EP0891359A1 - Novel oxazolidine derivatives, process for their production and medicaments containing them - Google Patents

Novel oxazolidine derivatives, process for their production and medicaments containing them

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Publication number
EP0891359A1
EP0891359A1 EP97916395A EP97916395A EP0891359A1 EP 0891359 A1 EP0891359 A1 EP 0891359A1 EP 97916395 A EP97916395 A EP 97916395A EP 97916395 A EP97916395 A EP 97916395A EP 0891359 A1 EP0891359 A1 EP 0891359A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
carboxylic acid
oxo
octahydro
piperidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP97916395A
Other languages
German (de)
French (fr)
Inventor
Christos Tsaklakidis
Liesel Doerge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19612827A external-priority patent/DE19612827A1/en
Priority claimed from DE1996154479 external-priority patent/DE19654479A1/en
Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0891359A1 publication Critical patent/EP0891359A1/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • oxazolidine derivatives effectively inhibit the aggregation of blood platelets and can therefore be used for the treatment of diseases which are attributable to thromboembolic events, such as stroke.
  • diseases which are attributable to thromboembolic events such as stroke.
  • the present invention relates to compounds of the general formula I
  • M represents oxygen, sulfur or NR 00 ,
  • X represents hydrogen or NR 1 R 2 ,
  • W denotes nitrogen or NH or CH or CH 7 ,
  • Y represents nitrogen or CH
  • Z is nitrogen, CH or C-OH
  • A denotes an optionally substituted alkylene chain - (CH 2 ) p -
  • n 1-3 means
  • R 1 , R 2 independently of one another are 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 are an optionally substituted five- or six-membered ring which may also contain 1 to 3 further heteroatoms, or a group (c)
  • R 3 represents hydrogen or a group -OR 5 or -NR 6 R 7 ,
  • R 4 is hydrogen, lower alkyl, aryl, arylalkyl, hetaryl or a group -OR 5
  • R 5 denotes hydrogen, lower alkyl, aryl or arylalkyl
  • R 6 represents hydrogen, lower alkyl or arylalkyl
  • R 7 is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl
  • R 8 is hydrogen, methyl, ethyl, isopropyl, tert. -Butyl, phenyl or benzyl,
  • R 10 denotes hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl, arylsulfonyl or a group (c),
  • R 0 denotes hydrogen, lower alkyl, arylalkyl or a group -NHR 00 ,
  • R 00 is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl
  • Lower alkyl should in all cases be a straight-chain or branched C 1 -C 6 -alkyl group such as, for. B .. represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, propyl, isobutyl and pentyl
  • Aryl generally means the optionally mono- or polysubstituted phenyl radical.
  • Hetaryl generally means an unsubstituted or mono- or polysubstituted pyridyl, pyrimidyl, piperazyl, imidazolyl, pyrrolyl, furyl or thiophenyl radical, preferably a pyridyl, pyrimidyl indolyl or imidazolyl radical.
  • Arylalkyl generally means an unsubstituted or mono- or polysubstituted benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl radical, preferably a benzyl, phenethyl or phenylpentyl radical.
  • the substituents are C 1 -C 6 -alkyl radicals, preferably methyl, ethyl or isopropyl, and also chlorine, bromine, fluorine, or hydroxyl, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, , Methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino groups in question.
  • Acyl generally means the formyl, acetyl, propionyl, butyryl or benzoyl radical, in particular the acetyl or benzoyl radical.
  • Alkylsulfonyl generally means methanesulfonyl, ethanesulfonyl, propanesulfonyl or the butanesulfonyl radical, in particular the butanesulfonyl radical.
  • Arylsulfonyl usually means the benzene or toluenesulfonic acid residue.
  • Carboclyclic ring generally means a saturated or unsaturated 5-6-membered ring, optionally monosubstituted or disubstituted by lower alkyl, such as the cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring.
  • Heterocyclic ring generally means a saturated or unsaturated, 5-6-membered ring which is optionally monosubstituted or disubstituted by lower alkyl, such as the pyrolidine, piperidine, piperazine, morpholine, tetrahydropyrimidine, dihydropyridine or dihydroimidazole ring, preferably the piperidine or tetrahydropyrimidine ring.
  • the radicals R 1 and R 2 together with the nitrogen to which they are attached form a five- or six-membered ring, it is a saturated or unsaturated, optionally substituted by lower alkyl 5- or 5- membered ring, such as the pyrrolidine, piperidine.
  • Piperazine, morpholine, tetrahydropyrimidine, dihydropyridine, or dihydroimidazole ring preferably the piperidine, pyrrolidine or tetrahydropyrimidine ring.
  • the heterocyclic ring of the formula (a) generally represents the pyridine, pyridazine or pyrimidine ring, in particular the pyridine or pyrimidine ring.
  • the heterocyclic ring of the formula (b) generally represents the piperidine or hexahydropyrimidine ring, in particular the piperidine ring.
  • Compounds of the general formula I contain at least one asymmetric carbon atom, which is why optically active compounds of the general formula I are also the subject of the present application.
  • the present application furthermore relates to conformational isomers of compounds of the general formula I which can optionally occur.
  • X, Q, W and Y have the meanings given above;
  • L usually means a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, in particular chlorine or tosylate.
  • R 4 , A, D, L and n have the meanings given above.
  • Compounds of the general formula VII can be prepared by reacting 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
  • a and n have the meanings given above and M has the meaning of a metal such as lithium, magnesium or titanium.
  • L 1 usually means the hydroxyl or acetyloxy group, or has one of the meanings of L.
  • R 1 1 usually means Methyl, ethyl, tert-butyl, phenyl or benzyl radical, in particular the tert-butyl or benzyl radical.
  • the compounds of the general formula XII are generally commercially available pipecoline carboxylic acid derivatives, in special cases compounds of the formula XII can be obtained by converting a commercially available 3- or 4-pperidone of the formula XXI,
  • R 3 , R 8 and m have the meanings given above.
  • R 9 means butyl, phenol or p-tolyl and shark - chloride, bromide or iodide.
  • Wittig reagents of the formula XXIII are partly commercially available and can be prepared from the corresponding commercially available halogen compounds and triphosphines.
  • the hydrolysis of an ester of the general formula I to the corresponding carboxylic acid of the general formula I is carried out by customary processes, in which a carboxylic acid ester of the general formula I is preferably in water or in a mixture of water, tetrahydrofuran, dioxane, methanol or ethanol a water / tetrahydrofuran mixture 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 and at temperatures between room temperature and 80 ° C., preferably at Room temperature, treated.
  • a carboxylic acid ester of the general formula I is preferably in water or in a mixture of water, tetrahydrofur
  • reaction of a compound of general formula XIII with 1 -benzylp ⁇ peraz ⁇ n or 4-hydroxy- or 4-oxop ⁇ perid ⁇ n is generally carried out in one aprotic solvents 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 hydrogen carbonate, preferably sodium hydride or potassium carbonate and at temperatures between room temperatures and 180 ° C. preferably at 120 ° C or room temperature.
  • aprotic solvents 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 hydrogen carbonate, preferably sodium hydride or potassium carbonate and at
  • a ketone of the formula XVI with dibenzylamine or an amine of the formula XXV is carried out by processes known from the literature by reacting the ketone and amine component in a solvent such as methanoi or ethanol in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoborohydride with the addition of a Bronsted or Lewis acid such as hydrochloric acid, acetic acid, titanium tetrachloride or titanium tetraisopropylate and at a temperature between 0 ° and 100 ° C.
  • a solvent such as methanoi or ethanol
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoborohydride
  • a Bronsted or Lewis acid such as hydrochloric acid, acetic acid, titanium tetrachloride or titanium tetraisopropylate and at a temperature between 0 ° and 100 ° C.
  • a hydrogenation catalyst such as platmdioxide and a hydrogen atom
  • a hydrogenation catalyst such as platmdioxide and a hydrogen atom
  • nitrosation of a compound of general formula XIV to 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.
  • the reduction of a nitroso compound of the general formula XV is carried out by known processes in that 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., but preferably at 70 ° C.
  • a catalyst such as palladium / carbon (Hatt, HH, Org.
  • the Wittig reagents used are optionally prepared analogously to processes known from the literature (Buddras J., Angew. Chem. 80, 535 (1968), Bestmann HJ Angew Chem. 77, 620, 651 (1965); Wittig G. Ber. German. Chem. Ges 88, 1654 (1955)).
  • the Wittig reaction is carried out according to known methods by refluxing the reactants in an aprotic solvent such as benzene, toluene or xylene, preferably toluene.
  • an aprotic solvent such as benzene, toluene or xylene, preferably toluene.
  • Phthalimide hydrolysis is generally carried out by known processes by treating the phthalimide with hydrazine hydrate or 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 generally carried out 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-dimethylaminopyridine and at a temperature between -10 ° C. and 50 ° C. but preferably at room temperature.
  • a solvent such as methylene chloride, dimethylformamide or pyridine, preferably methylene chloride or pyridine
  • an auxiliary base such as triethylamine or 4-dimethylaminopyridine
  • Suitable acylating agents are carboxylic acid halides such as acetyl chloride, propionide bromide or benzyloxycarbonyl chloride or carboxylic acid anhydrides such as acetic anhydride or di-tert-butyl dicarbonate, but preferably acetic anhydride, benzyloxycarbonyl chloride or di-tert-butyl dicarbonate.
  • the epoxidation of an olefin of the formula VII or of the formula X or of the formula VIII or of the formula XXVIII is carried out by processes which are known from the nature Reaction 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 room temperature; Furthermore, the olefins mentioned above can be converted into the corresponding epoxides by means of the Sharpless epoxidation (Sharpless KB, Org. Syntheses, Vol 63, 66 (1985)).
  • the organometallic reaction mentioned in Scheme 3 is usually the Grignard reaction, which is carried out using methods known from the literature.
  • the magnesium reagent of the formula XX can optionally be converted into a lithium or titanium reagent before it is reacted with a carbonyl compound of the formula VI (Reetz M.T., Chem. Ber. 118, 1421 (1985)).
  • An amino alcohol of the formula III is converted into a compound of the formula 1 (Scheme 1) by processes known from the literature by reacting an amino alcohol of the formula III with diethyl carbonate (Evans D. A, Org. Syntheses, Vol. 68, 77 (1989)) or Carbonyidiimidazole (Chadwick D. I, J. Chem. Soc. Perkin Trans. 481 (1984), Geflfken D. Arch Pharm 313, 817 (1980)) or Phosgene (Newman WS. J Am Chem. Soc. 73, 4199 (1951 )) or Di- or Triphosen (Hassner A, Synth Commun 23, 2839 (1993)), or chloroformic acid methyl.
  • diethyl carbonate Evans D. A, Org. Syntheses, Vol. 68, 77 (1989)
  • Carbonyidiimidazole Chadwick D. I, J. Chem. Soc. Perkin Trans. 481 (19
  • a solvent such as methylene chloride , Dimethylformamide, toluene, xylene, ethanol, dioxane, tetrahydrofuran, water or diethyl ether, preferably dimethylformamide, methylene chloride, ethanol or
  • the 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 a hydrogen atmosphere at a pressure of 1-200 bar, preferably at 200 bar and one Temperature between room temperature and 200 ° C. by (Rastin R H, 1 Chem.Soc. 1855 (1949).
  • a catalyst such as ruthenium oxide, rhodium oxide or palladium / strontium carbonate, preferably rhodium oxide in a hydrogen atmosphere at a pressure of 1-200 bar, preferably at 200 bar and one Temperature between room temperature and 200 ° C. by (Rastin R H, 1 Chem.Soc. 1855 (1949).
  • the epoxy opening of an epoxide of the formula V with an amine of the formula IV (Scheme 1) or an epoxide of the formula IX with an amine of the formula XII (Scheme 4) usually takes place 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. instead of.
  • 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. instead of.
  • the epoxy opening of an epoxide of the formula V (scheme 1) with a metal azide is carried out according to methods known from the literature by reacting an epoxide of the formula V with a metal azide such as lithium, sodium, potassium, tributyltin or magnesium azide, preferably sodium azide, in a solvent such as Methanol ethanol 1, 4-dioxane, water, dimethylformamide tetrahydrofuran acetomtril or hexamethylphosphoric triamide, or in mixtures of the solvents mentioned, but preferably in methanol, dimethylformamide or 1,4-dioxane-water mixtures and at a reaction temperature between - 10 ° C. and 120 ° C. preferably 80 ° C.
  • a metal azide such as lithium, sodium, potassium, tributyltin or magnesium azide, preferably sodium azide
  • reaction of a compound of formula XXXI with a metal azide to a compound of formula XXVI represents, in the event that L 1 is L, a nucleophilic substitution which is carried out according to standard methods of organic synthesis.
  • the deacyiation of a compound of the formula XXX to a compound of the formula XXV is carried out by customary methods in which a compound of the formula XXX is in water or in a mixture of water.
  • Tetrahydrofuran, dioxane, methanol or ethanol preferably in a water / tetrahydrofuran mixture 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
  • a hydroxide such as sodium, potassium or lithium hydroxide, preferably sodium or lithium hydroxide
  • an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid or with palladium / carbon
  • Racemates of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates can be mechanically or chemically separated into the enantiomers by methods known per se.
  • the racemic mixture is preferably reacted with an optically active acid such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphor sulfonic acids such as ß-camphor sulfonic acid diastereomers.
  • an optically active acid such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphor sulfonic acids such as ß-camphor sulfonic acid diastereomers.
  • optically active compounds of the formula I by the methods described above, using starting materials (for example those of the formula V or VIII) which are already optically active.
  • prodrug forms of compounds of the general formula I are also claimed, but especially carboxylic acid esters of the general formula I in which R 8 is methyl, ethyl, n-propyl, isopropyl, butyl or phenyl - or benzyl radical means in particular the methyl, ethyl or benzyl radical.
  • salts especially alkali salts, ammonium salts, trifluoroacetates or hydrochlorides are used.
  • B. by titration of the compounds with inorganic or organic bases or acids such.
  • the salts are usually purified by falling over from water / acetone.
  • novel substances of the formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form. All customary forms of administration, for example tablets, can be used here. Capsules, dragees, syrups, solutions, suspensions, etc. Water is preferably used as the injection medium, which contains the additives common to injection solutions such as stabilizers, solubilizers and buffers. Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, high molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the dosage can depend on various factors, such as the mode of administration and the species. Depend on age and / or individual condition.
