a dibenzylamine or an amine of formula XXX takes place according to methods known in the literature by reacting a ketone and an amine component in a solvent such as methanol or ethanol in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetate borohydride such as Lewis. hydrochloric acid, acetic acid, titanium tetrachloride or titanium isopropanol and at a temperature between 0 and 100 ° C, in particular at room temperature, or in the presence of a hydrogenation catalyst such as platinum oxide, and under a hydrogen atmosphere (Borch RF, Org. Coll., Vol. 6, 499 (1988), Heinzelman RVZ Chem., 8, 270 (1968), Mattson RJ, J. Org. Chem. 55, 2552 (1990); Bamey CL Tetr. Letters 31, 5547 (199). Hutchins RO, J. Org. Chem., 46, 3571 (1981)).

The nitrosation of a compound of formula XIV to a compound of formula XV is generally 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, especially at room temperature. temperature.

The reduction of the nitroso compound of formula XV occurs according to known methods by reacting the compound of formula XV in a solvent such as water, acetic acid, ethanol, tetrahydrofuran or diethyl ether, in particular acetic acid or tetrahydrofuran, with a reducing agent such as elemental zinc, sodium aluminum hydride. or lithium aluminum hydride, in particular elemental zinc or lithium aluminum hydride, and at a temperature between room temperature and 120 ° C, but preferably at 70 ° C. Conversion of a compound of formula XV to a compound of formula IV can also be carried out hydrogenolytically using a catalyst such as palladium / carbon (Hatt, HH, Org. Synth. Coll., Vol. 2, 211 (1943); Schiiler FW, J. Amer. Chem. Soc., 73, 4996 (1951) The oxidation of an alcohol of formula XX to a ketone of formula VI proceeds according to known procedures such as Jones oxidation (Jones ERH, J. Checm. Soc. 36 (1946)), Swern oxidation (Swern D., Tetrahedron 34, 1651 (1978), Dess-Martin oxidation (Dess DB, Martin J.

C., J. Org. Chem. 48, 4155 (1983) or by using a bromo-urotropin complex as an oxidant (Yavari I., J. Chem. Res.

(S) 274 (1994).

The Wittig reagents used are prepared, if appropriate, analogously to methods known from the literature (Buddras J., Angew. Chem. 80, 535 (1968); Bestmann H. J. Angew. Chem. 77,

620, 651 (1965); Wittig G. Ber. Deutsch. Chem. Ges. 88, 1654 (1955)].

The Wittig reaction is carried out according to known methods by heating under reflux in an aprotonic solvent such as benzene, toluene or xylene, in particular toluene.

The hydrolysis of the phthalimide is generally carried out according to known methods by treating the phthalimide with hydrazine hydrate or a semi-concentrated mineral acid such as hydrochloric acid or sulfuric acid, in particular hydrazine hydrate or hydrochloric acid, at room temperature.

The acylation of the amines is generally carried out in a solvent such as methylene chloride, dimethylformamide or pyridine, in particular methylene chloride or pyridine, with the addition of an auxiliary base such as triethylamine or 4-dimethylaminopyridine, and at a temperature between -10 ° C and 50 ° C. room temperature.

The ketal cleavage of the ketal of formula VIII is carried out by standard methods of organic chemistry (ORGANIKUM; VEB Deutscher Verlag der Wissenschaften, Berlin 1977, page 486, 490).

The catalytic hydrogenation of an alkene double bond is performed analogously to methods known in the literature (A. Nose. Chem. Pharm. Bull. 38, 2097 (1990); Tamura M. Bull. Chem. Soc. Jpn. 53, 561 (1980)). Liu H.-J., Synth. Commun., 15, 965 (1985), Chido N., J. Chem., Soc. Chem. Commun., 994 (1990), Buchi G., J. Amer., Chem. Soc. 89, 6745 (1967), Ernst I., Coll., Czech, Chem. Comm., 24, 3341 (1959), Johnson WS, J. Amer. Chem. Soc., 79. 1995 (1957), Muchowski JM, Can J Chem., 47, 857 (1969))

The epoxidation of the alkene of formula VII or formula X or formula XXIII occurs by methods known in the literature by reaction with a peroxyacid such as m-chloroperbenzoic acid, peracetic acid or trifluoroperacetic acid, in particular m-chloroperbenzoic acid, in an aprotonic solvent such as methylene chloride. -30 ° C and 50 ° C, especially at room temperature; furthermore, the above-mentioned alkenes can be converted to the corresponding epoxides by Sharpless epoxidation (Sharpless K. B., Org. Syntheses, vol 63, 66 (1985)).

The reaction of the organometallic compounds shown in Scheme 3 is generally a Grignard reaction which is carried out according to literature procedures. Optionally, however, the magnesium reagent of formula XXI can be converted to a lithium or titanium reagent before reacting with a carbonyl compound of formula VII (Reetz M.T. Chem. Ber. 118, 1421 (1985)).

The conversion of the amino alcohol of formula III into the oxazolidinone of formula II proceeds according to methods known in the literature by reacting the amino alcohol of formula III with diethyl carbonate (Evans DA, Org. Syntheses, vol. 68, 77 (1989)) or carbonyldiimidazole (Chadwick DI, J. Chem. Perkin Trans. 481 (1984); Geffken D.Arch. Pharm. 313, 817 (1980)) or with phosgene (Newman WS, J. Am. Chem. Soc. 73, 4199 (1951)) or with diphosgene or triphosgene (Hassner A., Synth. Commun. 23, 2839 (1993)) or with methyl, ethyl or benzyl chloroformate (Kanoshinzo, J. Org. Chem. 53, 3865 (1988)) in a solvent such as methylene chloride, dimethylformamide , toluene, dioxane, tetrahydrofuran, water or diethyl ether, in particular dimethylformamide, methylene chloride or tetrahydrofuran, and at a temperature between -50 ° C and 80 ° C, especially at room temperature.

Catalytic hydrogenation of a compound of formula XXVII is carried out in a solvent such as methanol or ethanol with the addition of a catalyst such as ruthenium oxide, rhodium oxide or a mixture of palladium and strontium carbonate, especially rhodium carbonate, in a hydrogen atmosphere at 1-200 bar =. 10 ⁵ Pa), in particular at a pressure of 200 bar and at a temperature between room temperature and 200 DEG C. (Rastin RH, J. Chem. Soc. 1855 (1949)).

The epoxide opening of the epoxide of formula V with an amine of formula IV is generally carried out in a solvent such as methanol, ethanol, dimethylformamide or toluene, in particular ethanol or toluene, and at a temperature between 0 ° C and 120 ° C, especially at 80 ° C.

The epoxide opening of an epoxide of formula V with a metal azide is carried out according to methods known in the literature by reacting an epoxide of formula V with a metal azide such as lithium azide, sodium azide, potassium azide, tributylstaniumazide or magnesium azide, especially sodium azide in a solvent such as methanol, ethanol 1,4-dioxane. water, dimethylformamide, tetrahydrofuran, acetonitrile or hexamethylphosphoric triamide, or mixtures thereof, but preferably in mixtures of water and methanol, dimethylformamide or 1,4-dioxane and at a reaction temperature between -10 ° C and 120 ° C, in particular 80 ° C ( Vanderverf CA, J. Am. Chem. Soc., 7, 1231 (1954), Saito S., Tetrahedron Lett., 30, 4153 (1989); Hudlicky, T., J. Chem., Soc., Perkin Trans. 1991)). The reaction of the epoxide of the formula V with trimethylsilyl azide is generally carried out in a solvent such as methanol, tetrahydrofuran, methylene chloride, chloroform, dichloroethane or benzene, in particular tetrahydrofuran or methylene chloride, without further additives or using additives such as titanium (IV) isopropanol, diethylaluminium fluoride, especially titanium (IV) isopropyl alcohol or aluminum isopropyl alcohol, and at a temperature between 0 and 100 ° C, preferably at room temperature (Emziane M., Synthesis, 541 (1988); Saito S., Tetrahedron Lett. 26, 5309 (1985) Blandy C., Tetrahedron Lett., 24, 4189 (1983), Jung ME, J. Org.

Chem. 56, 2614 (1991)).

The conversion of an azide of formula XXIX to an amine of formula XXX is carried out according to known methods; Suami T. Bull.Chem.Soc.Jpn., 51, 855 (1978); Boullanger P., Bull.Soc.Chim.Fr., S. 2149 (1973); Ackerman K. Can. J. Chem. 50, 3886 (1972); Hanessian S., Chem. Ind., S. 1296 (1965); Homer L., Liebigs Ann.Chem., 591, 117 (1955); Koziar A. Synthesis, S. 487 (1987); Vogel E., Ang. Chem. Int. Ed. Engl., 18, 962 (1979); Purwono, B., Synlett, 3, 231 (1992).

The compounds of formula I contain one or more chiral centers and therefore may exist in racemic or optically active form. Racemates can be separated into enantiomers mechanically or chemically according to methods known per se. Of the racemic mixtures, by reaction with an optically active acid such as the D- and L-form of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid,

Even malic acids, lactic acid, or the various optically active camphorsulfonic acids, such as β-camphorsulfonic acid, are mainly diastereomers.

Naturally, it is also possible to obtain optically active compounds of the formula I according to the methods described above by using starting materials (e.g., formula II) which are already optically active.

The pharmacologically tolerable salts used are, in particular, alkali metal salts, ammonium salts, trifluoroacetates or hydrochlorides which are prepared in the customary manner, for example by titrating compounds with inorganic or organic bases or acids, such as sodium or potassium bicarbonate, sodium hydroxide, potassium hydroxide, aqueous ammonia solution or amines such as trimethylamine or triethylamine, trifluoroacetic acid or hydrochloric acid. The salts are generally purified by precipitation from a mixture of water and acetone.

The novel compounds of the formula I according to the invention and their salts can be administered in liquid or solid form enterally or parenterally. All conventional dosage forms, for example tablets, capsules, dragees, syrups, solutions, suspensions, etc. are suitable for this purpose. In particular, water is used as the injection medium, which contains additives customary for injection solutions, such as stabilizers, solubilizers and buffers.

Such viscosity control additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and non-toxic salts thereof), high molecular weight polymers (such as liquid polyethylene oxide). Liquid carriers for injectable solutions must be sterile and filled, in particular, into ampoules. Solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, high disperse silicas, higher fatty acids (such as stearic acid), gelatin, agar-agar, and phosphate better. 21 magnesium, stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); compositions suitable for oral administration may optionally contain flavoring and sweetening agents.

The dosage may depend on a variety of factors such as the mode of administration, sex, age and / or individual condition. The daily doses to be administered are about 101000 mg / human, in particular about 100-500 mg / human, and can be taken at once or in divided doses.

Preferred compounds within the meaning of the present invention, in addition to those exemplified in the examples, and compounds which can be derived by combining all of the meanings of the substituents mentioned hereinabove, are the following pyridine or pyridazine derivatives:

1) 1- {2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] ethyl} piperidine- 4-carboxylic acid

2) 1- {3- [2- [3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] propyl} piperidine- 4-carboxylic acid

3) 1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyl} piperidine- 4-carboxylic acid

4) 1- {5- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] pentyl} piperidine- 4-carboxylic acid

5) 1- [2-oxo-5-phenyl-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidin-4 carboxylic acid

6) 1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-carbonyl] piperidine-4-carboxylic acid

7) 1- {2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] acetyl} piperidin-4 carboxylic acid

8) 1- {5- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -pentanoyl] -piperidine-4- carboxylic acid

9) 1- [2-oxo-3- (4-pyridin-4-yl-piperazin-1-yl) -oxazol-5-ylmethyl] -4-piperidine-4-carboxylic acid

10) {1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidin-3-yl] -acetic acid

11) (1- {2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] ethyl} piperidine acid 3-yl} acetic acid

12) {1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidin-3-yl} -acid acid

13) (1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyryl [piperidine] 3-y1) acetic acid

14) (3-Hydroxy-1- {5- [2- ΟΧΟ-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -pentanoyl acid [piperidine-3-yl) acetic acid

15) (3-Hydroxy-1- {2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -acetyl acid [piperidine-3-yl) acetic acid

16) [3-hydroxy-1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidin-3-yl acid } -acetic acid

17) [3-hydroxy-1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine- 3-yl} acetic acid

18) (3-Hydroxy-1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyl) [piperidine-3-yl) acetic acid

19) {1- [2-oxo-4-phenyl-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidin-4-yl acid } -acetic acid

20) {4-Hydroxy-1- [2-oxo-5-phenyl-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5- acid] carbonyl] -piperidin-4-yl [acid

21) {1- [4-Methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidin-4-yl acid } -acetic acid

22) {1- [4-Methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidin-3-yl acid [acetic acid

23) {3-Hydroxy-1- [5-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5- acid] carbonyl] piperidin-3-yl [acetic

24) 1- [2-oxo-5-phenyl-3- (3,4,5,6-tetrahydro-2H [1,4 '] bipyridinyl-4-yl) oxazolidine-5-carbonyl] piperidine-4-carboxylic acid

25.) (1- {2- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] ethyl} acid) piperidin-4-yl) acetic acid

26) (1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyl} piperidine 4-yl) O-tetraacetic

27) (4-Hydroxy-1- {2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] ethyl) } -piperidin-4-yl) acetic acid

28) (4-Hydroxy-1- {5- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -pentyl acid } -piperidin-4-yl) acetic acid

29) 11- [2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -acetyl} -piperidine- 4-yl) acetic acid

30) (1- {5- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] pentanoyl} piperidine acid 4-yl) acetic acid

31) (4-Hydroxy-1- {2- [2-oxo-3- (3,4,5,6-tetrahydro-2H-] 1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -acetyl] -piperidine 4-yl) acetic acid

32) (4-Hydroxy-1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyryl acid } -piperidin-4-yl) acetic acid

33) {1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] piperidin-4-yl] acetic acid

34) [4-hydroxy-1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidin-4-yl} -acetic acid acid

35) 1 '{2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) oxazolidin-5-yl] ethyl} piperidin-3 -carboxylic

36) 1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyl} piperidine- 3-carboxylic acid

37) 1 '[2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) oxazolidine-5-carbonyl] piperidine-3-carboxylic acid

38) 1- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyryl} piperidine- 3-carboxylic acid

39) 1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine-2-carboxylic acid

40) 1 '{5- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridin-4-yl) -oxazolidin-5-yl] -pentyl} -piperidine-2-carboxylic acid

41) 1 '{4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) oxazolidin-5-yl] butyryl} piperidin-2 carboxylic acid

42) 1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidine-5-carbonyl] piperidine-2-carboxylic acid

43) 1- {2- [5-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -ethyl acid } piperidine-2-carboxylic

44) 1- [5- [4-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -pentyl acid } piperidine-2-carboxylic

45) 1- {4- [5-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyryl acid } piperidine-2-carboxylic

46) 1- [5- [4-Methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -pentanoyl acid [piperidine-2-carboxylic acid

47) 1- [2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid

48) 1- [2-oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) -oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid

49) 1- [2-oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) -oxazolidine-5-carbonyl] -piperidine-4-carboxylic acid

50) 1- [2-oxo-3- (4-pyridin-4-yl-piperazin-1-yl) -oxazolidine-5-carbonyl] -piperidine-4-carboxylic acid

51) 1- [2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidine-5-carbonyl] -piperidine-4-carboxylic acid

52) {1- [2-oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) -oxazolidin-5-ylmethyl] -piperidin-4-yl [acetic acid

53) {4-hydroxy-1- [2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidin-5-yl] -piperidin-4-yl} -acetic acid

54) 1- {3- [2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidin-5-yl] -propyl} -piperidine-4-carboxylic acid

55) 1- [3- [4-Methyl-2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidin-5-yl] -propionyl} -piperidine-4-carboxylic acid

56) 1- [4-Methyl-2-oxo-3- (4-pyridin-4-yl-piperazin-1-yl) -oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid

57) (Butane-1-sulfonylamino) - {1- [4-methyl-2-oxo-3 (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidine] -5ylmetyl] -piperidin-4-ylJoctová

58) (Butane-1-sulfonylamino) - (1- {3- [2-oxo-3 (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidine- 5-yl] propyl} piperidin-4-yl} acetic acid

59) (Butane-1-sulfonylamino) - {1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidine-5-carbonyl-piperidine 4-yl [acid

60) 4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '[bipyridinyl-4-yl) oxazolidin-5-yl] cyclohexanecarboxylic acid

61) 4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -cyclohexanecarboxylic acid

62) 4- {3- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -propyl} -cyclohexanecarboxylic acid

63) 3- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] cyclohexanecarboxylic acid