  • the daily doses to be administered are approximately 1-1000 mg / person, preferably 100-500 mg / person, and can be taken in one or more times distributed.
  • (1R-2R-3S) -1-hydroxy-2,3-epoxycyclohexane can be isolated by epoxidation of the (R) -cyclohex-2-enol () Fukazawa et al, Tetrahedron Asymmetry 4, 2323 (1993)) by means of meta-chloroperbenzoic acid.
  • the title compound can be obtained by this process in better yield and higher purity than by process 1 h).
  • ⁇ NMR (d 6 -DMSO): ⁇ 8. 13 ppm (d, 2H); 7.25 (m, 2H); 7. 15 (m, 3H); 6.80 (d.
  • Microtiter plates were coated overnight with 2 ⁇ g / ml isolated activated GplIb / IIla receptor. After the unbound receptor was removed by a few washing steps, the surface of the plate was blocked with 1% casein and washed again. The test substance was added in the required concentrations, then the plates were incubated under rubble in a linear shaker for 10 minutes. The natural ligand of the gpIIb / IIIa receptor, fibronogen, was added.
  • the GpIIb / IIla fibrinogen ELISA is a modification of the assay described in the following references.

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Abstract

The present invention relates to novel oxazolidine derivatives, a process for their production and medicaments containing said substances. The object of the present invention are compounds of the general formula (I) in which the symbols have the meanings given in the claims.

Description

Neue Oxazolidinderivate, Verfahren zu deren  New oxazolidine derivatives, process for their
Herstellung und diese Verbindungen enthaltende Arzneimittel  Manufacture and pharmaceutical compositions containing these compounds
Es ist bekannt, daß Verbindungen, die eine basische und eine Säuregruppe tragen, in der Lage sind, die Blutplattchen-Aggregation zu hemmen, wenn die basische und Saure- gruppe in den Verbindungen einen ganz bestimmten Abstand einnehmen (Drugs of the Future 19(2). 135-159 ( 1994). In den Patentschriften WO 93/14077, EP-A-0 537-980, EP-A-0 542 363, WO 94/22834, WO 94/22835 und EP 0623615A1 sind Verbindungen mit antiaggregatorischer Wirkung an den Blutblattchen beschrieben . Die vorliegende Erfindung betrifft neue Oxazolidinderivate. Verfahren zu deren Herstellung sowie Arzneimittel, die diese Substanzen enthalten. It is known that compounds which carry a basic and an acid group are able to inhibit blood platelet aggregation if the basic and acid group take a certain distance in the compounds (Drugs of the Future 19 (2 ) 135-159 (1994) In the patent specifications WO 93/14077, EP-A-0 537-980, EP-A-0 542 363, WO 94/22834, WO 94/22835 and EP 0623615A1 are compounds with anti-aggregatory The present invention relates to new oxazolidine derivatives, processes for their preparation and medicaments which contain these substances.
Es wurde nun gefunden, daß Oxazolidinderivate effektiv die Aggregation der Blut- blattchen hemmen und damit zur Behandlung von Krankheiten eingesetzt werden können, die auf thromboembolische Ereignisse zurückzuführen sind, wie Schlaganfall. Myo- cardinfarkt oder arterielle Verschiußkrankheiten, sowie Entzündungen, Osteoporose oder Tumorerkrankungen. It has now been found that oxazolidine derivatives effectively inhibit the aggregation of blood platelets and can therefore be used for the treatment of diseases which are attributable to thromboembolic events, such as stroke. Myocardial infarction or arterial disease, as well as inflammation, osteoporosis or tumor diseases.
Gegenstand der vorliegenden Erfindung sind Verbindungen der allgemeinen Formel I, The present invention relates to compounds of the general formula I
in der E einen Rest der Formel (a) oder (b) in which E is a radical of the formula (a) or (b)
( ) ( ) () ()
bedeutet,  means
M Sauerstoff, Schwefel oder NR00 bedeutet, M represents oxygen, sulfur or NR 00 ,
X Wasserstoff oder NR1R2 bedeutet, X represents hydrogen or NR 1 R 2 ,
W Stickstoff bzw NH oder CH bzw. CH7 bedeutet, W denotes nitrogen or NH or CH or CH 7 ,
Q Stickstoff oder CH bedeutet,  Q represents nitrogen or CH,
Y Stickstoff oder CH bedeutet,  Y represents nitrogen or CH,
Z Stickstoff, CH oder C-OH bedeutet,  Z is nitrogen, CH or C-OH,
A eine gegebenenfalls substituierte Alkylenkette -(CH2)p- bedeutet, A denotes an optionally substituted alkylene chain - (CH 2 ) p -,
D eine Seitenkette der Form -(CHR3)m-COO-R8 oder =CR3-COO-R8 bedeutet. n = 1-3 bedeutet, D is a side chain of the form - (CHR 3 ) m -COO-R 8 or = CR 3 -COO-R 8 . n = 1-3 means
m = 0 oder 1 bedeutet, m = 0 or 1 means
p = 0-3 bedeutet, R1, R2 unabhängig voneinander Wasserstoff, niederes Alkyl, Aryl, Arylalkyl, Het- aryl,Acyl oder einen gegebenenfalls substituierten carbocyclischen oder heterocy- clischen Ring bedeuten, oder zusammen mit dem Stickstoff an dem sie gebunden sind, einen gegebenenfalls substituierten fünf- oder sechsgliedrigen Ring bilden, der noch 1 bis 3 weitere Heteroatome enthalten kann, oder eine Gruppe (c) p = 0-3 means R 1 , R 2 independently of one another are 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 are an optionally substituted five- or six-membered ring which may also contain 1 to 3 further heteroatoms, or a group (c)
bedeuten,  mean,
R3 Wasserstoff oder eine Gruppe -OR5 oder -NR6R7 bedeutet, R 3 represents hydrogen or a group -OR 5 or -NR 6 R 7 ,
R4 Wasserstoff, niederes Alkyl, Aryl, Arylalkyl, Hetaryl oder eine Gruppe -OR5 R 4 is hydrogen, lower alkyl, aryl, arylalkyl, hetaryl or a group -OR 5
bedeutet,  means
R5 Wasserstoff, niederes Alkyl, Aryl oder Arylalkyl bedeutet, R 5 denotes hydrogen, lower alkyl, aryl or arylalkyl,
R6 Wasserstoff, niederes Alkyl oder Arylalkyl bedeutet, R 6 represents hydrogen, lower alkyl or arylalkyl,
R7 Wasserstoff, niederes Alkyl, Arylalkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl R 7 is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl
bedeutet,  means
R8 Wasserstoff, Methyl, Ethyl, Isopropyl, tert. -Butyl, Phenyl oder Benzyl, R 8 is hydrogen, methyl, ethyl, isopropyl, tert. -Butyl, phenyl or benzyl,
insbesondere Wasserstoff, Ethyl, Phenyl oder Isopropyl bedeutet,  is in particular hydrogen, ethyl, phenyl or isopropyl,
R10 Wasserstoff, niederes Alkyl, Arylalkyl, Acyl, Alkylsulfonyl, Arylsulfonyl oder eine Gruppe (c) bedeutet, R 10 denotes hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl, arylsulfonyl or a group (c),
R0 Wasserstoff, niederes Alkyl, Arylalkyl oder eine Gruppe -NHR00 bedeutet, R 0 denotes hydrogen, lower alkyl, arylalkyl or a group -NHR 00 ,
R00 Wasserstoff, niederes AJkyl, Arylalkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl R 00 is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl
bedeutet, sowie deren pharmakologisch unbedenklichen Salze.  means, and their pharmacologically acceptable salts.
Niederes Alkyl soll in allen Fällen eine geradkettige oder verzweigte C 1 -C6-Alkylgruppe wie z. B.. Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, Pentyl oder Hexyl, insbeson- dere Methyl, Ethyl, Propyl, Isobutyl und Pentyl darstellen Lower alkyl should in all cases be a straight-chain or branched C 1 -C 6 -alkyl group such as, for. B .. represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, propyl, isobutyl and pentyl
Aryl bedeutet in der Regel den gegebenenfalls ein- oder mehrfach substituierten Phenyl- rest. Hetaryl bedeutet in der Regel einen unsubstituierten oder ein- oder mehrfach substituierten Pyridyl-, Pyrimidyl-, Piperazyl-, Imidazolyl,- Pyrrolyl-, Furyl- oder Thiophenylrest, vorzugsweise einen Pyridyl-, Pyrimidyl- Indolyl- oder Imidazolylrest. Arylalkyl bedeutet in der Regel einen unsubstituierten oder ein- oder mehrfach substituierten Benzyl-, Phenethyl-, Phenylpropyl-, Phenylbutyl- oder Phenylpentylrest, vorzugsweise einen Benzyl-, Phenethyl- oder Phenylpentylrest. Als Substituenten kommen C 1- C6-Alkylreste, vorzugsweise Methyl-, Ethyl- oder Isopropyl, sowie Chlor, Brom, Fluor, oder Hydroxy-, Methoxy-, Benzyloxy-, Acetyloxy-, Carboxy-, Ethoxycarbonyl-, Amino- carbonyl-, Methylaminocarbonyl-, Dimethylaminocarbonyl-, Cyano-, Amino-, Methyl- amino-, Dimethylamino-, Benzylamino-, Acetylamino-, Benzoylamino- und Amidino- gruppen infrage. Aryl generally means the optionally mono- or polysubstituted phenyl radical. Hetaryl generally means an unsubstituted or mono- or polysubstituted pyridyl, pyrimidyl, piperazyl, imidazolyl, pyrrolyl, furyl or thiophenyl radical, preferably a pyridyl, pyrimidyl indolyl or imidazolyl radical. Arylalkyl generally means an unsubstituted or mono- or polysubstituted benzyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl radical, preferably a benzyl, phenethyl or phenylpentyl radical. The substituents are C 1 -C 6 -alkyl radicals, preferably methyl, ethyl or isopropyl, and also chlorine, bromine, fluorine, or hydroxyl, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, , Methylaminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoylamino and amidino groups in question.
Acyl bedeutet in der Regel den Formyl-, Acetyl-, Propionyl-, Butyryl- oder Benzoylrest, insbesondere den Acetyl oder Benzoylrest. Acyl generally means the formyl, acetyl, propionyl, butyryl or benzoyl radical, in particular the acetyl or benzoyl radical.
Alkylsulfonyl bedeutet in der Regel den Methansulfonyl, Ethansulfonyl-, Propansuifonyl oder den Butansulfonylrest, insbesondere der Butansulfonylrest. Arylsulfonyl bedeutet in der Regel den Benzol- oder Toluolsulfonsaurerest. Alkylsulfonyl generally means methanesulfonyl, ethanesulfonyl, propanesulfonyl or the butanesulfonyl radical, in particular the butanesulfonyl radical. Arylsulfonyl usually means the benzene or toluenesulfonic acid residue.
Carboclyclischer Ring bedeutet in der Regel einen gesattigten oder ungesättigten, gegebenenfalls durch niederes Alkyl einfach oder zweifach substituierten 5-6-gIiedrigen Ring, wie den Cyclopentyl-, Cyclohexyl-, Cyclopentenyl- oder Cyclohexenylring . Carboclyclic ring generally means a saturated or unsaturated 5-6-membered ring, optionally monosubstituted or disubstituted by lower alkyl, such as the cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring.
Heterocyclischer Ring bedeutet in der Regel einen gesattigten oder ungesättigten, gegebenenfalls durch niederes Alkyl einfach oder zweifach substituierten 5-6-gliedrigen Ring, wie den Pyrolidin-, Piperidin-, Piperazin-, Morpholin-, Tetrahydropyrimidin, Dihydropy- ridin-, oder Dihydroimidazol-ring, vorzugsweise den Piperidin- oder Tetrahydropyrimi- dinring. Falls die Reste R1 und R2 zusammen mit dem Stickstoff an dem sie gebunden sind einen fünf- oder sechsgliedrigen Ring bilden, handelt es sich um einen gesattigten oder ungesättigten, gegebenenfalls durch niederes Alkyl einfach oder zweifach substituierten 5-6-gliedrigen Ring, wie den Pyrrolidin-, Piperidin-. Piperazin-, Morpholin-, Tetrahydropyrimidin, Dihydropyridin-, oder Dihydroimidazol-ring, vorzugsweise den Piperidin-, Pyrrolidin oder Tetrahydropyrimidinring. Heterocyclic ring generally means a saturated or unsaturated, 5-6-membered ring which is optionally monosubstituted or disubstituted by lower alkyl, such as the pyrolidine, piperidine, piperazine, morpholine, tetrahydropyrimidine, dihydropyridine or dihydroimidazole ring, preferably the piperidine or tetrahydropyrimidine ring. If the radicals R 1 and R 2 together with the nitrogen to which they are attached form a five- or six-membered ring, it is a saturated or unsaturated, optionally substituted by lower alkyl 5- or 5- membered ring, such as the pyrrolidine, piperidine. Piperazine, morpholine, tetrahydropyrimidine, dihydropyridine, or dihydroimidazole ring, preferably the piperidine, pyrrolidine or tetrahydropyrimidine ring.
Der heterocyclische Ring, der Formel (a) stellt in der Regel den Pyridin-, Pyridazin- oder Pyrimidinring, insbesondere den Pyridin- oder Pyrimidinring dar. The heterocyclic ring of the formula (a) generally represents the pyridine, pyridazine or pyrimidine ring, in particular the pyridine or pyrimidine ring.
Der heterocyclische Ring, der Formel (b) stellt in der Regel den Piperidin- oder Hexahydropyrimidinring, insbesondere den Piperidinring dar. The heterocyclic ring of the formula (b) generally represents the piperidine or hexahydropyrimidine ring, in particular the piperidine ring.
Verbindungen der allgemeinen Formel I enthalten mindestens ein asymmetrisches Koh- lenstoffatom, daher sind auch optisch aktive Verbindungen der allgemeinen Formel I Gegenstand der vorliegenden Anmeldung Gegenstand der vorliegenden Anmeldung sind weiterhin Konformationsisomere von Verbindungen der allgemeinen Formel I, die gegebenenfalls auftreten können. Bevorzugte Verbindungen sind Verbindungen der Formel I. in der n= 1 -2, p=0- 1 und E, D, Y, Z und R4 die angegebene Bedeutung haben . Compounds of the general formula I contain at least one asymmetric carbon atom, which is why optically active compounds of the general formula I are also the subject of the present application. The present application furthermore relates to conformational isomers of compounds of the general formula I which can optionally occur. Preferred compounds are compounds of the formula I. in which n = 1 -2, p = 0-1 and E, D, Y, Z and R 4 have the meaning given.