64) 4-hydroxy-4- {3- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] propyl acid [cyclohexane

65) [4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -cyclohexyl-acetic acid

66) (4-Hydroxy-4- {3- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl) -acid ] propyl [cyclohexyl [-acetic

67) {1,4-dihydroxy-4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -cyclohexyl [ acid

68) 3- [2- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-yl] -ethyl [cyclohexanecarboxylic acid

69) 2- {4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-yl] butyl} cyclohexanecarboxy- Lova

70) 4- [4-Methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl [cyclohexanecarboxylic acid]

71) 4- [2-Oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) -oxazolidin-5-ylmethyl] -cyclohexanecarboxylic acid

72) 4- [2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidin-5-ylmethyl] -cyclohexanecarboxylic acid

73) (Butane-1'-sulfonylamino) - {4- [4,5-dimethyl-2-oxo-3- (4-pyridazin-4-yl-piperazin-1-yl) -oxazolidin-5-ylmethyl] -1-hydroxy-cyclohexyl} -acetic acid

74) 1 '[2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) -4- (3,4,5-trimethoxyphenyl) acid] oxazolidine-5-carbonyl] piperidine-4-carboxylic acid, m.p. Mp 108-114 ° C

75) 1 '- [4- (3,4-dimethoxyphenyl) -2-oxo- (3,4,5,6-tetrahydro-2 H- [1,4'] bipyridinyl-4-yl) oxazolidin-5- carbonyl] piperidine-4-carboxylic acid, m.p. 118 ° C

76) 1 '[4- (4-cyanophenyl) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) oxazolidine-5-carbonyl] piperidine-4-carboxylic acid, m.p. Mp 100-105 ° C

77) 1 '[4-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H-[1,4'] bipyridinyl-4-yl) oxazolidine-5-carbonyl] piperidine-4-carboxylic acid, m.p. Mp 73-75 ° C

78) (5S) -1- [5-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5- ylmethyl] piperidine-4-carboxylic acid, m.p. 223 ° C (decomposition)

79) 1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -4- (3-trifluoromethylphenyl) oxazolidin-5-ylmethyl] acid piperidine-4-carboxylic acid, m.p. 125-130 ’C

80) 1 '[4- (4-chlorophenyl) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid, mp 110-115 ° C

81) 1- [4- (4-Isopropyl-phenyl) -2-oxo-3- (3,4,5,6-tetrahydro-2 H- [1,4 '] bipyridinyl-4-yl) -oxazolidine- 5-ylmethyl] -piperidine-4-carboxylic acid

82) 1 '- [4- (4-tert-butylphenyl) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'] bipyridinyl-4-yl) oxazolidin-5- ylmethyl] -piperidine-4-carboxylic acid

83) 1- {3- [1- (2-Amino-pyrimidin-4-yl) -piperidin-4-yl] -oxooxazolidin-5-ylmethyl-piperidine-4-carboxylic acid

84) 1- {2-Oxo-3- [1- (2-piperidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -oxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid

85) 1- {2-oxo-3- [1- (2-phenylamino-pyrimidin-4-yl) -piperidin-4-yl] -oxazolidin-5-ylmethyl-piperidine-4-carboxylic acid

86) 1- (2-Oxo-3- {1- [2- (pyrimidin-2-ylamino) pyrimidin-4-yl] piperidin-4-yl} oxazolidin-5-ylmethyl) piperidine-4-carboxylic acid

87) 1- {3- [1- (2-Amino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-hexahydrobenzooxazol-7a-ylmethyl} -piperidine-4-carboxylic acid

88) 1- {3- [1- (2-Benzylaminopyrimidin-4-yl) piperidin-4-yl] -2-oxohexahydrocyclopentaoxazol-6a-ylmethylpiperidine-4-carboxylic acid

I

89) 1- {3- [1- (2-guanidinopyrimidin-4-yl) piperidin-4-yl] -2-oxooxazolidin-5-ylmethyl} piperidine-4-carboxylic acid

90) 1- {3- [1- (2-acetimidoylaminopyrimidin-4-yl) piperidin-4-yl] -2-oxooxazolidin-5-ylmethyl} piperidine-4-carboxylic acid

91) 1- {3- [1- (2-Amino-pyrimidin-4-yl) -piperidin-4-yl] -ethyl-2-oxooxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid

92) 1- [4-ethyl-2-oxo-3- (3,4,5,6-tetrahydro-2H-[1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidin-4 acid carboxylic acid

93) 1- [4-butyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl] oxazolidin-5-ylmethyl) piperidine-4-carboxylic acid

94) 1- [2-oxo-4-pentyl-3- (3,4,5,6-tetrahydro-2H [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine- 4-carboxylic acid

95) 1- [4-hexyl-2-oxo-3- (3,4,5,6-tetrahydro-2H-[1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid

96) 1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -4- (2-p-tolylethyl) oxazolidin-5-yl] acid ylmethyl] -piperidine-4-carboxylic acid

97) 1- {3- [1- (2-Benzylaminopyrimidin-4-yl) piperidin-4-yl] -4-butyl-2-oxooxazolidin-5-ylmethyl} piperidine-4-carboxylic acid

The following examples represent several process variants that can be used to synthesize the compounds of the invention. However, they should not constitute a limitation of the invention. The structure of the compounds was determined by and optionally ¹³ C-NMR spectroscopy as well as mass spectrometry. The purity of the substances was determined by C, H, N as well as thin layer chromatography.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

1 - [(5S) -2-oxo-3- (3,4,5,6-tetrahydro-2H-1,4'-bipyridinyl-4-yl) oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid

a) A solution of 46 g (0.4 mol) of 4-chloropyridine and 123.5 g of ε (0.86 mol) of 4-piperidone-ethyl-talc was heated in refluxing 400 ml of p-xylene for 48 h. The reaction mixture was cooled, the precipitated precipitate was filtered off, the crystallization solution was concentrated to dryness and the residue was purified by silica gel column chromatography (ethyl acetate-saturated, ammonia alkaline methanol 9: 1). 79.7 g (90%) of 8-pyridin-4-yl-1,4-dioxa-8-azaspiro [4,6] decane are obtained as a white powder, m / e = 220; mp 68 ° C.

b) A solution of 79.7 g of the ketal prepared in a) in 2 L of tetrahydrofuran is treated with 1 L of 6N hydrochloric acid and the reaction mixture is stirred at room temperature for 2 h. Immediately afterwards, the tetrahydrofuran is removed by rotary evaporation in vacuo, the hydrochloric acid solution is basified with a half-concentrated 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 sucking off the solvent, the residue is purified by chromatography on a silica gel column. 64.2 g (100% yield) of 2,3,5,6-tetrahydro- [1,4 '] bipyridinyl-4-one are obtained in the form of a gray powder, m / e = 176;

1.1. = 102 ° C.

c) A solution of 32 g of the ketone obtained in b) and 19.9 ml of benzylamine in 400 ml of methylene chloride is mixed portionwise with 50.4 g of sodium triacetate borohydride under ice-cooling. Then, 12 ml of 100% acetic acid is added dropwise, the reaction mixture is then allowed to stir at room temperature for 4 hours and then mixed with 100 ml of water. After phase separation, the pH of the aqueous phase is adjusted to 12 with 2N sodium hydroxide and extracted five times with 50 ml of methylene chloride each time. After drying the combined organic extracts with sodium sulfate and removing the solvent in a rotary evaporator, the benzyl- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -amine thus obtained is extracted in 100 ml of methanol. and the solution is mixed with 3.5 g of a 10% palladium-carbon mixture. Then the methanolic mixture is hydrogenated

at room temperature until hydrogen uptake ceased (30 h), then the catalyst was filtered off and concentrated in a rotary evaporator. In this way, 22 g of 3,4,5,6-tetrahydro-2H [1,4'-bipyridinyl-4-ylamine is obtained in the form of a pale yellow, thick oil which gradually crystallizes, m / e = 177; ¹ H-NMR (d ⁶ -DMSO): δ '= 8.10 ppm (d, 2H); 6.85 ppm (d, 2H); 3.80 ppm (d with fine resolution, 2H): 2.85 ppm (with fine resolution, 2H); 2.70 ppm (m, 1 H); 1.70 ppm (d with fine resolution, 2H); 1.20 ppm (q with fine resolution, 2H); 1.1. = ° C.

d) A mixture of 5.7 g of (2R) -glycidyltosylate (Fluka, GmbH), 4 ml of piperidine-4-carboxylic acid ethyl ester and 3.5 g of potassium carbonate in 100 ml of acetonitrile was heated at reflux for 2 h. After cooling, the reaction mixture is mixed with 50 ml of water and extracted three times with 50 ml of methylene chloride and 50 ml of diethyl ether each time. After drying the combined organic phases with sodium sulfate and sucking off the solvent in a rotary evaporator, the residue is purified by silica gel column chromatography (ethyl acetate-saturated methanolic solution of ammonia 95):

5). 2.5 g of (2S) -1-oxiran-2-ylmethyl-piperidine-4-carboxylic acid ethyl ester are obtained.

@ 1 H-NMR (d6 -DMSO): ^.delta . = 4.05 ppm (q, 2H); 3.00 (m, IH); 2.95 (bdd, 1H); 2.85 (broad t-1H); 2.70 (q, 1 H); 2.62 (dd, 1H); 2.45 (dd, 1H); 2.30 (m, IH); 2.15 (dd, 1H); 2.02 (m. 2H); 1.75 (broad d, 2H); 1.52 (Sextet 2H); 1.15 (t. 3H).

e) A solution of 0.43 g of the amine prepared in c) and 0.173 g of oxoxane prepared in d) in 10 ml of ethanol was heated under reflux for 48 h. The ethanol is then filtered off under vacuum and the residue is purified on silica gel by column chromatography (acetic acid-saturated, 85: 15 methanolic ammonia solution). The product thus obtained (325 mg) is absorbed in 2 ml of dimethylformamide, the solution is mixed with 200 mg of carbonyldiimidazole and the reaction mixture is stirred at room temperature for 15 h. The reaction mixture is then treated with 10 ml of water and shaken three times with 10 ml of methylene chloride each time. After drying the combined organic phases with sodium sulfate and removing the solvent in vacuo, the residue is purified by preparative HPLC (RP 18, methanol buffer (pH = 7.5) 7: 3). 235 mg of 1 - [(5S) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -oxazolidin-5-yl] ethyl ester were obtained. ylmethyl] -piperidine-4-carboxylic acid.

m / e = 416; ¹ H-NMR (d ⁶ -DMSO): δ = 8.12 ppm (d, 2H); 6.82 (d. 2H); 4.60 (q, IH);

4.05 (q. 2H); 3.99 (broad d, 2H); 3.75 (m, IH); 3.50 (t, 1 H); 3.15 (t, 1 H);

2.90 (broad t, 2H); 2.75 (m, 2H); 2.50 (m. 2H); 2.25 (m. 1H); 2.10 (m, 2H); 1.801.40 (m. 8H); 1.12 (t. 3H).

f) A solution of 230 mg of the ethyl ester prepared in 1) in 2 ml of tetrahydrofuran and 1 ml of water was mixed with 0.7 ml of 1N sodium hydroxide and stirred for 1 hour at room temperature. Immediately thereafter, the tetrahydrofuran is suctioned off in vacuo and the product is purified by ion exchange (Dowex 50, H-form). This gives 120 mg of the title compound as a white powder. FAB = 388; H-NMR (d ⁶ -DMSO): δ = 8.15 ppm (d, 2H); 6.82 (d. 2H); 4.60 (m, IH); 4.02 (broad d, 2H); 3.75 (m, IH); 3.50 (t, 1 H); 3.15 (dd, IH); 2.95 (broad, d, 2H); 2.80 (m. 2H); 2.52 (m. 2H); 2.10 (m. 3H); 1.80-1.40 (m, 8H).

Example 2

1 - [(rac) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine-4 acid carboxylic acid

a) A mixture of 3.1 g of piperidine-4-carboxylic acid ethyl ester, 6.4 ml of epichlorohydrin and 0.1 g of tetrabutylammonium bromide in 15 ml of concentrated sodium hydroxide solution is stirred at room temperature for 4 hours and then mixed with 50 ml of water. The organic phase is separated, the aqueous phase is shaken three times with 20 ml of methylene chloride each time, the combined organic phases are dried over sodium sulphate and the solvent is removed in vacuo. 2.1 g of (rac) -1-oxiran-2-ylmethyl-piperidine-4-carboxylic acid ethyl ester are obtained.

m / e = 213.1.

b) As in Example 1e), 520 mg of 1 - [(rac) -2-oxo-3- (ethyl) ester was obtained from 2.1 g of epoxide 2a), 2.6 g of amine 1c) and 0.4 g of carbonyldiimidazole. 3,4,5,6-tetrahydro-2H-1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid. m / e = 416.

c) As in Example 1f), 190 mg of the title compound are obtained from 520 mg of ethyl ester 2b) and 1.5 ml of 1 N sodium hydroxide solution. FAB: 388, ¹ H-NMR (d ⁶ -DMSO): identical to ¹ H-NMR of compound 1f).

Example 3

{1 - [. (Rac) -2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine-4 acid ylidene} acetic

a) As in Example 2a), 1.6 g of 8-oxiran-2-ylmethyl-1,4-dioxa-8 is obtained from 1.43 g of 4-piperidone ethylene ketal, 3.1 ml of epichlorohydrin and 0.2 g of tetrabutyl ammonium bromide. -aspiro [4,5] decane in the form of a yellow oil.

@ 1 H-NMR (d6 -DMSO): ^.delta . = 3.85 ppm (s, 4H); 3.0 (m, 1H); 2.70 (dt, 2H);

2.60 (d, IH); 2.50 (m. 3H); 2.40 (m, IH); 2.20 (dd, 1H); 1.60 (t, 4 H).

(b) As in Example 1e), 0.35 g of 5 (1,4-dioxa-8-azaspiro [4]) was obtained from 1.6 g of epoxide 3a), 1.9 g of amine 1c) and 0.4 g of carbonyldimidazole. 5] dec-8-ylmethyl) -3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -oxazolidin-2-one.

m / e = 402; H-NMR ^(d6-DMSO): 5 = 8.15 ppm (d, 2H); 6.82 (d, 2H); 4.60 (m, IH); 4.0 (broad d, 2H); 3.85 (s. 4H); 3.75 (m, IH); 3.52 (t, 1 H); 3.15 (t, 1 H);

2.90 (broad t, 2H); 2.55 (m. 6H); 1.60 (m, 8H).

c) In a similar manner to Example 1b), 1.1 g of 1- [2-oxo-3 (3,4,5,6-tetrahydro-2H-f1) were obtained from 1.2 g of ketal 3b) and 10 ml of 6N hydrochloric acid. 4 '(Bipyridinyl-4-yl) -oxazolidin-5-ylmethyl-piperidin-4-one as a gray powder.

m / e = 358; ¹ H-NMR (CDCl ₃ ): δ = 8.20 ppm (d, 2H); 6.55 (d. 2H); 4.65 (m, IH); 3.95 (m. 3H); 3.50 (t, 1 H); 3.20 (t, IH); 2.85 (m, 7 H); 2.65 (dd, IH); 2.45 (t, 4 H); 1.80 (m. 2H); 1.65 (dq, 2 H).

d) A mixture of 840 mg of ketone 3c) and 820 mg of ethoxycarbonylethylidene triphenylphosphorane (Aldrid GmbH & Co.) in 15 ml of toluene was heated at 100 ° C for 24 h. Thereafter, the toluene was evaporated in vacuo and the crude product was purified on silica gel (ethyl acetate saturated with ammonia methanol solution 85: 15). 820 mg of {1-f (rac) -2-oxo-3- (3,4,5,6-tetrahydro-2H-1,1,4-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine4 ethyl ester are obtained. ylidene} acetate.

m / e 428.

(e) As in Example 1f), 48 mg of the title compound is obtained as a white powder from 210 mg of ethyl ester 3d) and 0.6 ml of 1 N sodium hydroxide solution. FAB; 400; @ 1 H-NMR (d, DMSO): .delta. = 8.15 ppm (d, 2H); 6.80 (d, 2 H); 5.60 (s, 1 H); 4.65 (m, IH); 4.05 (broad d, 2H); 3.75 (m, IH); 3.60 (t, IH); 3.20 (t, IH); 2.88 (m, 4 H); 2.55 m

6H); 2.20 (m. 2H); 1.65 (m, 4 H).