Insbesondere sind Verbindungen der Formel I bevorzugt, in der D eine Gruppe -COOR5, n=2, p=0, und Y=CH , Z Stickstoff, M Sauerstoff und E den substituierten oder unsubstituierten Pyridin-, Pyrimidin- oder Piperidinring bedeuten. In particular, compounds of the formula I are preferred in which D is a group --COOR 5 , n = 2, p = 0, and Y = CH, Z nitrogen, M oxygen and E are the substituted or unsubstituted pyridine, pyrimidine or piperidine ring.
Verbindungen der allgemeinen Formel I, in der R8 Wasserstoff bedeutet, werden nach an sich bekannten Verfahren durch Hydrolyse eines Esters der allgemeinen Formel I, in der R8≠H ist, hergestellt. Verbindungen der allgemeinen Formel I, in der R8≠H ist, können nach dem im Schema skizzierten Reaktionsweg hergestellt werden. Compounds of the general formula I in which R 8 is hydrogen are prepared by processes known per se by hydrolysis of an ester of the general formula I in which R 8 is H. Compounds of the general formula I in which R 8 is ≠ H can be prepared by the reaction route outlined in the scheme.
Schema 1 Scheme 1
Im Schema 1 besitzen R4, A, D, E, M, Y, Z und n die obengenannten Bedeutungen "Cyclisierungssynthon" "M=C"" bedeutet in der Regel Phosgen, Diphosgen, Triphosgen, Carbonyldiimidazol, Kohlensauredimethyldiethyl oder -diphenylester, Chlor- ameisensauremethyl- oder -ethylester, Thiophosgen, Thiocarbonyldiimidazol, Schwefelkohlenstoff, Alkylisonitril, N,N-Dimethylformamid, Brom- oder Chlorcyan, (N-Acyl- oder N-Sulfonyl)-dithiocarbaminsauredimethylester, Dialkylcarbonyldiimid, 1-Amιdιno- 3,5-pyrazol-nitrat, insbesondere Carbonyldimidazol, Kohlensaurediethylester, Chloramei- sensaureethylester, Thiocarbonyldiimidazol oder Bromcyan MN3 bedeutet ein Metall- azid wie Lithium-, Natrium-, Kalium- Tributvlzinn- oder Magnesiumazid. insbesondere Lithium- oder Natrium-azid. TMSN3 ist die Abkürzung für Trimethvlsilylazid. In Scheme 1, R 4 , A, D, E, M, Y, Z and n have the meanings given above. "Cyclization synthon""M = C""generally means phosgene, diphosgene, triphosgene, carbonyldiimidazole, dimethyl carbonate or diphenyl ester, chlorine - Methyl or ethyl formate, thiophosgene, thiocarbonyldiimidazole, carbon disulfide, alkylisonitrile, N, N-dimethylformamide, bromine or cyanogen chloride, (N-acyl or N-sulfonyl) dithiocarbamic acid dimethyl ester, dialkyl carbonyl diimidol, 1-amyl 3,5-diimidol nitrate, in particular carbonyldimidazole, diethyl carbonate, ethyl chloroformate, thiocarbonyldiimidazole or cyanogen bromide MN 3 means a metal azide such as lithium, sodium, potassium, tributin tin or magnesium azide. In particular lithium or sodium azide. TMSN 3 is the abbreviation for Trimethvlsilylazid.
Verbindungen der allgemeinen Formel IV, in der E die Formel (a) bedeutet, können nach den im Schema 2 wiedergegebenen Reaktionswegen hergestellt werden. . Compounds of the general formula IV, in which E denotes the formula (a), can be prepared according to the reaction routes shown in Scheme 2. .
Schema 2 Scheme 2
Im Schema 2 besitzen X, Q, W und Y die oben angegebenen Bedeutungen; L bedeutet in der Regel eine Abgangsgruppe wie Chlor, Brom, Iod, Mesylat, Triflat oder Tosylat, insbesondere Chlor oder Tosylat . In Scheme 2, X, Q, W and Y have the meanings given above; L usually means a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, in particular chlorine or tosylate.
Verbindungen der allgemeinen Formel IV, in der E die Formel (b) bedeutet, können durch Kernhydrierung von Verbindungen der Formel XVI oder XVIII hergestellt werden. Compounds of the general formula IV, in which E denotes the formula (b), can be prepared by nuclear hydrogenation of compounds of the formula XVI or XVIII.
Verbindungen der allgemeinen Formel V sind über Reaktionswege zuganglich, die im Schema 3 wiedergegeben sind. Compounds of the general formula V are accessible via reaction routes which are shown in Scheme 3.
h Schema 3 H Scheme 3
Im Schema 3 besitzen R4, A, D, L und n die oben angegebenen Bedeutungen . Verbindungen der allgemeinen Formel VI sind zum Teil kauflich erwerblich und lassen sich in speziellen Fällen durch Oxidation eines Alkohols der allgemeinen Formel XI, In scheme 3, R 4 , A, D, L and n have the meanings given above. Some of the compounds of the general formula VI are commercially available and, in special cases, can be obtained by oxidation of an alcohol of the general formula XI,
in der D und R4 die oben angegebenen Bedeutungen besitzen, erhalten. in which D and R 4 have the meanings given above, obtained.
Verbindungen der allgemeinen Formel VII lassen sich dadurch herstellen, daß man eine Verbindung der allgemeinen Formel VI mit einer aus einer Verbindung der allgemeinen Formel VIII hergestellten metallorganischen Verbindung der allgemeinen Formel XX Compounds of the general formula VII can be prepared by reacting 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 der A und n die oben angegebenen Bedeutungen besitzen und M die Bedeutung eines Metalls wie Lithium, Magnesium oder Titan besitzt, zur Reaktion bringt. in which A and n have the meanings given above and M has the meaning of a metal such as lithium, magnesium or titanium.
Verbindungen der allgemeinen Formel XXV (Schema 1), in der R8≠H, p=0 und Z=N bedeuten, können auch nach den im Schema 4 skizzierten Reaktionswegen hergestellt werden. Schema 4 Compounds of the general formula XXV (Scheme 1) in which R 8 is ≠ H, p = 0 and Z = N can also be prepared by the reaction routes outlined in Scheme 4. Scheme 4
Im Schema 4 besitzen R4, D, MN3, TMSN3 und n die oben angegebenen Bedeutungen L1 bedeutet in der Regel die Hydroxyl- oder Acetyloxy-Gruppe, oder besitzt eine der Bedeutungen von L. R1 1 bedeutet in der Regel den Methyl-, Ethyl-, tert -Butyl-, Phenyl- oder Benzylrest, insbesondere den tert -Butyl- oder Benzylrest. In scheme 4, R 4 , D, MN 3 , TMSN 3 and n have the meanings given above. L 1 usually means the hydroxyl or acetyloxy group, or has one of the meanings of L. R 1 1 usually means Methyl, ethyl, tert-butyl, phenyl or benzyl radical, in particular the tert-butyl or benzyl radical.
Bei den Verbindungen der allgemeinen Formel VIII handelt es sich, für den Fall, daß p=0 ist, um käuflich erwerbliche Cycloalkenyl-halogenide oder -alkohole Für den Fall, daß p>0 ist, sind Verbindungen der Formel VIII literaturbekannt, oder lassen sich nach den dort beschriebenen Verfahren herstellen (Brinker U. H. , Tetrahedron Lett. , 1991, 4461 - 4464, Atkinson P.H. , J . Chem. Soc. Perkin Trans 1, 1977, 230-238, Müller E. , Chem Ber. 108, 1401 - 1412 ( 1975), Walton J . C. , J. Chem. Soc. Perkin Trans 2, 1986, 1641 - 1646, Balme G., Tetrahedron, 48, 3891 -3902 ( 1992), Fieser et al , J Amer Chem. Soc. , 70, 3174-3 196 (1948), Lee G.M , J Oerg. Chem. , 55, 1281- 1285 ( 1990)). The compounds of the general formula VIII are, if p = 0, commercially available cycloalkenyl halides or alcohols. In the event that p> 0, compounds of the formula VIII are known from the literature or can be according to the processes described there (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 J.C., J. Chem. Soc. Perkin Trans 2, 1986, 1641-1646, Balme G., Tetrahedron, 48, 3891-3902 (1992), Fieser et al, J Amer Chem. Soc., 70, 3174-3 196 (1948), Lee GM, J Oerg. Chem., 55, 1281-1285 (1990)).
Bei den Verbindungen der allgemeinen Formel XII handelt es sich in der Regel um kauflich erwerbliche Pipecolincarbonsaure-Derivate, in Spezialfallen lassen sich Verbindun- gen der Formel XII durch Umsetzung eines käuflich erwerbiichen 3- oder 4-Pιperidons der Formel XXI, The compounds of the general formula XII are generally commercially available pipecoline carboxylic acid derivatives, in special cases compounds of the formula XII can be obtained by converting a commercially available 3- or 4-pperidone of the formula XXI,
mit einem käuflich erwerblichen Essigsaureester der allgemeinen Formel XXII, in der R 3 und R8 die oben angegebenen Bedeutungen besitzen, oder mit einem Wittis. reagenz der allgemeinen Formel XXIII, with a commercially available acetic acid ester of the general formula XXII, in which R 3 and R 8 have the meanings given above, or with a Wittis. reagent of the general formula XXIII,
in der R3, R8, und m die oben genannten Bedeutungen besitzen. R9 Butyl, Phenvl oder p-Tolyl und Hai - Chlorid, Bromid oder Iodid bedeutet, herstellen . Verbindungen der allgemeinen Formel XI sind zum Teil kauflich erwerblich und lassen sich in Spezialfallen nach bekannten Verfahren durch Kernhydrierung einer Arylcarbon- saure der allgemeinen Formel XXIV, in which R 3 , R 8 and m have the meanings given above. R 9 means butyl, phenol or p-tolyl and shark - chloride, bromide or iodide. Some of the compounds of the general formula XI are commercially available and, in special cases, can be obtained by known processes by nuclear hydrogenation of an arylcarboxylic acid of the general formula XXIV
in der R4 und D die oben angegebenen Bedeutungen besitzen- erhalten. in which R 4 and D have the meanings given above.
Verbindungen der allgemeinen Formel XX lassen sich in situ nach den allgemeinen Verfahren zur Herstellung metallorganischer Verbindungen synthetisieren. Compounds of the general formula XX can be synthesized in situ by the general processes for the preparation of organometallic compounds.
Wittigreagenzien der Formel XXIII sind teilweise käuflich erwerblich und lassen sich aus den entsprechenden käuflichen Halogenverbindungen und Triphosphinen herstellen. Die Hydrolyse eines Ester der allgemeinen Formel I zu der entsprechenden Carbonsaure der allgemeinen Formel I führt man nach üblichen Verfahren durch, in dem man einen Carbonsaureester der allgemeinen Formel I in Wasser oder in einem Gemisch aus Wasser, Tetrahydrofuran, Dioxan, Methanol oder Ethanol vorzugsweise in einem Wasser/ Tetrahydrofurangemisch mit einem Hydroxid wie Natrium- Kalium-, oder Lithium- hydroxid, vorzugsweise Natrium- oder Lithiumhydroxid, oder mit einer Saure wie Salzsaure, Schwefelsaure oder Trifluoressigsaure, vorzugsweise Trifluoressigsaure und bei T emperaturen zwischen Raumtemperatur und 80°C, vorzugsweise bei Raumtemperatur, behandelt. Wittig reagents of the formula XXIII are partly commercially available and can be prepared from the corresponding commercially available halogen compounds and triphosphines. The hydrolysis of an ester of the general formula I to the corresponding carboxylic acid of the general formula I is carried out by customary processes, in which a carboxylic acid ester of the general formula I is preferably in water or in a mixture of water, tetrahydrofuran, dioxane, methanol or ethanol a water / tetrahydrofuran mixture 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 and at temperatures between room temperature and 80 ° C., preferably at Room temperature, treated.
Die Umsetzung einer Verbindung der allgemeinen Formel XIII mit 1 -Benzylpιperazιn oder 4-Hydroxy- bzw 4-Oxopιperidιn (Schema 2) oder die U msetzung einer Verbindung der Formel IX mit einer Verbindung der Formel XII (Schema 3) erfolgt in der Regel in einem aprotischen Losungsmittel wie Toluol, Tetrahydrofuran, Diethylether, Dimethylformamid oder Methylenchlorid, vorzugsweise Dimethylformamid oder Tetrahydrofuran unter Verwendung einer Base wie Kaliumhydrid, Natriumhydrid, Kahumcarbonat oder Natriumhydrogencarbonat, vorzugsweise Natriumhydnd oder Kahumcarbonat und bei Temperaturen zwischen Raumtemperaturen und 180°C. vorzugsweise bei 120°C oder Raumtemperatur. The reaction of a compound of general formula XIII with 1 -benzylpιperazιn or 4-hydroxy- or 4-oxopιperidιn (Scheme 2) or the reaction of a compound of formula IX with a compound of formula XII (Scheme 3) is generally carried out in one aprotic solvents 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 hydrogen carbonate, preferably sodium hydride or potassium carbonate and at temperatures between room temperatures and 180 ° C. preferably at 120 ° C or room temperature.
Die Reaktion zwischen 3- oder 4-Pιperidon der Formel XXI und einem Ester der Formel XXII findet unter den Bedingungen der Aldolreaktion, in einem Losungsmittel wie Methanol, Ethanol, Toluol, Tetrahydrofuran, Diethylether oder Dimethylformamid, vorzugsweise Tetrahydrofuran oder Dimethylformamid, unter Verwendung einer Base wie Natrium- oder Kahummethylat oder -ethylat, Natriumhydrid, Kaliumhvdrid Lithiumdiisopropylamid, Kaliumhexamethyldisilazid, vorzugsweise Natriumhydrid oder Lithiumdnsopropylamid und bei Temperaturen zwischen -78°C. und 90°C. bevorzugt jedoch bei -78°C. und Raumtemperatur statt. Die Entfernung von Benzylschutzgruppen erfolgt bei Bedarf durch katalytischc Hydrierung wie z B durch Palladium/Kohle/Wasserstoff. Die Mitsunobureaktion zwischen einer Verbindung der Formel XVIII und Phthalimid wird nach Literaturverfahren durchgeführt (Mitsunobu O. , Synthesis, Seite 1 ( 1981 )). The reaction between 3- or 4-pιperidone of formula XXI and an ester of formula XXII takes place under the conditions of the 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 or potassium methylate or ethylate, sodium hydride, potassium hydride, lithium diisopropylamide, potassium hexamethyldisilazide, preferably sodium hydride or lithium diisopropylamide, and at temperatures between -78 ° C. and 90 ° C. however preferred at -78 ° C. and room temperature instead. If necessary, benzyl protective groups are removed by catalytic hydrogenation, for example by palladium / carbon / hydrogen. The Mitsunobu reaction between a compound of formula XVIII and phthalimide is carried out according to literature methods (Mitsunobu O., Synthesis, page 1 (1981)).