Example 4 (

{1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidin-4-yl} - -acetic

a) A solution of 560 mg of 3d) in 20 ml of methanol was treated with 50 mg of a palladium-carbon (10%) mixture and hydrogenated at room temperature and normal pressure until hydrogen uptake ceased. Then the catalyst is filtered off and the solution is evaporated to dryness. 400 mg of {1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] - ethyl ester are thus obtained. piperidin-4-yl} -acetic acid as a colorless oil.

m / e = 430.

b) As in Example 1f), 180 mg of the title compound as a light gray powder was obtained from 400 mg of ethyl ester 4a) and 1.1 ml of 1 N sodium hydroxide solution. FAB = 402; H-NMR (d ⁶ -DMSO): δ = 8.15 ppm (d, 2H); 6.80 (d, 2H); 4.60 (m, IH);

4.05 (broad d, 2H); 3.75 (m, IH); 3.50 (t, 1 H); 3.12 (t, 1 H); 2.85 (m, 4 H); 2.48 m

2H); 2.0 (m, 4 H); 1.65 (m. 7H); 1.12 (m, 2H).

Example 5

{4-Hydroxy-1- 1,2-oxo-3- (3,4,5,6-tetrahydro-2H-1,1,4,4'-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidin-4 acid yl} acetic acid

a) 0.5 ml of diisopropylamine was mixed with 2.3 ml of n-butyllithium (1.6M in n-hexane) under nitrogen at -10 ° C. The mixture was stirred at -10 ° C for 10 min, then cooled to -78 ° C and 10 mL of dry tetrahydrofuran was added. To the thus prepared solution of lithium diisopropylamide was added dropwise 0.45 ml of tert-butyl acetate in 2 ml of dry tetrahydrofuran, the reaction mixture was then allowed to stir for 30 min at -78 ° C, mixed with a solution of 1.1 g of ketone 3c) in 10 ml. ml of dry tetrahydrofuran, allowed to stir for 1 h at -78 ° C and then warmed slowly to room temperature. The reaction mixture is stirred for 15 hours at room temperature and then treated with 10 ml of saturated ammonium chloride solution. After extraction of the aqueous solution three times with 10 ml of methylene chloride each time, drying of the combined organic phases with sodium sulfate and removal of the solvent by rotary evaporation, the crude product is purified by preparative HPLC (Select B / methanol-buffer (pH 7.5) 6): 4). There was obtained 0.85 g of {4-hydroxy-1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- (R 1,4,4)] bipyridinyl-4-yl) tert-butyl ester. -oxazolidin-5-ylmethyl} -piperidin-4-yl} -acetic acid as a yellow oil.

m / e = 474.

b) A solution of 100 mg of tert-butyl ester 5a) in 2 ml of trifluoroacetic acid is stirred for 5 h at room temperature. Thereafter, the reaction mixture is evaporated to dryness, the residue is extracted with 3 ml of water and the product is purified by means of an ion exchanger (Dowex 50, H-form). This gives 30 mg of the title compound as a white powder.

H-NMR (d ⁶ -DMSO): δ = 8.15 ppm (d, 2H); 6.85 (d. 2H); 4.60 (m, IH);

4.05 (broad d, 2H); 3.75 (m, IH); 3.52 (t, 1 H); 3.15 (t, 1 H); 2.92 (t, 2 H); 2.48 m

6H); 2.25 (s. 2H); 1.60 (m, 8H).

Example 6

1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine-3-carboxylic acid

a) Similar to Example 1e) from 2.7 g of 1-oxiran-2-ylmethylpiperidine-3-carboxylic acid ethyl ester (prepared from epichlorohydrin and piperidine-3-carboxylic acid ethyl ester similar to Example 2a), 3.2 g of amine 1c) and 260 mg of carbonyldiimidazole gave 550 mg of 1- [2-ΟΧΟ-3- (3,4,5,6-tetrahydro-2H- [1,4-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] ethyl ester 1-piperidine-3-carboxylic acid in the form of a mixture of diastereomers m / e = 416.

(b) As in Example 1f), 300 mg of the title compound was obtained as a light gray powder from 550 mg of ethyl ester 6a) and 1.5 ml of 1 N sodium hydroxide solution. m / e = 388; 1 H-NMR (d ⁶ -DMSO): mixture of diastereomers δ = 8.15 ppm (d, 2H);

6.85 (d. 2H); 4.60 (m. 2H); 4.02 (breites d, 2 H); 3.72 (m, IH); 3.50 (t, 1 H); 3.15 (t, 1 H); 2.90 (breites t, 3 H); 2.65 (m, IH); 2.50 (m. 2H); 2.30-1.95 (m. 3H); 1.80-1.50 (m. 6H); 1.45-1.20 (m, 2H).

Example 7

1- [4-Methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -piperidine-4- acid carboxylic acid

a) As in Example 1d), 13.9 ml of piperidine acid ethyl ester was prepared from 20.3 g of (rac) -trans 2- (p-toluenesulfonyloxymethyl) -3-methyloxirane (Evans RD, Synthesis, p. 862 (1988)). After stirring for 12 hours at room temperature, 14.7 g of ethyl 1- (3-methyloxiranylmethyl) -piperidine-4-carboxylic acid ethyl ester is obtained as a yellowish oil. H-NMR (d ^f -DMSO): δ = 8.4 ppm (q, 2H); 2.99 (dt, 1H); 2.90-2.65 (m, 3H); 2.55 (dd, IH); 2.32-2. 12 (m, 2H); 2.10-1.95 (m. 2H); 1.90-1.62 (m. 4H); 1.21 (d. 3H);

1.18 (t, 3 H). ·,

b) A solution of 2.5 g of the epoxide prepared in 7a), 1.0 g of sodium azide and 0.810 g of ammonium chloride in 25 ml of ethanol (80: 20) was heated at 50 ° C for 24 h. The ethanol is then filtered off under vacuum, 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 sucking off the solvent in a rotary evaporator, the crude product is chromatographed on silica gel (ethyl acetate: isohexane 3: 1). 1.4 g of 1- (3-azido-2-hydroxybutyl) -piperidine-4-carboxylic acid ethyl ester is obtained.

H-NMR _(CDC1?): Δ = 5.4 ppm (q. 2H); 3.48 (m, 1H); 2.40 (m, IH); 2.77-2.57 m

2H); 2.48 (d, 1H); 2.35-2.08 (m. 4H); 2.02-1.55 (m, 5H); 1.20 (d and t, 5H).

c) A solution of 1.4 g of the azide prepared in 7b) in 20 ml of ethanol is treated with 0.5 g of a palladium-carbon (10%) mixture and the mixture is hydrogenated for 8 hours at room temperature. The catalyst is then filtered off and the solution is concentrated in a rotary evaporator. 1.1 g of 1- (3-amino-2-hydroxybutyl) -piperidine-4-carboxylic acid ethyl ester are obtained.

d) A solution of 1.0 g of amine 7c), 0.721 g of ketone 1b) and 1.1 g of sodium triacetate borohydride in 15 ml of methylene chloride is stirred for 15 hours at room temperature. The reaction mixture was then treated with 10 ml of water and acidified with 1N hydrochloric acid. After phase separation, the aqueous phase is extracted once more with 10 ml of methylene chloride and then basified with 1N sodium hydroxide solution. After extraction of the alkaline mixture three times with 15 ml of methylene chloride each time and drying of the combined organic phases with sodium sulfate, the solvent is removed by rotary evaporation. The crude product is then purified by preparative HPLC (RP 18, methanol-buffer (pH = 7.5) 70:30). 0.5 g of ethyl 1- [2-hydroxy-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-ylamino) butyl] ethyl ester is obtained. -piperidine-4-carboxylic.

Δ H-NMR (CDCl 3): δ = 8.15 ppm (d, 2H); 6.60 (d, 2 H); 4.05 (q. 2H); 3.78 (t, 1 H);

3.72 (t, IH); 3.58 (m, IH); 2.97-2.70 (m. 5H); 2.40-2.25 (m, 4H), 2.06-1.60 (m,

7 H); 1.38-1. 10 (m, 3H); 2.20 (t. 3H); 0.98 (d, 3H).

e) A solution of 0.5 g of amino alcohol 7d) and 243 mg of carbonyldiimidazole in 5 ml of dimethylformamide is stirred at room temperature for 24 h. The reaction solution was then evaporated to dryness and the residue was purified by preparative HPLC (Merck, Select B, methanol-buffer (pH = 7.5) 65:35). There was thus obtained 1- [4-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4,3-bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] ethyl ester (0.26 g). ! -piperidine-4-carboxylic acid.

m / e = 430.

f) A solution of 0.26 g of ethyl ester 7e) and 0.72 ml of 1N sodium hydroxide solution in 5 ml of methanol is stirred for 1 hour at room temperature. The methanol was then evaporated in vacuo and the product purified by ion exchange (Dowex 50, H-form). This afforded 0.11 g of the title compound as a white powder.