Die reduktive Aminierung eines Ketons der Formel XVI mit Dibenzylamin oder einem Amin der Formel XXV erfolgt nach literaturbekannten Verfahren durch Umsetzung der Keton- und Aminkomponente in einem Losungsmittel wie Methanoi oder Ethanol in Gegenwart eines Reduktionsmittels wie Natriumcyanoborhydrid oder Natriumtriacetato- borhydrid unter Zugabe einer Bronsted - oder Lewissaure wie Salzsaure, Essigsaure, Titantetrachlorid oder Titantetraisopropylat und bei einer Temperatur zwischen 0° und 100°C. vorzugsweise bei Raumtemperatur, oder in Gegenwart eines Hydrierkatalysators wie Platmdioxid und einer Wasserstoffatomosphare (Borch R. F. , Org.. Synth Coll Vol 6, 499( 1988), Heinzelman R . V. Z. Chem. 8, 270 ( 1968), Mattson R. J ., J . Org.. Chem 55, 2552 ( 1990), Barney C. L. Tetr Letters 3 1, 5547 ( 1990), Hutchins R. O ., J Org.. Chem. 46, 3571 ( 1981)). The reductive amination of a ketone of the formula XVI with dibenzylamine or an amine of the formula XXV is carried out by processes known from the literature by reacting the ketone and amine component in a solvent such as methanoi or ethanol in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoborohydride with the addition of a Bronsted or Lewis acid such as hydrochloric acid, acetic acid, titanium tetrachloride or titanium tetraisopropylate and at a temperature between 0 ° and 100 ° C. preferably at room temperature, or in the presence of a hydrogenation catalyst such as platmdioxide and a hydrogen atom (Borch RF, Org. Synth Coll Vol 6, 499 (1988), Heinzelman R. VZ Chem. 8, 270 (1968), Mattson R. J., J. Org. Chem 55, 2552 (1990), Barney CL Tetr Letters 3 1, 5547 (1990), Hutchins R. O., J Org .. Chem. 46, 3571 (1981)).
Die Nitrosierung einer Verbindung der allgemeinen Formel XIV zu einer Verbindung der Formel XV führt man in der Regel mit Natriumnitrit oder Isoamylnitrit in Wasser oder Ethanol unter Zusatz einer Saure wie Salzsaure oder Essigsaure und bei einer Temperatur zwischen -20°C. und 80°C., vorzugsweise bei Raumtemperatur durch. The nitrosation of a compound of general formula XIV to 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.
Die Reduktion einer Nitrosoverbindung der allgemeinen Formel XV erfolgt nach bekannten Verfahren dadurch, daß man eine Verbindung der Formel XV in einem Losungsmittel wie Wasser, Essigsaure, Ethanol, Tetrahydrofuran oder Diethylether, vorzugsweise Essigsaure oder Tetrahydrofuran mit einem Reduktionsmittel wie elementares Zink, Lithiumaluminiumhydrid oder Natriumaluminiumhydrid, vorzugsweise elementares Zink oder Lithiumaluminiumhydrid und bei einer Temperatur zwischen Raumtemperatur und 120°C., bevorzugt jedoch bei 70°C. umsetzt Die Überführung einer Verbindung der allgemeinen Formel XV in einer Verbindung der Formel IV kann auch hydrogenolytisch unter Verbindung eines Katalysators wie Palladium/Kohle stattfinden (Hatt, H. H. , Org. Synth. Coll Vol . 2, 21 1 (1943), Schuler F. W. , J. Amer. Chem. Soc. 73. 4996 ( 1951 ). Die Oxidation eines Alkohols der allgemeinen Formel XI zu einem Keton der allgemeinen Formel VI erfolgt nach bekannten Verfahren wie der Jones-Oxidation (Jones E. R. H ., J Chem. Soc. 36 (1946)), der Swern-Oxidation (Swern D. , Tetrahedron 34, 1651 (1978), der Dess-Martin Oxidation (Dess D. B. , Martin J. C ., J Org. Chem. 48, 4155 (1983) oder mit einem Brom-Urotropin-Komplex als Oxidationsmittel (Yavari I . , J. Chem. Res. (S) 274 ( 1994) . The reduction of a nitroso compound of the general formula XV is carried out by known processes in that 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., but preferably at 70 ° C. The conversion of a compound of the general formula XV into a compound of the formula IV can also take place hydrogenolytically using a catalyst such as palladium / carbon (Hatt, HH, Org. Synth. Coll Vol. 2, 21 1 (1943), Schuler FW, J. Amer. Chem. Soc. 73, 4996 (1951). The oxidation of an alcohol of the general formula XI to a ketone of the general formula VI is carried out by known processes such as Jones oxidation (Jones ER H., J Chem. 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 with a bromine-urotropin complex as an oxidizing agent (Yavari I., J Chem. Res. (S) 274 (1994).
Die verwendeten Wittigreagenzien werden gegebenenfalls analog zu literaturbekannten Verfahren herstellt (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 reagents used are optionally prepared analogously to processes known from the literature (Buddras J., Angew. Chem. 80, 535 (1968), Bestmann HJ Angew Chem. 77, 620, 651 (1965); Wittig G. Ber. German. Chem. Ges 88, 1654 (1955)).
Die Wittigreaktion erfolgt nach bekannten Verfahren durch Ruckflußerhitzen der Reaktanten in einem aprotischen Losungsmittel wie Benzol, Toluol oder Xylol, vorzugsweise Toluol. The Wittig reaction is carried out according to known methods by refluxing the reactants in an aprotic solvent such as benzene, toluene or xylene, preferably toluene.
Die Phthalimidhydrolyse erfolgt in der Regel nach bekannten Verfahren durch Behandlung des Phthalimids mit Hydrazinhydrat oder halbkonzentrierter Mineralsaure wie Salzsaure oder Schwefelsaure, vorzugsweise mit Hydrazinhydrat oder Salzsaure bei Raumtemperatur. Phthalimide hydrolysis is generally carried out by known processes by treating the phthalimide with hydrazine hydrate or semi-concentrated mineral acid such as hydrochloric acid or sulfuric acid, preferably with hydrazine hydrate or hydrochloric acid at room temperature.
Die Acylierung von Aminen mit einem Acylierungsmittel führt man in der Regel in einem Losungsmittel wie Methylenchlorid, Dimethylformamid oder Pyridin, vorzugsweise Methylenchlorid oder Pyridin unter Zusatz einer Hilfsbase wie Triethylamin oder 4-Dime- thylaminopyridin und bei einer Temperatur zwischen - 10°C. und 50°C. bevorzugt jedoch bei Raumtemperatur durch. Als Acylierungsmittel kommen Carbonsaurehalogenide wie Acetylchlorid, Propionidbromid oder Benzyloxycarbonylchlorid oder Carbonsaureanhy- dride wie Acetanhydrid oder Di-tert -butyl-dicarbonat bevorzugt jedoch Acetanhydrid, Benzyloxycarbonylchlorid oder Di-tert -butyl-dicarbonat in Frage. Die Epoxydierung eines Olefins der Formel VII oder der Formel X oder der Formel VIII oder der Formel XXVIII erfolgt nach hteraturbekannten Verfahren durch ihre Umsetzung mit einer Persaure wie m-Chlorperbenzoesaure, Peressigsaure oder Trifluorperessigsaure, vorzugsweise m-Chlorperbenzoesaure in einem aprotischen Losungsmittel wie Methylenchlorid und bei einer Temperatur zwischen -30°C. und 50°C., vorzugsweise Raumtemperatur; weiterhin lassen sich die oben angeführten Olefine mittels der Sharpless-Epoxydierung in die entsprechenden Epoxyde überführen (Sharpless K. B. , Org. Syntheses, Vol 63, 66 ( 1985)). The acylation of amines with an acylating agent is generally carried out 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-dimethylaminopyridine and at a temperature between -10 ° C. and 50 ° C. but preferably at room temperature. Suitable acylating agents are carboxylic acid halides such as acetyl chloride, propionide bromide or benzyloxycarbonyl chloride or carboxylic acid anhydrides such as acetic anhydride or di-tert-butyl dicarbonate, but preferably acetic anhydride, benzyloxycarbonyl chloride or di-tert-butyl dicarbonate. The epoxidation of an olefin of the formula VII or of the formula X or of the formula VIII or of the formula XXVIII is carried out by processes which are known from the nature Reaction 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 room temperature; Furthermore, the olefins mentioned above can be converted into the corresponding epoxides by means of the Sharpless epoxidation (Sharpless KB, Org. Syntheses, Vol 63, 66 (1985)).
Bei der im Schema 3 erwähnten metallorganischen Reaktion handelt es sich in der Regel um die Grignard-Reaktion, die nach literaturbekannten Verfahren durchgeführt wird. Gegebenenfalls kann jedoch das Magnesiumreagenz der Formel XX in ein Lithium- oder Titanreagenz überführt werden, bevor es mit einer Carbonylverbindung der Formel VI umgesetzt wird (Reetz M . T. , Chem. Ber . 118, 1421 ( 1985)) . The organometallic reaction mentioned in Scheme 3 is usually the Grignard reaction, which is carried out using methods known from the literature. However, the magnesium reagent of the formula XX can optionally be converted into a lithium or titanium reagent before it is reacted with a carbonyl compound of the formula VI (Reetz M.T., Chem. Ber. 118, 1421 (1985)).
Die Überführung eines Aminoalkohols der Formel III in eine Verbindung der Formel 1 (Schema 1) erfolgt nach literaturbekannten Verfahren durch Umsetzung eines Aminoalkohols der Formel III mit Diethylcarbonat (Evans D. A , Org. Syntheses, Vol. 68, 77 ( 1989)) oder Carbonyidiimidazol (Chadwick D .I , J . Chem. Soc. Perkin Trans. 481 ( 1984), Geflfken D . Arch Pharm 313, 817 ( 1980)) oder Phosgen (Newman W S . J Am Chem. Soc. 73, 4199 ( 1951 )) oder Di-oder Triphosen (Hassner A , Synth Commun 23, 2839 ( 1993)), oder Chlorameisensauremethyl-. -ethyl oder -benzylester (Kanoshinzo. J Org. Chem. 53, 3865 ( 1988)), oder Thiophosgen (Dubey S . K , Can. J . Chem. , 6 1 565. ( 1983)), oder Thiocarbonyldiimidazol (Goering B . K. , Tetrahedron Lett 35 (38), 6997, (1994)) oder Kohlenschwefelstoff (Zinner H. , J . Prakt Chem. , 15, 72 ( 1962)) oder Bromcyan (Mousseron, Bull Soc. Chim Fr , 737 (1953)) oder Alkylisonitril (lto Y. , J Orga. nomet Chem. , 1 31 121 ( 1977)) oder (N-Acyl- oder N-Sulfonyi)- dithiocarbaminsauredimethylester (Bretschneider H. , Monatsh Chem. 103, 1377 ( 1972), Evers R., J. Prakt Chem. , 333, 699 (1991)) oder l-Amidino-3,5-pyrazol-nitrat (Fotsch C H , Tetrahedron Lett., 35, 2481 (1994) in einem Losungsmittel wie Methylenchlorid, Dimethylformamid, Toluol, Xylol, Ethanol, Dioxan, Tetrahydrofuran, Wasser oder Diethylether, vorzugsweise Dimethylformamid, Methylenchlorid, Ethanol oder Tetrahydrofuran, gegebenenfalls unter Zusatz einer Hilfsbase wie Triethylamin oder Pyridm und bei einer Temperatur zwischen -50°C. und 80°C., vorzugsweise bei Raumtemperatur. An amino alcohol of the formula III is converted into a compound of the formula 1 (Scheme 1) by processes known from the literature by reacting an amino alcohol of the formula III with diethyl carbonate (Evans D. A, Org. Syntheses, Vol. 68, 77 (1989)) or Carbonyidiimidazole (Chadwick D. I, J. Chem. Soc. Perkin Trans. 481 (1984), Geflfken D. Arch Pharm 313, 817 (1980)) or Phosgene (Newman WS. J Am Chem. Soc. 73, 4199 (1951 )) or Di- or Triphosen (Hassner A, Synth Commun 23, 2839 (1993)), or chloroformic acid methyl. ethyl or benzyl ester (Kanoshinzo. J Org. Chem. 53, 3865 (1988)), or thiophosgene (Dubey S.K., Can. J. Chem., 6 1 565. (1983)), or thiocarbonyldiimidazole (Goering B . K., Tetrahedron Lett 35 (38), 6997, (1994)) or carbon sulfide (Zinner H., J. Prakt Chem., 15, 72 (1962)) or bromine cyan (Mousseron, Bull Soc. Chim Fr, 737 ( 1953)) or alkylisonitrile (lto Y., J Orga. Nomet Chem., 1 31 121 (1977)) or (N-acyl- or N-sulfonyi) - dimethyl dithiocarbamate (Bretschneider H., monthly H Chem. 103, 1377 (1972 ), Evers R., J. Prakt Chem., 333, 699 (1991)) or l-amidino-3,5-pyrazole nitrate (Fotsch CH, Tetrahedron Lett., 35, 2481 (1994) in a solvent such as methylene chloride , Dimethylformamide, toluene, xylene, ethanol, dioxane, tetrahydrofuran, water or diethyl ether, preferably dimethylformamide, methylene chloride, ethanol or tetrahydrofuran, optionally with the addition of an auxiliary base such as triethylamine or Pyridm and at a temperature between -50 ° C. and 80 ° C., preferably at room temperature.