Fp. &Gt; 220 ° C. FAB = 402. 1 H-NMR (d ⁶ -DMSO): δ = 8.15 ppm (d, 2H); 6.80 (d,

2H); 4.55 (q. 1H); 3.98 (m. 3H); 3.55 (m, IH); 2.82 (m, 4 H); 2.50 (m, 8 lines,

1H); 2.0 (m, 4 H); 1.75 (m, 6 H); 1.50 (breites q, 2 H); 1.09 (d. 3H).

Example 8

1- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-4-yl) -oxazolidin-5-methyl] -piperidine-4-carboxylic acid

a) To a solution of 16 ml of 4-piperidone ethylene ketal and 17.5 ml of triethylamine in 100 ml of ethanol is added dropwise a solution of 18.5 g of 2,4-dichloropyrimidine in 150 ml of ethanol under ice-cooling. The reaction mixture is stirred for a further 2.5 hours, the ethanol is evaporated off under vacuum, the residue is treated with 100 ml of water and the aqueous mixture is extracted three times with 50 ml of methylene chloride each time. After drying the combined organic phases with sodium sulfate and filtering off the solvent, the solid residue is recrystallized from ethyl acetate-isohexane. 11 g of 8- (2-chloropyrimidin-4-yl) -1,4-dioxa-8-azaspiro [4.5] decane are obtained in the form of a white powder. MP: 135-137 C. C.

(b) 6 g of 2-chloropyrimidine 8a) are dissolved in 60 ml of methanol and 20 ml of tetrahydrofuran and, after addition of 4.2 g of potassium carbonate and 1 g of 10% palladium-carbon, hydrogenated for 6 hours at room temperature and 44 mbar (1 bar) = 10 ⁵ Pa). Thereafter, the reaction mixture is filtered, the filtrate is evaporated to dryness, the residue is extracted with 20 ml of water and the aqueous mixture is extracted three times with 20 ml of methylene chloride each time. After drying the combined organic phases with sodium sulfate and filtering off the solvent, 4.9 g of 8-pyrimidin-4-yl-1,4-dioxa-8-azaspiro 4,5 decane is obtained in the form of a white powder, m / e ⁼ 221.

c) As in Example 1b), 3.9 g of 1-pyrimidin-4-yl-piperidin-4-one is obtained as a yellow powder from 4.9 g of ketal 8b) and 60 ml of 6N hydrochloric acid in 60 ml of tetrahydrofuran after 55 hours of reaction time. . MP: 75 - 80 C. C.

d) From 8 g of epoxide 2a), 3.8 g of sodium azide and 3.2 g of ammonium chloride in 100 ml of methanol-water (8: 1), similar to Example 7b), 8.5 g of a crude product are obtained. Purification by silica gel column chromatography (ethyl acetate-0.1% methanolic ammonia solution) afforded 7.4 g (77%) of 1- (3-azido-2-hydroxypropyl) -piperidine-4-carboxylic acid ethyl ester in ethyl acetate. in the form of a yellow oil. H-NMR (d ⁶ -DMSO): δ = 5.1 ppm (br.s. 1 H, OH); 4.05 (q. 2H); 3.80 m

1H); 3.20 (dddd, 2H); 2.85 (m. 2H); 2.30 (m, 3H); 2.05 (q, 2H); 1.88 (broad d,

2H); 1.55 (m. 2H); 1.12 (t. 3H).

e) Similar to Example 7c), 2.9 g of 1- (3-amino-2-hydroxypropyl) -piperidine-4-carboxylic acid ethyl ester is obtained as a yellow thick oil by hydrogenation of 3.6 g of azide 8d).

f) As in Example 7d), 1 g of 1- [2-hydroxy-3- (1-pyrimidine) ethyl ester is obtained from 2.5 g of amine 8e), 1.9 g of ketone 8c) and 4.6 g of sodium triacetate borohydride.

4-yl-piperidin-4-ylamino) -propyl] -piperidine-4-carboxylic acid as a pale yellow oil. H-NMR (d ⁶ -DMSO): δ = ppm 8:49 (s. 1H); 8.15 (d. 1H); 6.80 (d, IH); 4.21 (broad d, 2H)); 4.05 (q. 2H); 3.61 (m, 1H); 3.02 (t. 2H); 2.80 (m, IH); 2.65 (m. 2H); 2.45 (m, IH); 2.24 (m. 3H); 2.00 (t, 3 H); 1.88-1.68 (m. 4H); 1.57 (m. 2H); 1.25 (t. 3H); 1.19 (m, 3 H).

g) As in Example 7e), the reaction gave 1 g of amino alcohol 8f) and 0.83 g of 1,1'-carbonyldiimidazole in 10 ml of dimethylformamide to give 1.2 g of ethyl 2-oxo-3- (1-py) Rimidin-4-yl-piperidin-4-yl) -oxazolidin-5-ylmethyl-piperidine-4-carboxylic acid as a yellow oil.

FAB (MH &lt; ^{+ &gt;} ): 418.

h) As in Example 7f), the saponification gave 1.1 g of ethyl ester 8g) of 0.61 g of the title compound as a white powder. Mp 145 ° C. FAB (MH): 418. 1 H-NMR (d ⁶ DMSO): δ = 8.22 ppm (s, 1H); 7.90 (d, IH); 6.60 (d, IH); 4.40 (m, IH); 4.30 (m. 2H); 3.58 (m, IH); 3.31 (t, 1 H); 2.92 (m, IH); 2.70 (t, 3H); 2.25 (m, 3H); 1.81 (m. 3H); 1.50 (m. 4H); 1.32 (m, 4 H).

Example 9

1- {3- [1- (2-Benzylaminopyrimidin-4-yl) -piperidin-4-yl] -2-oxooxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid

a) A mixture of 8 g of 8- (2-chloropyrimidin-4-yl) -1,4-dioxa-8-azaspiro [4,5] decane 8a) and 7.2 ml of benzylamine is heated at 150 ° C for 2 hours, then The mixture was cooled, treated with 20 ml of water and extracted three times with 20 ml of methylene chloride. After drying the combined organic phases with sodium sulfate and evaporating the solvent, the residue is washed with cold isohexane. 9.6 g of benzyl-4- (1,4-dioxa-8-azaspiro [4.51 dec-8-yl) -pyrimidin-2-yl] -amine is thus obtained in the form of a yellow powder. 1 H-NMR (d ⁶ -DMSO); = 7.85 ppm (d, 1 H); 7.40-7. 18 (m, 5H); 7.15 (broad s, 1H, NH); 6.12 (d, 1H); 4.45 (d, 2 H); 3.96 (s, 4 H); 3.65 (m, 4 H); 1.61 (m, 4 H).

b) As in Example 1b), 9.6 g of ketal 9a) and 85 ml of 6N hydrochloric acid in 80 ml of tetrahydrofuran are obtained after 20 hours. reaction time 10.29 g of 1- (2-benzylaminopyrimidin-4-yl) -piperidin-4-one as a brown powder.

Mp.98-102 ° C.

c) As in Example 7d), 3.1 g of ketone are obtained

9b), 2.5 g of amine 8e) and 4.6 g of sodium triacetate borohydride 3.4 g of ethyl 1- {3- [11-benzylaminopyrimidin-4-yl) -piperidin-4-ylamino} -2-hydroxypropyl} -piperidine- 4-carboxylic acid in the form of a yellow oil. .

m / e = 496 ^lH-NMR (d ^s -DMSO): δ = 7.52 ppm (d, 1H); 7.10-6.95 (m. 5H); 6.80 (broad s, 1H, NH); 5.80 (d, IH); 4.15 (d. 2H); 3.90 (m. 2H); 3.80 (q. 2H); 3.39 (m, IH); 3.05 (broad s, 1H); 2.75-2. 52 (m, 3H); 2.40 (m, IH); 2.25 (m. 1H); 2.05 (m. 2H); 1.75 (m, IH); 1.55 (m. 4H); 1.32 (m. 2H); 0.95 (t. 3H); 0.88 (m, 5 H).

d) As in Example 7e), the reaction yielded 3.4 g of amino alcohol 9c) and 2.2 g of 1,1'-carbonyldiimidazole in 20 ml of dimethylformamide, 2.3 g of ethyl ester of 1- {3- [1- (2-benzylaminopyrimidine) -4-yl) -piperidin-4-yl] -2-oxooxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid as a yellow powder. MP: 122 [deg.] C.

e) As in Example 7f), the saponification of 0.26 g of ethyl ester 9d) gave 0.21 g of the title compound as a white powder.

T. t. 125-130 ° C. FAB (MH +): 495. H-NMR (d ⁶ / /

/

DMSO): δ = 7.90 ppm (d, 1 H); 7.39 (d. 2H); 7.24 (m. 3H); 6.12 (d, 1 H); 4.68 (q,

1H); 4.51 (d. 2H); 4.45 (m. 2H); 3.85 (t, 1 H); 3.55 (t, 1 H); 3.20 (t, 1 H), 2.85 (m,

3H); 2.55 (m. 3H); 2.18 (m, 3H); 1.75 (m. 3H); 1.50 (m, 3 H).

Example 10

In a similar manner to Example 9, the following compounds were prepared:

(a) 1- [2-oxo-4-phenyl-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] piperidine- 4-carboxylic acid; mp 150 ° C (dec.); m / e = 464

b) 1- [2-oxo-4-phenyl-3- (3,4,5,6-tetrahydro-2H- [1,4-bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidinecarboxylic acid; mp 77-80 ° C; m / e = 478

c) 4-hydroxy-4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] -cyclohexanecarboxylic acid ; 1.1. &Gt; 250 ° C; m / e = 403

d) 1- [4- (4-methoxyphenyl) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4] bipyridinyl-4-yl) -oxazolidine-5-carbonyl] -piperidene-4-carboxylic acid; mp 199 ° C (dec.); m / e = 508 &quot; x!

Example 11

1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-ylmethyl) -oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid

a) A mixture of 4.4 g (39 mmol) of 4-chloropyridine and 4.4 g (39 mmol) of 4-aminomethylpiperidine was stirred for 1 h at 150 ° C in an oil bath. The melt is then extracted with water, washed with ether, the aqueous phase is rendered alkaline with 10N sodium hydroxide solution and extracted with dichloromethane. After drying the extract with sodium sulfate and evaporating the solvent, 4.4 g (59%) of 3,4,5,6-tetrahydro-2 H- [1,4 '] bipyridinyl-4-ylmethylamine remains as a thick oil, m / e = 191; ¹ H-NMR (DCC1 _3):? = 8.25 ppm (d, 2H); 6.70 (d, 2 H); 3.90 (d with fine resolution, 2H); 2.85 (t with fine resolution, 2H); 2.60 (d, 2 H); 1.80 (m, 4 H);

1.55 (m, 1H); 1.25 (q with fine resolution, 2H).

b) As in Example 1e) from 2.8 g of epoxide 2a),

2.6 g of amine 11a) and 0.5 g of carbonyldiimidazole yield 1.0 g of 1- [2-oxo-3- (3,4,5,6-tetrahydro-2 H- 1,4,4] bipyric acid ethyl ester). (4-Methyl-4-ylmethyl) -oxazolidin-5-ylmethyl] -piperidine-4-carboxylic acid. ⁼ 404; @ 1 H NMR (CDCl3): .delta. = 8.20 ppm (d, 2H); 6.65 (d. 2H); 4.65 (q, 1 H); 4.10 (q, 2H);

3.90 (shin d, 2H); 3.65 (m, 1H) 3.50 (s, 1H); 3.35 (t, 1 H); 3.15 (d. 2H); 2.85 m

4H), 2.60 (d, 1 H); 2.50 (m, IH); 2.25 (m, 2H); 1.80 (m, 8H); 1.25 (t + m, 5 H).

c) As in Example 1f), 1.5 g of the title compound was obtained from 3.0 g of ethyl ester 11b) and 12 ml of 1 N sodium hydroxide solution as a white powder, m.p. Mp 94-96 ° C.

= 402; H-NMR (d ₆ -DMSO): δ = 8.10 ppm (d, 2H); 6.85 (d. 2H); 4.60 (m, IH);

3.95 (broad d, 2H); 3.25 (dd, IH); 3.05 (d. 2H); 2.85 (m, 4 H); 2.15 (m. 3H); 1.75 (m. 8H); 1.15 (m, 4 H).

Example 12

1- {2-Oxo-3- [2- (3,4,5,6-tetrahydro-2H-1,4) bipyridinyl-4-yl) -ethyl] -oxazolidin-5-ylmethyl} piperidine-4-carboxylic acid

a) Similar to Example 11a) from 5.7 g of 4-chloropyridine and 12.8 g of 4- (2-aminoethyl) piperidine (Sdp _{2 at} 100-104 ° C) prepared by hydrogenation of 4- (2-aminoethyl) pyridine J. Amer.

Soc. 78, 4129 (1956)] by ruthenium at 150 ° C and 150 bar hydrogen pressure yielded 5.2 g (51%) of 2- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4). -yl) ethylamine. m / e = 205; @ 1 H-NMR (CDCl3): .delta. = 8.20 ppm (d, 2H); 6.65 (d. 2H); 3.80 (broad d, 2H); 2.75 (m, 4 H); 1.80-1.10 (m, 9H).

b) As in Example 1e) and 1.9 epoxide 2a), 5.1 g of amine 12a) and 0.5 g of carbonyldiimidazole were obtained 0.8 g of ethyl 1- {2-oxo-3- [2- ( 3,4,5,6-tetrahydro-2H- [1,4'-bipyridin-4-yl) -ethyl] -oxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid. m / e = 444.

c) As in Example 1f), 0.4 g of the title compound was obtained from 0.7 ethyl ester 12b) and 5 ml of 1 N sodium hydroxide solution as an amorphous powder. ^{111/6 =} 416; @ ¹ H-NMR (CDCl3): .delta. = 8.15 ppm (d, 2H); 6.65 (d. 2H); 4.60 (m, IH); 3.80 (broad d, 2H);

3.55 (t, 1 H); 3.25 (m. 2H); 2.80 (m. 6H); 2.55 (br. 1H); 2.15 (m. 2H); 1.90 - 0.80

Example 13

1- {2-Oxo-3- [1- (2-pyridin-4-yl-ethyl) -piperidin-4-yl] -oxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid

a) As in Example 7b), 29 g (94%) of ethyl acid ester are obtained from 25.6 g of epoxide 2a) and 39 g of sodium azide.

1- (3-azido-2-hydroxypropyl) piperidine-4-carboxylic acid as an oil, m / e = 256.

b) As in Example 7c), from 29 g of azide 13a) was obtained by catalytic reduction of 21.1 g (81%) of 1- (3-amino-2-hydroxypropyl) piperidine-4-carboxylic acid ethyl ester.

m / e = 230; @ 1 H-NMR (CDCl3): .delta. = 4.15 ppm (q, 2H); 3.65 (m, IH); 2.95 (m, IH); 2.80 (dd, 2 H); 2.65 (dd, 1H); 2.30 (m, 7 H). 2.05-1.65 (m.

4H); 1.25 (t. 3H).

c) A solution of 4-vinylpyridine (16.2 ml, 150 mmol) in glacial acetic acid (5.7 ml) was treated with 4-piperidone ethylene ketal (12.8 ml) and heated at 100 ° C for 3 h. The reaction mixture was then basified with 2N sodium hydroxide solution, stirred at room temperature for 15 min and then treated with 10N sodium hydroxide solution to separate the base. It is extracted with dichloromethane, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel. Eluted with 3: 1 isohexane-ethyl acetate 16.3 g (66%) of 8- (2-pyridin-4-ylethyl) -1,4-dioxa-8-azaspiro [4,5] decane. 1 H-NMR (CDCl 3); δ = 8.50 ppm (d, 2 H); 7.15 (d. 2H); 3.95 (s,

4H); 2.75 (m. 2H); 2.55 (m. 6H); 1.75 (dd, 4 H).

d) Similar to Example 1b), 10.2 g (100%) of 1- (2-pyridin-4-yl-ethyl) -piperidin-4-one are obtained from 12.4 g of ketal 13c) as an oil. 'H-NMR (CDCl3): δ = 8.50 ppm (d,

2H); 7.15 (d. 2H); 2.75 (m. 8H); 2.45 (t, 4 H).

e) In analogy to Example 7d), 0.9 g of 1- {2-hyd49-roxy-3- [1- (2-pyridine-2-carboxylic acid) ethyl ester was obtained from 2.1 g of amine 13b) and 1.9 g of ketone 13d). 4-Ylethyl) -piperidin-4-ylamino] propyl} piperidine-4-carboxylic acid oil.