Die katalytische Hydrierung einer Verbindung der Formel XXIV fuhrt man in einem Losungsmittel wie Methanol oder Ethanol unter Zusatz eines Katalysators wie Ruthe- niumoxid, Rhodiumoxid oder Palladium/Strontiumcarbonat vorzugsweise Rhodiumoxid in einer Wasserstoffatmosphare bei einem Druck von 1-200 bar vorzugsweise bei 200 bar und einer Temperatur zwischen Raumtemperatur und 200°C. durch (Rastin R H , 1 Chem. Soc. 1855 (1949). The 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 a hydrogen atmosphere at a pressure of 1-200 bar, preferably at 200 bar and one Temperature between room temperature and 200 ° C. by (Rastin R H, 1 Chem.Soc. 1855 (1949).
Die Epoxidoffhung eines Epoxids der Formel V mit einem Amin der Formel IV (Schema1 ) oder eines Epoxids der Formel IX mit einem Amin der Formel XII (Schema 4) findet in der Regel in einem Losungsmittel wie Methanol, Ethanol, Dimethylformamid oder Toluol, vorzugsweise Ethanol oder Toluol und bei einer Temperatur zwischen 0°C. und 120°C. vorzugsweise 80°C. statt. The epoxy opening of an epoxide of the formula V with an amine of the formula IV (Scheme 1) or an epoxide of the formula IX with an amine of the formula XII (Scheme 4) usually takes place 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. instead of.
Die Epoxidoffnung eines Epoxids der Formel V (Schema 1 ) mit einem Metallazid erfolgt nach literaturbekannten Verfahren durch Umsetzung eines Epoxids der I ormel V mit einem Metallazid wie Lithium- Natrium-, Kalium- Tributylzinn- oder Magnesi- umazid vorzugsweise Natriumazid, in einem Losungsmittel wie Methanol Ethanol 1 ,4-Dιoxan, Wasser, Dimethylformamid Tetrahydrofuran Acetomtril oder Hexame- thylphosphortriamid, oder in Mischungen der genannten Losungsmittel bevorzugt jedoch in Methanol, Dimethylformamid oder 1,4-Dιoxan-Wasser Gemischen und bei einer Reaktionstemperatur zwischen - 10 °C. und 120 °C. vorzugsweise 80 °C. (Vanderverf C. A. , J. Am. Chem. Soc. 76, 1231 (1954), Saito S ., Tetrahedron Lett 30, 4153 ( 1989), Hudlicky T. , J . Chem. So Perkin Trans 1, 2907 (1991)) Die Umsetzung eines Epoxids der Formel V mit Trimethylsilylazid findet in der Regel in einem Losungsmittel wie Methanol Tetrahydrofuran, Methylenchlorid, Chloroform, Dichlor-ethan oder Benzol vorzugsweise Tetrahydrofuran oder Methylenchlorid, ohne weitere Zusätze oder unter Verwendung von Zusätzen wie Titantetraisopropylat Aluminiumtriisopropylat Dichlor-titandrisopropylat oder Diethylaluminumfluorid, v orzugsweise Titantetraiso- propylat oder Aluminiumtriisopropylat und bei einer Temperatur zwischen 0 °C. und 100 °C. bevorzugt jedoch bei Raumtemperatur statt (Emziane M., Synthesis, S . 541 ( 1988); Saito S., Tetrahedron Lett. 26, 5309 (1985); Blandy C , Tetrahedron Lett. 24, 4189 (1983); Jung M. E., J. Org. Chem. , 56, 2614 ( 1991 )) . The epoxy opening of an epoxide of the formula V (scheme 1) with a metal azide is carried out according to methods known from the literature by reacting an epoxide of the formula V with a metal azide such as lithium, sodium, potassium, tributyltin or magnesium azide, preferably sodium azide, in a solvent such as Methanol ethanol 1, 4-dioxane, water, dimethylformamide tetrahydrofuran acetomtril or hexamethylphosphoric triamide, or in mixtures of the solvents mentioned, but preferably in methanol, dimethylformamide or 1,4-dioxane-water mixtures and at a reaction temperature between - 10 ° C. and 120 ° C. preferably 80 ° C. (Vanderverf CA, J. Am. Chem. Soc. 76, 1231 (1954), Saito S., Tetrahedron Lett 30, 4153 (1989), Hudlicky T., J. Chem. So Perkin Trans 1, 2907 (1991)) The reaction of an epoxide of the formula V with trimethylsilyl azide usually takes place in a solvent such as methanol, tetrahydrofuran, methylene chloride, chloroform, dichloroethane or benzene, preferably tetrahydrofuran or methylene chloride, without further additives or using additives such as titanium tetraisopropylate, aluminum triisopropylate, dichlorotitanium trisaluminum fluoride or diethyl fluoride , preferably titanium tetraiso propylate or aluminum triisopropylate and at a temperature between 0 ° C. and 100 ° C. however, preferred at room temperature instead (Emziane M., Synthesis, p. 541 (1988); Saito S., Tetrahedron Lett. 26, 5309 (1985); Blandy C, Tetrahedron Lett. 24, 4189 (1983); Jung ME, J Org. Chem., 56, 2614 (1991)).
Die Umsetzung einer Verbindung der Formel XXXI mit einem Metallazid zu einer Verbindung der Formel XXVI (Schema 4) stellt, für den Fall, daß L1 die Bedeutung von L besitzt, eine nucleophile Substitution dar, die nach Standard verfahren der organischen Synthese durchgeführt wird . The reaction of a compound of formula XXXI with a metal azide to a compound of formula XXVI (Scheme 4) represents, in the event that L 1 is L, a nucleophilic substitution which is carried out according to standard methods of organic synthesis.
Die Deacyiierung einer Verbindung der Formel XXX zu einer Verbindung der Formel XXV führt man nach üblichen Verfahren durch, in dem man eine Verbindung der Formel XXX in Wasser oder in einem Gemisch aus Wasser. Tetrahydrofuran, Dioxan, Methanol oder Ethanol vorzugsweise in einem Wasser/ Tetrahydrofürangemisch mit einem Hydroxid wie Natrium-, Kalium-, oder Lithiumhydroxid, vorzugsweise Natriumoder Lithiumhydroxid, oder mit einer Säure wie Salzsaure, Schwefelsäure oder Trifluoressigsaure, vorzugsweise Trifluoressigsaure oder mit Palladium/KohleAVasserstoff und bei Temperaturen zwischen Raumtemperatur und 80°C., vorzugsweise bei Raumtemperatur, behandelt. The deacyiation of a compound of the formula XXX to a compound of the formula XXV is carried out by customary methods in which a compound of the formula XXX is in water or in a mixture of water. Tetrahydrofuran, dioxane, methanol or ethanol preferably in a water / tetrahydrofuran mixture 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 A hydrogen and at Temperatures between room temperature and 80 ° C., preferably at room temperature, treated.
Die Überführung eines Azids der Formel XXVI in ein Amin der Formel XXV erfolgt nach bekannten Verfahren 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); Horner L , Liebigs Ann. Chem. , 591, 1 17 (1955); Koziara A Synthesis, S. 487 (1987), Vogel E. , Ang Chem. Int Ed Engl , 18, 962 (1979); Purwono B. , Synlett, 3, 231 (1992) An azide of the formula XXVI is converted into an amine of the formula XXV by known processes Suami T., Bull Chem. Soc.Jpn, 51, 855 (1978), Boullanger P, Bull.Soc. Chim.Fr, p. 2149 (1973); Ackerman K., Can J. Chem. , 50, 3886 (1972); Hanessian S., Chem. Ind., S 1296 (1965); Horner L, Liebigs Ann. Chem., 591, 1 17 (1955); Koziara A Synthesis, p. 487 (1987), Vogel E., Ang Chem. Int Ed Engl, 18, 962 (1979); Purwono B., Synlett, 3, 231 (1992)
Verbindungen der Formel I enthalten ein oder mehrere chirale Zentren und können daher in racemischer oder in optisch-aktiver Form vorliegen Racemate können nach an sich bekannten Methoden mechanisch oder chemisch in die enantiomeren getrennt werden Vorzugsweise werden aus dem racemischen Gemisch durch Umsetzen mit einer optisch aktiven Saure wie die D- und L-Formen von Weinsaure, Diacetylweinsaure, Dibenzoylweinsaure, Mandelsaure, Apfelsaure, Milchsaure oder die verschiedenen optisch-aktiven Camphersulfonsauren wie ß-Camphersulfonsaure Diastereomere gebildet . Compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates can be mechanically or chemically separated into the enantiomers by methods known per se. The racemic mixture is preferably reacted with an optically active acid such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphor sulfonic acids such as ß-camphor sulfonic acid diastereomers.
Naturlich ist es auch möglich, optisch-aktive Verbindungen der Formel I nach den oben beschriebenen Methoden zu erhalten, indem man Ausgangsstoffe (z. B. solche der FormelV oder VIII) verwendet, die bereits optisch-aktiv sind . Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above, using starting materials (for example those of the formula V or VIII) which are already optically active.
Im Sinne der vorliegenden Erfindung sind auch alle Prodrug-Formen von Verbindungen der allgemeinen Formel I beansprucht, besonders jedoch Carbonsaureester der allgemeinen Formel I, in der R8 den Methyl-, Ethyl-, n-Propyl-, Isopropyl-, Butyl-, Phenyl- oder Benzylrest insbesondere den Methyl-, Ethyl- oder Benzylrest bedeutet. For the purposes of the present invention, all prodrug forms of compounds of the general formula I are also claimed, but especially carboxylic acid esters of the general formula I in which R 8 is methyl, ethyl, n-propyl, isopropyl, butyl or phenyl - or benzyl radical means in particular the methyl, ethyl or benzyl radical.
Als pharmakologisch vertragliche Salze werden vor allem Alkalisalze, Ammoniumsalze, Trifluoracetate oder Hydrochloride verwendet, die man üblicher Weise z. B. durch Titration der Verbindungen mit anorganischen oder organischen Basen oder Sauren wie z. B. Natrium- oder Kaliumhydrogencarbonat, Natronlauge, Kalilauge, wäßrigem Ammoniak oder Amine wie z. B. Trimethyl- oder Triethylamin, Trifluoressigsaure oder Salzsaure herstellt Die Salze werden in der Regel durch Umfallen aus Wasser/Aceton gereinigt. As pharmacologically acceptable salts, especially alkali salts, ammonium salts, trifluoroacetates or hydrochlorides are used. B. by titration of the compounds with inorganic or organic bases or acids such. B. sodium or potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous ammonia or amines such as. B. Trimethyl- or triethylamine, trifluoroacetic acid or hydrochloric acid. The salts are usually purified by falling over from water / acetone.
Die erfindungsgemaßen neuen Substanzen der Formel I und ihre Salze können in flussiger oder fester Form enteral oder parenteral appliziert werden Hierbei kommen alle üblichen Apphkationsformen infrage, beispielsweise Tabletten. Kapseln, Dragees, Sirupe, Losungen, Suspension etc Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslosungen üblichen Zusätze wie Stabilisierungsmittel, Losungsvermittler und Puffer enthalt. Derartige Zusätze sind z. B. Tartrat- und Citrat-Puffer, Ethanol, Komplexbildner (wie Ethylendiamintetraessigsaure und deren nichttoxische Salze), hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregelung Flussige Trägerstoffe für Injektionslόsungen müssen steril sein und werden vorzugsweise in Ampullen abgefüllt Feste Tragerstoffe sind z. B. Starke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsauren, hohermolekulare Fettsauren (wie Stearinsaure), Gelatine, Agar-Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette, feste hochmolekulare Polymere (wie Polyethylenglykole); für orale Applikation geeignete Zubereitungen können gewunschtenfalls Geschmacks- und Süßstoffe enthalten. The novel substances of the formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form. All customary forms of administration, for example tablets, can be used here. Capsules, dragees, syrups, solutions, suspensions, etc. Water is preferably used as the injection medium, which contains the additives common to injection solutions such as stabilizers, solubilizers and buffers. Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, high molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
Die Dosierung kann von verschiedenen Faktoren, wie Applikationsweise, Spezies. Alter und/oder individuellem Zustand abhangen. Die tägliche zu verabreichenden Dosen liegen bei etwa 1-1000 mg/Mensch, vorzugsweise bei 100-500 mg/Mensch und können auf einmal oder mehrere Male verteilt eingenommen werden. The dosage can depend on various factors, such as the mode of administration and the species. Depend on age and / or individual condition. The daily doses to be administered are approximately 1-1000 mg / person, preferably 100-500 mg / person, and can be taken in one or more times distributed.
Bevorzugt im Sinne der vorliegenden Erfindung sind außer den in den Beispielen genannten Verbindungen und durch Kombination aller in den Ansprüchen genannten Bedeutungen der Substituenten ableitbaren Verbindungen die folgenden Oxazolidinmonderivate: For the purposes of the present invention, preference is given to the following oxazolidinone derivatives in addition to the compounds mentioned in the examples and by combining all the meanings of the substituents mentioned in the claims:
1 ) 1-[2-Oxo-3-( 1 -pyrimidin-4-yl-piperidin-4-yl)-octahydro-benzooxazol-7-yl]-piperidin¬1) 1- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-4-yl) octahydro-benzooxazol-7-yl] -piperidin¬
4-carbonsaure 4-carboxylic acid
2) 1 -{2-Oxo-3-[ 1-(2-pyrrolidin- 1-yl-pyrimidin-4-yl)-piperidin-4-yl]-octahydrobenzooxazol-7-yl }-piperidin-4-carbonsaure  2) 1 - {2-Oxo-3- [1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) piperidin-4-yl] octahydrobenzooxazol-7-yl} piperidine-4-carboxylic acid
3) { 1-[2-Oxo-3-(1-pyrimidin-4-yl-piperidin-4-yl)-octahydro-benzooxazol-7-yl]piperidin-4-yl }-essigsaure 3) {1- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-4-yl) octahydro-benzooxazol-7-yl] piperidin-4-yl} acetic acid
4) ( 1-{3-[ 1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro-benzooxazol-7yl}-piperidin-4-yl)-essigsäure  4) (1- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7yl} -piperidin-4-yl) acetic acid
5) (1-{3-[ 1-(2-Methylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydrobenzooxazol-7-yl}-piperidin-4-yl)-essigsäure 6) ( 1 -{2-Oxo-3-[ 1-(2-phenylamino-pyrimidin-4-yl)-piperidin-4-yl]-octahydro- benzooxazol-7-yl }-piperidin-4-yl)-essigsaure 5) (1- {3- [1- (2-Methylamino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydrobenzooxazol-7-yl} piperidin-4-yl) acetic acid 6) (1 - {2-oxo-3- [1- (2-phenylaminopyrimidin-4-yl) piperidin-4-yl] octahydro-benzooxazol-7-yl} piperidin-4-yl) - acetic acid
7) 2-Methanesulfonylamino-3-{ 1-[2-oxo-3-( l-pyrimidin-4-yl-piperidin-4-yl)-octahydro- benzooxazol-7-yl]-piperidin-4-yl}-propionsäure  7) 2-methanesulfonylamino-3- {1- [2-oxo-3- (l-pyrimidin-4-yl-piperidin-4-yl) octahydro-benzooxazol-7-yl] -piperidin-4-yl} - propionic acid
8) 1-[2-Oxo-3-(1-pyrimidin-4-yl-piperidin-4-yl)-octahydro-benzooxazol-7-ylmethyl]- piperidin-4-carbonsaure 8) 1- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-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-carbonsaure  9) 1 - [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-ylmethyl] -piperidin-4- carboxylic acid
10) 1-{ 3-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro-benzooxazol-7- ylmethyl }-piperidin-4-carbonsaure  10) 1- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-ylmethyl} piperidine-4-carboxylic acid
1 1) 1-{ 2-Oxo-3-[ 1-(2-piperidin-1-yl-pyrimidin-4-yl)-piperidin-4-yl]-octahydro- benzooxazol-7-ylmethyl }-piperidin-4-carbonsaure  1 1) 1- {2-Oxo-3- [1- (2-piperidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-benzooxazol-7-ylmethyl} -piperidin-4 -carboxylic acid
12) 1-{ 3-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro-benzooxazol-7- yl}-piperidin-4-carbonsäure  12) 1- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} piperidine-4-carboxylic acid
13) 1-{3-[1-(2-Benzylamιno-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- benzooxazol-7-ylmethyl}-piperidin-4-carbonsaure 13) 1- {3- [1- (2-Benzylaminopyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-ylmethyl} -piperidine-4-carboxylic acid
14) 4-{3-[1-(2-Benzylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- benzooxazol-7-ylmethyl }-cyclohexancarbonsaure  14) 4- {3- [1- (2-Benzylamino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-ylmethyl} cyclohexane carboxylic acid
15) 4-{ 3-[1-(2-Benzylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- benzooxazol-7-ylmethyl }-4-hydroxy-cyclohexancarbonsaure  15) 4- {3- [1- (2-Benzylaminopyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-ylmethyl} -4-hydroxy-cyclohexane carboxylic acid
16) 4-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[ 1,4']bipyridinyi-4-yl)-octahydro-benzooxazol- 16) 4- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyi-4-yl) octahydro-benzooxazole-
7-yl]-cyclohexancarbonsaure 7-yl] cyclohexane carboxylic acid
17) 4-{3-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro-benzooxazol-7- yl }-cyclohexancarbonsaure  17) 4- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} cyclohexane carboxylic acid
18) 4-Ηydroxy-4-[2-oxo-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-cyclohexancarbonsaure 18) 4-hydroxy-4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] - cyclohexane carboxylic acid
19) 4-Hydroxy-4-{2-oxo-3-[1 -(2-pyrrolidin- 1 -yl-pyrimidin-4-yl)-piperidin-4-yl]- octahydro-benzooxazol-7-yl}-cyclohexancarbonsaure  19) 4-Hydroxy-4- {2-oxo-3- [1 - (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] - octahydro-benzooxazol-7-yl} - cyclohexane carboxylic acid
20) { 1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridtnyl-4-yl)-octahydro-benzooxazol- 7-yl]-piperidin-4-yl}-essigsaure 21 ) 2-(Butane- 1 -sulfonylamino)-3-{ 1-[2-oxo-3-(3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-20) {1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridtnyl-4-yl) octahydro-benzooxazol-7-yl] piperidin-4 -yl} -acetic acid 21) 2- (butanes-1 -sulfonylamino) -3- {1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyl-
4-yl)-octahydro-benzooxazol-7-yl]-piperidin-4-yl}-propionsaure 4-yl) octahydro-benzooxazol-7-yl] piperidin-4-yl} propionic acid
22) 1-{2-[2-Oxo-3-(3,4,5,6-tetrahydro-2H -[1,4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-ethyl }-piperidin-4-carbonsaure  22) 1- {2- [2-Oxo-3- (3,4,5,6-tetrahydro-2H - [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] ethyl } -piperidine-4-carboxylic acid
23 ) 1-{3-[1-(2-Methylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- benzooxazol-7-yl}-piperidin-4-carbonsaure 23) 1- {3- [1- (2-Methylamino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} piperidine-4-carboxylic acid
24) 1-{ 3-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[ 1 ,4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-propyl}-piperidin-4-carbonsaure  24) 1- {3- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] propyl } -piperidine-4-carboxylic acid
25) 1-{ 3-[2-Oxo-3-( 1 -pyrimidin-4-yl-piperidin-4-yl)-octahydro-benzooxazol-7-yl]- propyl }-piperidin-4-carbonsaure  25) 1- {3- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-4-yl) octahydro-benzooxazol-7-yl] propyl} -piperidine-4-carboxylic acid
26) 1 -(3-{ 3-[1-(2-A mino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro-benzooxazol- 26) 1 - (3- {3- [1- (2-A mino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazole-
7-yl }-propyl)-piperidin-4-carbonsaure 7-yl} propyl) piperidine-4-carboxylic acid
27) 1 -[2-Oxo-3-(1-pyrida zin-4-yl-piperidin-4-yl)-octahydro-bernzooxazol-7-yl]- piperidin-4-carbonsaure  27) 1 - [2-Oxo-3- (1-pyrida zin-4-yl-piperidin-4-yl) octahydro-bernzooxazol-7-yl] - piperidine-4-carboxylic acid
28) { 1-[2-Oxo-3-(1-pyridazin-4-yl-piperidin-4-yl)-octahydro-benzoox azol-7-yl]- piperidin-4-yl}-essigsaure 28) {1- [2-Oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) octahydro-benzoox azol-7-yl] - piperidin-4-yl} acetic acid
29) 1-[2-Oxo-3-( 1-pyridazin-4-yl-piperidin-4-yl)-octahydro-benzooxazol-7-ylmethyl]- piperidin-4-carbonsaure  29) 1- [2-Oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) octahydro-benzooxazol-7-ylmethyl] - piperidine-4-carboxylic acid
30) 4-[2-Oxo-3-( 1-pyridazin-4-yl-pιperidin-4-yl)-octahydro-benzooxazol-7-yl]- cyclohexancarbonsaure  30) 4- [2-Oxo-3- (1-pyridazin-4-yl-pιperidin-4-yl) octahydro-benzooxazol-7-yl] cyclohexane carboxylic acid
3 1 ) 1 -{3-[2-Oxo-3-(1-pyridazin-4-yl-piperidin-4-yl)-octahydro-benzooxazol-7-yl]- propyl }-piperidin-4-carbonsaure  3 1) 1 - {3- [2-Oxo-3- (1-pyridazin-4-yl-piperidin-4-yl) octahydro-benzooxazol-7-yl] propyl} piperidine-4-carboxylic acid
32) 1-[2-Oxo-3-(4-pyrimidin-4-yl-piperazin-1 -yl)-octahydro-benzooxazol-7-yl]- piperidin-4-carbonsaure 32) 1- [2-Oxo-3- (4-pyrimidin-4-yl-piperazin-1-yl) octahydro-benzooxazol-7-yl] - piperidine-4-carboxylic acid
33) 4-[2-Oxo-3-(4-pyrimidin-4-yl-piperazin-1-yl)-octahydro-benzooxazol-7-yl]- cyclohexancarbonsaure 33) 4- [2-Oxo-3- (4-pyrimidin-4-yl-piperazin-1-yl) octahydro-benzooxazol-7-yl] cyclohexane carboxylic acid
34) (±)-(3'α,7'β,7α)-1-{3-[1-(2-Benzylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo- octahydro-benzooxazol-7-yl}-piperidin-4-carbonsaure  34) (±) - (3'α, 7'β, 7α) -1- {3- [1- (2-Benzylamino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro -benzooxazol-7-yl} -piperidine-4-carboxylic acid
35) 1-{2-[2-Oxo-3-(4-pyridin-4-yl-piperazin-1-yl)-octahydro-benzooxazol-7-yl]-ethyl}- piperidin-4-carbonsaure 36) 1-[2-Oxo-3-(1-pyrimidin-4-yl-piperidin-4-yl)-hexahydro-cyclopentaoxazol-6-yl]- piperidin-4-carbonsaure 35) 1- {2- [2-Oxo-3- (4-pyridin-4-yl-piperazin-1-yl) octahydro-benzooxazol-7-yl] ethyl} - piperidine-4-carboxylic acid 36) 1- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-4-yl) hexahydro-cyclopentaoxazol-6-yl] - piperidine-4-carboxylic acid
37) 1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-y l)-hexahydro- cyciopentaoxazol-6-yl]-piperidin-4-carbonsaure  37) 1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) hexahydro-cyciopentaoxazol-6-yl] piperidin-4- carboxylic acid
38) 1-{3-[ 1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-hexahydro- cyclopentaoxazol-6-yl }-piperidin-4-carbonsaure 38) 1- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-hexahydro-cyclopentaoxazol-6-yl} piperidine-4-carboxylic acid
39) ( 1 -{2-Oxo-3-[1-(2-phenylamino-pyrimidin-4-yl)-piperidin-4-yl]-hexahydro- cyclopentaoxazol-6-yl}-piperidin-4-yl)-essigsäure  39) (1 - {2-oxo-3- [1- (2-phenylaminopyrimidin-4-yl) piperidin-4-yl] hexahydrocyclopentaoxazol-6-yl} piperidin-4-yl) - acetic acid
40) 1-{ 2-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1 ,4']biρyridinyl-4-yl)-hexahydro- cyclopentaoxazol-6-yl]-ethyl }-piperidin-4-carbonsaure  40) 1- {2- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] biyridinyl-4-yl) hexahydrocyclopentaoxazol-6-yl] ethyl } -piperidine-4-carboxylic acid
41 ) 1 -[2-Oxo-3-( 1 -pyridazin-4-yl-piperidin-4-yl)-hexahydro-cyclopentaoxazol-6-yl]- piperidin-4-carbonsaure  41) 1 - [2-Oxo-3- (1-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-cvclopentaoxazol-6-yl]- piperidin-4-carbonsäure  42) 1- [2-Oxo-3- (4-pyridin-4-yl-piperazin-1-yl) hexahydro-cclopentaoxazol-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]-cyclohexancarbonsaure 43) 4-Hydroxy-4- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) hexahydrocyclopentaoxazol-6-yl] - cyclohexane carboxylic acid
44) 1-[2-Oxo-3-( 1-pyrimidin-4-yl-piperidin-4-yl)-octahydro-cycloheptaoxazol-8-yl]- piperidin-4-carbonsaure  44) 1- [2-Oxo-3- (1-pyrimidin-4-yl-piperidin-4-yl) octahydro-cycloheptaoxazol-8-yl] - piperidine-4-carboxylic acid
45) 1 -{ 2-Oxo-3-[1-(2-phenylamino-pyrimidin-4-yl)-piperidin-4-yl]-octahydro- benzooxazol-7-yl }-piperidin-4-carbonsaure  45) 1 - {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']bipyridinyi-4-yl)-octahydro- cycloheptaoxazol-8-yl]-piperidin-4-carbonsaure  46) 1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyi-4-yl) octahydrocycloheptaoxazol-8-yl] piperidin-4- carboxylic acid
47) 1-{ 3-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- cycloheptaoxazol-8-yl}-piperidin-4-carbonsaure  47) 1- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-cycloheptaoxazol-8-yl} piperidine-4-carboxylic acid
48) (1-{ 3-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- cycloheptaoxazol-8-yl}-piperidin-4-yl)-essigsaure 48) (1- {3- [1- (2-aminopyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-cycloheptaoxazol-8-yl} -piperidin-4-yl) - acetic acid
49) 1-{2-Oxo-3-[ 1-(2-piperidin-1 -yl-pyrimidin-4-yl)-piperidin-4-yl]-octahydro- cycloheptaoxazol-8-ylmethyl}-piperidin-4-carbonsaure  49) 1- {2-Oxo-3- [1- (2-piperidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -octahydro-cycloheptaoxazol-8-ylmethyl} -piperidin-4- carboxylic acid
50) 1-(2-Oxo-3-{ 1-[2-(pyridin-4-ylamino)-pyrimidin-4-yl]-piρeridin-4-yl}-octahydro- benzooxazol-7-yl)-piperidin-4-carbonsäure 51) 1-(2-Oxo-3-{1-[2-(pyrimidin-2-ylamino)-pyrimidin-4-yl]-piperidin-4-yl}-octahydro- benzooxazol-7-yl)-piperidin-4-carbonsaure 50) 1- (2-Oxo-3- {1- [2- (pyridin-4-ylamino) pyrimidin-4-yl] -piperidin-4-yl} -octahydro-benzooxazol-7-yl) -piperidine- 4-carboxylic acid 51) 1- (2-Oxo-3- {1- [2- (pyrimidin-2-ylamino) pyrimidin-4-yl] piperidin-4-yl} octahydro-benzooxazol-7-yl) piperidine- 4-carboxylic acid