1 H-NMR (CDCl 3): δ = 8.50 ppm (d, 2H); 7.15 d

2H); 4.10 (q. 2H); 3.80 (m, IH); 2.90 (m. 4H); 2.75 (m, 4 H); 2.55 (m. 4H); 2.30 (m. 4H); 2.05 (m. 2H); 1.85 (br. D, 4H); 1.75 (m. 2H); 1.40 (m. 2H); 1.25 (t. 3H).

f) As in Example 7e), 1.7 g of 1- {2-oxo-3- [1- (2-pyridin-4-ylethyl) ethyl ester was obtained from 2.6 g of amino alcohol 13e) and 1.3 g of carbonyldiimidazole. 1-Piperidin-4-yl-7-oxazolidin-5-ylmethyl} -piperidine-4-carboxylic acid as an oil _and m / e = 444; @ 1 H NMR (CDCl3): .delta. = 8.50 ppm (d, 2H); 7.15 (d. 2H); 4.60 (m, IH); 4.15. (Q, 2H);

3.70 (m, IH); 3.55 (t, 1 H); 3.30 (t, 1 H); 3.05 (br. D, 2H); 2.80 (m. 4H); 2.60 m

4H); 2.20 (m. 5H); 1.80 (m. 8H); 1.25 (t. 3H).

(g) As in Example 1f), 1.2 g (75 g) of ethyl acetate 13f) and 5.2 ml of 1 N sodium hydroxide solution were obtained from 75 g of ethyl ester 13f).

%) of the title compound as an amorphous powder, m / e 416; H-NMR (d ₆ -DMSO): δ = 8.20 ppm (d, 2H); 7.05 (d. 2H); 4.40 (br. T, 1H);

3.30 (m. 2H); 2.95 (t, 1 H); 2.75 (br. D, 2H); 2.55 (m. 4H); 2.25 (m, 4H); 1.80 m

5H); 1.55 (m. 2H); 1.35 (m, 6 H).

Example 14

Pharmacological data

Assay

Microtiter plates were coated overnight with 2 µg / ml isolated activated GpIIb / IIIa-receptor. After unbound receptor was removed by several washing steps, the plate surface was blocked with 1% casein and washed once more. The test substance was added at the necessary concentrations, after which the plates were incubated for 10 minutes with shaking in a linear shaker. Natural gpIIb / IIIa receptor ligand, fibrinogen, was added. After one hour incubation, unbound fibrinogen was removed by several washing steps and bound fibrinogen was determined by determining the change in optical density at 405 nm using a peroxidase-conjugated monoclonal antibody in an ELISA reader. Inhibition of fibrinogen-GpIIb / IIIa interaction results in low optical densities. The IC ₅₀ value was determined based on the concentration-effect curve.

literature:

GpIIb / IIIa-fibrinogen-ELISA is a modification of Assay, which is described in the following references:

Nachman, R.L. & Leung, L.L.K. (1982): Complex formation of platelet membrane glycoproteins Ilb and Hla with fibrinogen. J; Clin. Invest. 69: 263-269.

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

Table:

Example

IC 50 (gmol / l) Name <0.30 1 - [(5S) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5 acid 4-carboxylic acid-1-methylmethyl-piperidine <0.30 1 - [(rac) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl acid ] piperidine-4-carboxylic acid

1.40 {1 - [(rac) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) · oxazolidin-5-ylmethyl] piperidine- 4-ylidene) acetic acid

1.00 {4-Hydroxy-1- [2-oxo-3 (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine- 4-yl [acetic <0.30 1- [4-methyl-2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5- acid] ylmethyl] -piperidine-4-carboxylic acid

0.30 1- [2-Oxo-3- (1-pyrimidin-4-yl piperidin-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid

0.070 1- {3- [1- (2-Benzylaminopyrimidin-4-yl) piperidin-4-yl] -2-oxooxazolidin-5-ylmethyl} piperidine-4-carboxylic acid

Table - continued

Example IC with ((.unol / 1))

10a) 0.30

10c) <0.30

No.78 0.60

no. 79 1,30

no. 80 0.50

1- [2-Oxo-4-phenyl-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid

4-Hydroxy-4- [2-oxo-3 (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] cyclohexanecarboxylic acid

(5S) -1- [5-Methyl-2-oxo-3 (3,4,5,6-tetrahydro-2H - [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine acid -4, carboxylic acid

1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H - [1,4 '] bipyridinyl-4-yl) -4- (3-trifluoromethylphenyl) oxazolidin-5-ylmethyl] piperidine-4 acid 1- [4- (4-Chloro-phenyl) -2-oxo-3 (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl-carboxylic acid ] -piperidine-4-carboxylic acid

Claims (5)

PATENT CLAIMS Compounds of formula I M? E — N Y θ> -Q - W (D in which X, Y and Q independently of one another are nitrogen or CH, W represents hydrogen or NR ° R ⁰⁰ , Z is nitrogen, CH or C-OH, A, E and G independently. of one another denote a valency dash or an alkylene chain - _{(CH2) n} B denotes a valency dash, and where Z is equal to N, is the carbonyl, D stands for - (CHR ³ ) _m -COO- or = CR ³ -COO-, n stands for 1-5, m stands for 0,1, R ¹ , R ² independently of one another are hydrogen, lower alkyl or aryl, or together form a carbocyclic five- or six-membered ring, R ³ is hydrogen or a radical -OR ⁵ or -NR ⁶ R ^7, R ⁴ is hydrogen or -OR ^5, R ⁵ is hydrogen, lower alkyl, aryl or arylalkyl, R ⁶ is hydrogen, lower alkyl or arylalkyl, R ⁷ is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl. R 0, R ⁰⁰ are, independently of one another, hydrogen, lower alkyl, aryl, arylalkyl, heteroaryl, 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 it may still contain 1 to 3 additional heteroatoms, or represent a pOOO skupinu group -C-NH R ⁰⁰⁰ represents hydrogen, lower alkyl, arylalkyl or NHR ⁰⁰⁰⁰ , R ⁰⁰⁰⁰ represents hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl, as well as their conformational isomers and their pharmacologically acceptable salts. Compounds of general formula I according to claim 1, characterized in that n is 1 or 3. Compounds of formula I according to claim 1 or 2: 1 - [(5S) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid, 1 - [(rac) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4'-bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid {1 - [(rac) -2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidin-4 acid -ylidene} -acetic acid {4-hydroxy-1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5- ylmethyl] piperidin-4y-1} acetic acid 1- [4-methyl-2-oxo-3- (3,4,5,6,6-tetrahydro-2 H- [1,4 '] bipyridinyl-4-yl) ) oxazolidin-5-ylm piperidine-4-carboxylic acid _/ 1- [2-oxo-3- (l-pyrimidin-4-yl-piperidin-4-yl) oxazo1idin-5-ylmethyl] -piperidine-4-carboxylic acid 1- {3- [1- (2-Benzylaminopyrimidin-4-yl) piperidin-4-yl] -2-oxooxazolidin-5-ylmethyl} piperidine-4-carboxylic acid 1- [2-oxo-4-phenyl-3- (3) 4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid 4-hydroxy-4- [2-oxo-3- ( 3,4,5,6-tetrahydro- o-2H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] cyclohexanecarboxylic acid (5S) -1- [5-methyl-2-oxo-3- (3,4,5,6) -tetrahydro-2 H- [1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid 1- [2-oxo-3- (3,4,5,6-tetrahydro-2 H-) -. - [1,4 '] bipyridinyl-4-yl) -4- (3-trifluoromethylphenyl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid 1- [4- (4-chlorophenyl) -2-oxo-3 - (3,4,5,6-tetrahydro-2H-[1,4 '] bipyridinyl-4-yl) oxazolidin-5-ylmethyl] piperidine-4-carboxylic acid as well as their conformational isomers and their pharmacologically acceptable salts. A pharmaceutical composition comprising at least one compound of the formula I according to one of claims 1-3 in addition to the usual carriers and excipients. Use of the substances according to one of claims 1 - 3 for the manufacture of medicaments for the treatment of diseases which can lead to platelet aggregation.