52) 1-(2-Oxo-3-{1-[2-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-pyrimidin-4-yl]- piperidin-4-yl}-octahydro-benzooxazol-7-yl)-piperidιn-4-carbonsaure  52) 1- (2-Oxo-3- {1- [2- (1,4,5,6-tetrahydro-pyrimidin-2-ylamino) pyrimidin-4-yl] piperidin-4-yl} octahydro -benzooxazol-7-yl) -piperidιn-4-carboxylic acid
53) 1-{3-[1-(2-Cyclohexylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- benzooxazol-7-yl}-piperidin-4-carbonsaure 53) 1- {3- [1- (2-Cyclohexylamino-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid
54) 1-{3-[1-(2-Pyrroiidin-1-yl-pyrimidin-4-yl)-piperidin-4-yl]-2-thioxo-octahydro-benz- ooxazol-7-yl}-piperidin-4-carbonsaure  54) 1- {3- [1- (2-Pyrroiidin-1-yl-pyrimidin-4-yl) piperidin-4-yl] -2-thioxo-octahydro-benzooxazol-7-yl} -piperidine- 4-carboxylic acid
55) 1-{2-Oxo-3-[1-(2-pyrrolidin-1-yl-hexahydro-pyrimidin-4-yl)-piperidin-4-yl]-octahy- dro-benzooxazol-7-yl}-piperidin-4-carbonsaure  55) 1- {2-Oxo-3- [1- (2-pyrrolidin-1-yl-hexahydro-pyrimidin-4-yl) -piperidin-4-yl] -octahyro-dro-benzooxazol-7-yl} - piperidine-4-carboxylic acid
56) 1-{2-Oxo-3-[1-(2-pyrroiιdin-1-yl-1,4,5,6-tetrahydro-pyrimidin-4-yl)-piperidin-4-yl]- octahydro-benzooxazol-7-yl}-piperidin-4-carbonsaure  56) 1- {2-Oxo-3- [1- (2-pyrroidin-1-yl-1,4,5,6-tetrahydro-pyrimidin-4-yl) -piperidin-4-yl] octahydro-benzooxazole -7-yl} -piperidine-4-carboxylic acid
57) 1-[3-(1-Benzyl-[1,4']bipiperidinyl-4-yl)-2-thioxo-octahydro-benzooxazol-7-yl]- piperidin-4-carbonsaure  57) 1- [3- (1-Benzyl- [1,4 '] bipiperidinyl-4-yl) -2-thioxo-octahydro-benzooxazol-7-yl] - piperidine-4-carboxylic acid
58) 1-[2-Acetylimino-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-octahydro-ben- zooxazol-7-yl]-piperidin-4-carbonsaure 58) 1- [2-acetylimino-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] piperidine- 4-carboxylic acid
59) 1-[2-Imino-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-octahydro-benzooxazol- 59) 1- [2-Imino-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazole-
7-yl]-piperidin-4-carbonsaure 7-yl] piperidine-4-carboxylic acid
60) 4-(1H-lndol-3-ylmethvl)-1-[2-oxo-3-(3,4,5,6-tetrahydro-2H-[l,4']bipyridinyl-4-vl)- octahydro-benzooxazol-7-yl]-pιperidin-4-carbonsaure  60) 4- (1H-Indol-3-ylmethylene) -1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-vl) octahydro -benzooxazol-7-yl] -pιperidin-4-carboxylic acid
61) 4-Butyl-1-[2-oxo-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-octahydro-ben- zooxazol-7-yl]-piperidin-4-carbonsaure  61) 4-Butyl-1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl ] -piperidine-4-carboxylic acid
62) 1-[2-Oxo-3-(3,4,5,6-tetrahydro-2-7-[l,4']bipyridinyl-4-yl)-octahydro-benzooxazol- 62) 1- [2-Oxo-3- (3,4,5,6-tetrahydro-2-7- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazole-
7-yl]-4-phenethyl-piperidin-4-carbonsaure 7-yl] -4-phenethyl-piperidine-4-carboxylic acid
63) (-)-(3'S,7'S,7R)-1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1.4,]bipyridinyl-4-yl)-octahy- dro-ber-Zθoxazol-7-yl]-piperidin-4-carbonsaure [α]20 D=-174°(c= 1.18;63) (-) - (3'S, 7'S, 7R) -1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1.4 , ] bipyridinyl-4-yl) octahyroid -ber-Zθoxazol-7-yl] -piperidin-4-carboxylic acid [α] 20 D = -174 ° (c = 1.18;
CHCl3) CHCl 3 )
64) (+)-(3'R,7'R,7S)-1-[2-Oxo-3-(3,4,5,6-tetrahydro-2//-[1.4,]bipyridinyl-4-yl)-octahy- dro-benzooxazol-7-yl]-piperidin-4-carbonsaure [α]20 D=+187°(c= 12, CHCl3) Die nachfolgenden Beispiele zeigen einige der Verfahrensvarianten, die zur Synthese der erfindungsgemaßen Verbindungen verwendet werden können Sie sollten jedoch nicht eine Einschränkung des Erfindungsgegenstandes darstellen. Die Struktur der Verbindungen wurde durch 1Η-, und gegebenenfalls durch 13C-NMR-Spektroskopie sowie durch Massenspektrometrie gesichert. Die Reinheit der Substanzen wurde mittels C, H, N, sowie dunnschichtchromatographisch bestimmt . 64) (+) - (3'R, 7'R, 7S) -1- [2-oxo-3- (3,4,5,6-tetrahydro-2 // - [1.4 , ] bipyridinyl-4- yl) -octahyro-dro-benzooxazol-7-yl] -piperidine-4-carboxylic acid [α] 20 D = + 187 ° (c = 12, CHCl 3 ) The following examples show some of the process variants which can be used for the synthesis of the compounds according to the invention. However, they should not constitute a restriction of the subject matter of the invention. The structure of the compounds was confirmed by 1 Η and, if necessary, by 13 C-NMR spectroscopy and by mass spectrometry. The purity of the substances was determined by means of C, H, N and by thin layer chromatography.
Beispiel 1 example 1
(±)-(3'α ,7 'ß,7α)- 1 -[2-Oxo-3-(3,4,5,6-tetrahydro-2 H-[1,4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-piperidin-4-carbonsaυre (±) - (3'α, 7 'ß, 7α) - 1 - [2-oxo-3- (3,4,5,6-tetrahydro-2 H- [1,4'] bipyridinyl-4-yl ) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid
a) Die Losung von 46 g (0 4 Mol) 4-Chlorpyridin und 123 5 g (0 86 Mol) 4-Pipen- don-ethylenketal wird in 400 ml p-Xylol 48 h am Ruckfluß erhitzt Anschließend wird die Reaktionsmischung abgekühlt, der ausgefallene Niederschlag abfiltriert, die Mutterlauge zur Trockne eingeengt und der Rückstand an Kieselgel saulen- chromatographisch (Essigsaureethylester/gesätt ammonialkalisches Methanol 9/1 ) gereinigt. Mann erhalt so 79.7 g (90 %) 8-Pyridin-4-yl- 1,4-dιoxa-8-aza-spιro- [4.5]decan als weißes Pulver.m/e = 220, Fp = 65°C. a) The solution of 46 g (0 4 mol) of 4-chloropyridine and 123 5 g (0 86 mol) of 4-pipedonethylene ketal is refluxed in 400 ml of p-xylene. The reaction mixture is then cooled, the precipitated precipitate was filtered off, the mother liquor was evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate / saturated ammoniacal methanol 9/1). This gives 79.7 g (90%) of 8-pyridin-4-yl-1,4-dιoxa-8-aza-spιro- [4.5] decane as a white powder. M / e = 220, F p = 65 ° C.
b) Die Losung von 79 7 g des unter a) hergestellten Ketals in 2 1 Tetrahydrofuran wird mit 1 I 6 N Salzsaure versetzt und die Reaktionsmischung 2 h bei Raumtemperatur gerührt Anschließend wird das Tetrahydrofuran am Rotationsverdamp- fer im Vakuum abgezogen, die salzsaure Losung mit halbkonzentrierter Ammoni- umhydroxidlösung alkalisiert und viermal mit je 100 ml Methylenchlorid extrahiert Nach dem Trocknen der vereinigten organischen Extrakte über Natriumsulfat und Abziehen des Lösungsmittels wird der Ruckstand an Kieselgel saulenchromatogra- phisch gereinigt Man erhält so 64.2 g (100 % Ausbeute) 2,3,5,6-Tetrahydro- [ 1. 4']bipyridinyl-4-on als graues Pulver, m/e = 176, Fp = 102°C.. c) Die Losung von 41 6 g cis-2,3-Epoxycyclohexanol (Svante T . , J Org. Chem. , 38, 1380 ( 1973)) und 54 g Imidazol in 650 ml Dimethylformamid (DMF) wird bei 0 °C. mit 67.7 g tert -Butyl-dimethylchlorsilan tropfenweise versetzt. Anschließend wird die Reaktionsmischung noch vier Stunden bei 0 °C. gerührt, dann mit 600 ml Wasser versetzt und die wäßrige Losung v iermal mit je 100 ml Essigsaureethylester extrahiert Nach dem Trocknen der vereinigten organischen Phasen über Natriumsulfat und Abziehen des Losungsmittels unter reduziertem Druck wird der Rückstand im Vakuum destilliert Man erhalt 50 g eis- 1 -tert - Butyl-dimethyl-silyloxy-2,3-epoxycyclohexan Kp0.05=74 °C. . b) The solution of 79 7 g of the ketal prepared under a) in 2 l of tetrahydrofuran is mixed with 1 l of 6 N hydrochloric acid and the reaction mixture is stirred at room temperature for 2 h. The tetrahydrofuran is then removed in vacuo on a rotary evaporator, and the hydrochloric acid solution is also removed semi-concentrated ammonium hydroxide solution alkalized and extracted four times with 100 ml of methylene chloride. After drying the combined organic extracts over sodium sulfate and stripping off the solvent, the residue is purified by column chromatography on silica gel. 64.2 g (100% yield) 2,3,5 are thus obtained , 6-tetrahydro- [1. 4 '] bipyridinyl-4-one as a gray powder, m / e = 176, F p = 102 ° C .. c) The solution of 41 6 g of cis-2,3-epoxycyclohexanol (Svante T., J Org. Chem., 38, 1380 (1973)) and 54 g of imidazole in 650 ml of dimethylformamide (DMF) is at 0 ° C. added dropwise with 67.7 g of tert-butyl-dimethylchlorosilane. The reaction mixture is then left at 0 ° C. for a further four hours. stirred, then mixed with 600 ml of water and the aqueous solution extracted four times with 100 ml of ethyl acetate. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off under reduced pressure, the residue is distilled in vacuo. 50 g of ice are obtained. tert - butyl-dimethyl-silyloxy-2,3-epoxycyclohexane bp 0.05 = 74 ° C. ,
1H-NMR (CDCl3) δ = 3 .90 ppm (m, 1H); 3 .10 (breites s, 1 H); 3.0 (breites s, 1H); 1 .65 (m, 2H); 1 .40 (m, 3H); 1. 15 (m, 1H); 1 .82 (s, 9H). 0.01 (s, 6H) 1 H NMR (CDCl 3 ) δ = 3.90 ppm (m, 1H); 3 .10 (broad s, 1 H); 3.0 (broad s, 1H); 1.65 (m, 2H); 1.40 (m, 3H); 1. 15 (m, 1H); 1.82 (s, 9H). 0.01 (s, 6H)
d) Die Mischung aus 20 g Epoxid 1c) und 34 ml 4-Piperidincarbonsaureethylester in 160 ml Ethanol wird 48 Stunden am Ruckfluß erhitzt Anschließend wird die Reaktionsmischung zur Trockne eingedampft und der Ruckstand an Kieselgel saulen- chromatographisch (Essigsaureethylester/Isohexan=1/2) gereinigt Man erhält 22.2 g (±)-(1α,2ß,3ß)- 1 -[3-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-cyccohexyi]-pi- peridin-4-carbonsaureethylester als weißes Pulver m/e = 385. d) The mixture of 20 g of epoxy 1c) and 34 ml of 4-piperidinecarboxylic acid ethyl ester in 160 ml of ethanol is heated under reflux for 48 hours. The reaction mixture is then evaporated to dryness and the residue is chromatographed on silica gel (ethyl acetate / isohexane = 1/2) purified 22.2 g (±) - (1α, 2ß, 3ß) - 1 - [3- (tert-butyl-dimethyl-silanyloxy) -2-hydroxy-cyccohexyi] -piperidine-4-carboxylic acid ethyl ester are obtained as white powder m / e = 385.
e) Die Losung von 18 7 g des Alkohols ld) und 12 ml Triethylamin in 200 ml Methylenchlorid wird bei 5-10 °C. Innentemperatur mit 5.4 ml Methansolfonsaurechlorid versetzt. Man läßt die Reaktionsmischung eine Stunde bei Raumtemperatur rühren, fügt anschließend 50 ml gesattigte Natriumhydrogencarbonat-Losung hinzu, trennt die Phasen ab, wascht die organische Phase mit 100 ml Wasser und trocknet se dann über Natriumsulfat Nach Abziehen des Lösungsmittels am Rotationsverdampfer wird der Rückstand an Kieselgel saulenchromatographisch (Essigsäureethylester/lsohexan=1/3) gereinigt Man erhalt 21 g (±)-( lα,2ß,3ß)-l - [3-(tert-Butyl-dimethyl-silanyloxy)-2-methansulfonyloxy-cyclohexyl]-piperidin-4- carbonsaureethylester als hellgelbes OI Η-NMR (d"-DMSO) δ=4.45 ppm (d, 1H); 4.20 (breites s, 1H); 3.95 (q, 2H); 3. 10 (s, 3H); 2.88-2.63 (m, 2H); 2.50 (m. 1H) 2.20-2.00 (m, 2H); 1.75-1.62 (m, 1H); 1.58- 1. 18 (m, 7H); 1.10 (t, 3H); 0 80 (s, 9H); 0 01 (s, 6H) . f) Die Losung von 21 g des Silylderivats 1e) in 200 ml Tetrahydrofuran wird mit 63 ml einer 1 1 molaren Tetrabutylammoniumfluorid-Losung in Tetrahydrofuran versetzt. Man läßt nun die Reaktionsmischung 30 Stunden bei Raumtemperatur rühren, engt sie dann zur Trockne ein und chromatographiert den Rückstand an Kieselgel (Essigsaureethylester/Isohexan=95/5) Man erhalt 6.3 g (±)-( 1α,2ß,3ß)- 1 -(3-Hydroxy-2-methansulfonyloxy-cyclohexyl)-piperidin-4-carbonsaureethylester als weißes Pulver m/e = 349. e) The solution of 18 7 g of the alcohol ld) and 12 ml of triethylamine in 200 ml of methylene chloride is at 5-10 ° C. 5.4 ml of methanesol acid chloride are added to the internal temperature. The reaction mixture is left to stir at room temperature for one hour, then 50 ml of saturated sodium bicarbonate solution are added, the phases are separated off, the organic phase is washed with 100 ml of water and then dried over sodium sulfate. After the solvent has been stripped off on a rotary evaporator, the residue becomes silica gel purified by column chromatography (ethyl acetate / isohexane = 1/3) 21 g (±) - (lα, 2ß, 3ß) -l - [3- (tert-butyl-dimethyl-silanyloxy) -2-methanesulfonyloxy-cyclohexyl] -piperidine are obtained -4- carboxylic acid ethyl ester as light yellow OI Η NMR (d "-DMSO) δ = 4.45 ppm (d, 1H); 4.20 (broad s, 1H); 3.95 (q, 2H); 3. 10 (s, 3H); 2.88-2.63 (m, 2H); 2.50 (m. 1H) 2.20-2.00 (m, 2H); 1.75-1.62 (m, 1H); 1.58-1.18 (m, 7H); 1.10 (t, 3H); 0 80 (s, 9H); 0 01 (s, 6H). f) The solution of 21 g of the silyl derivative 1e) in 200 ml of tetrahydrofuran is mixed with 63 ml of a 1 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture is then stirred for 30 hours at room temperature, then concentrated to dryness and the residue is chromatographed on silica gel (ethyl acetate / isohexane = 95/5). 6.3 g (±) - (1α, 2ß, 3ß) - 1 - (3-Hydroxy-2-methanesulfonyloxy-cyclohexyl) piperidine-4-carboxylic acid ethyl ester as white powder m / e = 349.
g) Die Mischung aus 5 48 g des Hydroxymesylats 1 f) und 550 mg Natriumhydrid in 200 ml Tetrahydrofuran (THF) wird eine Stunde bei 5 ºC und nach anschließenderg) The mixture of 5 48 g of hydroxymesylate 1 f) and 550 mg of sodium hydride in 200 ml of tetrahydrofuran (THF) is at 1 ° C for one hour and then
Zugabe von 50 ml Wasser 15 Stunden bei 50 °C. gerührt Danach wird das THF am Rotationsverdampfer abgezogen und die wäßrige Mischung dreimal mit je 30 ml Methylenchlorid extrahiert Nach dem Trocknen der vereinigten organischen Phasen über Natriumsulfat und Abziehen des Losungsmittels im Vakuum erhalt man 3 9 g (±)-trans- 1 -(2,3-Epoxy-cyclohexyl)-piperidin-4-carbonsaureetfιylester als gelbes OI, das ohne zusatzliche Reinigung weiter umgesetzt wird. Add 50 ml of water for 15 hours at 50 ° C. The THF is then removed on a rotary evaporator and the aqueous mixture is extracted three times with 30 ml of methylene chloride. After drying the combined organic phases over sodium sulfate and removing the solvent in vacuo, 3 9 g (±) -trans- 1 - (2, 3-epoxy-cyclohexyl) piperidine-4-carboxylate as a yellow oil, which is further reacted without additional purification.
h) Die Losung von 3.4 g des unter 1g) hergestellten Epoxids, 5.3 g Natriumazid und 4.3 g Ammoniumchlorid in 50 ml einer Ethanol/Wasser-(80/20)-Mischung wird 24 h bei 70 °C. erhitzt Anschließend wird das Ethanol im Vakuum abgezogen, der Rückstand mit 10 ml Wasser verdünnt und die wäßrige Losung dreimal mit je 15 ml Methylenchlorid extrahiert. Nach dem Trocknen der vereinigten organischen Phasen über Natriumsulfat und Abziehen des Losungsmittels am Rotations- Verdampfer wird das Rohprodukt an Kieselgel chromatographierth) The solution of 3.4 g of the epoxide produced under 1g), 5.3 g of sodium azide and 4.3 g of ammonium chloride in 50 ml of an ethanol / water (80/20) mixture is 24 hours at 70 ° C. The ethanol is then 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. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off on a rotary evaporator, the crude product is chromatographed on silica gel
(Essigsaureethylester/ Isohexan 4/1). Man erhalt so 2 74 g (±)-(1α,2ß,3α)- 1-(3- Azido-2-hydroxy-cyclohexyl)-piperidin-4-carbonsaureethylester als orangfarbenes OI, das allmählich fest wird. 1H-NMR (d6-DMSO) δ=4.53 ppm (breites s. 1H, OH); 4.05 (q, 2H); 3. 30 (breites d, 2H); 2.80 (quasi d, 1H); 2. 65 (quasi d, ! H); 2.50 (m, 1 H); 2.25 (m, 3H); 1 .90- 1. 40 (m, 7H); 1. 301. 02 (m+t, 6H). i) Die Losung von 2. 7 g des unter 1 h) hergestellten Azids in 20 ml Ethanol wird mit(Ethyl acetate / isohexane 4/1). This gives 2 74 g (±) - (1α, 2ß, 3α) - 1- (3- Azido-2-hydroxy-cyclohexyl) piperidine-4-carboxylic acid ethyl ester as an orange-colored OI, which gradually solidifies. 1 H-NMR (d 6 -DMSO) δ = 4.53 ppm (broad see 1H, OH); 4.05 (q, 2H); 3. 30 (broad d, 2H); 2.80 (quasi d, 1H); 2. 65 (quasi d,! H); 2.50 (m, 1H); 2.25 (m, 3H); 1.90-1.40 (m, 7H); 1. 301.02 (m + t, 6H). i) The solution of 2.7 g of the azide prepared under 1 h) in 20 ml of ethanol is mixed with
0.8 g 10%iger Palladium/Kohle versetzt, und die Mischung 6 h/40 mbar bei0.8 g of 10% palladium / carbon are added, and the mixture at 6 h / 40 mbar
Raumtemperatur hydriert Anschließend wird der Katalysator abfiltriert und dieRoom temperature hydrogenated Then the catalyst is filtered off and the
Losung am Rotationsverdampfer eingeengt Man erhalt so 2 4 g (±)-( 1α,2ß,3α)-1- (3-Amino-2-hydroxy-cyclohexyl)-piperidιn-4-carbonsaureethylester. FAB 271 Concentrated solution on a rotary evaporator. This gives 2 4 g (±) - (1α, 2ß, 3α) -1- (3-amino-2-hydroxy-cyclohexyl) -piperidιn-4-carboxylic acid ethyl ester. FAB 271
j) Die Losung von 2 4 g Amin 1 i), 1 6 g Keton 1b) und 3 75 g Natriumtriacetatobor- hydrid in 40 ml Methylenchlorid wird 48 h bei Raumtemperatur gerührt An- schließend wird die Reaktionsmischung mit 10 ml Wasser versetzt und mit 1 Nj) The solution of 2 4 g of amine 1 i), 1 6 g of ketone 1b) and 3 75 g of sodium triacetate borohydride in 40 ml of methylene chloride is stirred at room temperature for 48 h. Then the reaction mixture is mixed with 10 ml of water and 1 N
Salzsaure angesäuert Nach der Phasentrennung wird die waßrigsaure Phase noch einmal mit 10 ml Methylenchlorid extrahiert und dann mit 1 N Natronlauge alkali- siert Nach dreimaligem Extrahieren der alkalischen Mischung mit je 15 ml Methylenchlorid und Trocknen der vereinigten organischen Phasen über Natriumsulfat wird das Losungsmittel am Rotationverdampfer abgezogen Das Rohprodukt wird dann mittels prap HPLC (RP 18, Methanol/Puffer (pH=7.5) 70/30) gereinigt Man erhalt so 2.5 g (±)-( 1α,2ß,3α)-1-[2-Hydroxy-3-(3,4,5,6-tetrahydro-2H- [ 1,4']bipyridinyl-4-ylamino)-cyclohexyl]-pιperidin-4-carbonsaureethylester Acidified with hydrochloric acid After phase separation, the aqueous acidic phase is extracted once more with 10 ml of methylene chloride and then alkalized with 1 N sodium hydroxide solution. After extracting the alkaline mixture three times with 15 ml of methylene chloride each time and drying the combined organic phases over sodium sulfate, the solvent is removed on a rotary evaporator The crude product is then purified using prap HPLC (RP 18, methanol / buffer (pH = 7.5) 70/30). 2.5 g (±) - (1α, 2ß, 3α) -1- [2-hydroxy-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-ylamino) -cyclohexyl] -pιperidin-4-carboxylic acid ethyl ester
Η-NMR (d6-DMSO) δ=8.20 ppm (d, 2H); 6.85 (d, 2H); 4.15 (m, 1 H); 4. 12 (q, 2H); 3.85 (breites d, 2H); 3. 10 (t, 1H); 3.0-2.8 (m, 4H); 2.70 (d, 1 H); 2.55 (m,Η NMR (d 6 -DMSO) δ = 8.20 ppm (d, 2H); 6.85 (d. 2H); 4.15 (m, 1H); 4. 12 (q, 2H); 3.85 (broad d, 2H); 3. 10 (t, 1H); 3.0-2.8 (m, 4H); 2.70 (d, 1H); 2.55 (m,
2H); 2.30 (breites t, 3H); 2.0 (d, 1H); 1. 88 (m, 4H); 1. 80-1 .50 (m, 5H); 1. 38-0.88 (m, 5H); 1.25 (t, 3H). 2H); 2.30 (broad t, 3H); 2.0 (d, 1H); 1. 88 (m, 4H); 1. 80-1.50 (m, 5H); 1. 38-0.88 (m, 5H); 1.25 (t, 3H).
k) Die Losung von 2.5 g des Aminoalkohols 1j) und 1 9 g Carbonyldiimidazol in 20 ml Dimethylformamid wird 15 h bei Raumtemperatur gerührt Anschließend wird die Reaktionslösung zur Trockne eingedampft und der Ruckstand mitteis prap HPLC (Merck, Select B, Methanol/Puffer (pH=7. 5) 65/35) gereinigt Man erhalt so 2.78 g (±)-(3'α,7'ß,7α)- 1 -[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1 ,4']bipyridιnyl-4- yl)-octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaureethylester als gelbes OI m/e=456. l) Die Losung von 1 85 g des Ethylesters 1 k) und 4. 60 ml IN Natronlauge in 30 mlk) The solution of 2.5 g of the amino alcohol 1j) and 1 9 g of carbonyldiimidazole in 20 ml of dimethylformamide is stirred for 15 h at room temperature the reaction solution was evaporated to dryness and the residue was purified by means of HPLC (Merck, Select B, methanol / buffer (pH = 7.5) 65/35). 2.78 g (±) - (3'α, 7'ß, 7α) - 1 - [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridιnyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidin-4 -carboxylic acid ethyl ester as a yellow oil m / e = 456. l) The solution of 1 85 g of the ethyl ester 1 k) and 4. 60 ml IN sodium hydroxide solution in 30 ml
Methanol wird 1 h bei Raumtemperatur gerührt. Anschließend wird das Methanol im Vakuum abgezogen und das Produkt mittels Ionenaustauscher (Dowex 50, H- Form) gereinigt Man erhalt so 0.95 g der Titelverbindung als weißes PulverMethanol is stirred for 1 h at room temperature. The methanol is then stripped off in vacuo and the product is purified by means of an ion exchanger (Dowex 50, H form). This gives 0.95 g of the title compound as a white powder
Fp.>200 °C. m/e (Ei-Spektrum) = 500 (gemessen als Trimethylsilylderivat). Mp> 200 ° C. m / e (egg spectrum) = 500 (measured as trimethylsilyl derivative).
Beispiel la Example la
(-)-(3'S,7'S,7R)-1-[2-Oxo-3-(3,4.5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-piperidin-4-carbonsaure (-) - (3'S, 7'S, 7R) -1- [2-oxo-3- (3,4.5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7 -yl] -piperidine-4-carboxylic acid
Der Ersatz des racemischen cis-2,3-Epoxycyclohexanols im Beispiel 2a) durch ( 1R,2R-3S)-1-Hydroxy-2,3-epoxycyciohexan liefert nach der Durchführung der Reaktionsschritte 2a)-2c) die optisch aktive Verbindung ( 1 S,2S,3R)- 1 -Azido-2-hydroxy- cyclohexyl)-piperidin-4-carbonsaureethylester ([a]D 20 = -41.4° (C 1.2, CH CI3)), aus der man analog zum Beispiel 1 i)-1l) die Titelverbindung erhalt [a]D = -17 4 ° (Cl .18; CH CI3). Replacing the racemic cis-2,3-epoxycyclohexanol in Example 2a) with (1R, 2R-3S) -1-hydroxy-2,3-epoxycyciohexane provides the optically active compound (1 S, 2S, 3R) - 1 -azido-2-hydroxycyclohexyl) -piperidine-4-carboxylic acid ethyl ester ([a] D 20 = -41.4 ° (C 1.2, CH CI 3 )), from which analogously to Example 1 i) -1l) the title compound receives [a] D = -17 4 ° (Cl .18; CH CI 3 ).
( 1R-2R-3S)-1-Hydroxy-2,3-epoxycyclohexan ist nach Svante T (J.Org. Chem. , 38, 1380 (1973)) durch Epoxydierung des literaturbekannten (R)-Cyclohex-2-enol (Fukazawa et al , Tetrahedron Asymmetry 4, 2323 ( 1993)) mittels meta-Chlorperbenzoesaure erhältlich. According to Svante T (J.Org. Chem., 38, 1380 (1973)), (1R-2R-3S) -1-hydroxy-2,3-epoxycyclohexane can be isolated by epoxidation of the (R) -cyclohex-2-enol () Fukazawa et al, Tetrahedron Asymmetry 4, 2323 (1993)) by means of meta-chloroperbenzoic acid.
Beispiel 2 Example 2
Weiteres Verfahren zur Herstellung von (±)-(1α,2ß,3α)- 1-(3-Azido-2-hydroxy-cyclohe- xyl)-piperidin-4-carbonsaureethylester 1h) Another process for the preparation of (±) - (1α, 2ß, 3α) - 1- (3-azido-2-hydroxy-cyclohexyl) piperidine-4-carboxylic acid ethyl ester 1h)
a) Die Losung von 1 19.65 g cis-2,3-Epoxycyclohexanol (siehe Bsp 1c) und 188 ml Triethylamin in 400 ml Methylenchlorid wird bei 0 °C. mit einer Losung von 240 g p-Toluolsulfonsaurechlorid in 500 ml Methylenchlorid versetzt Anschließend wird die Reaktionsmischung 15 Stunden bei Raumtemperatur gerührt, dann das ausge- fallene Salz abfiltriert und das Filtrat mit 100 ml gesättigter Natriumhydrogencar- bonat-Losung gewaschen Nach Trocknen der Methvlenchloridphase über Natriumsulfat und Abziehen des Losungsmittels wird das Rohprodukt sauienchromato- graphisch an Kieselgel gereinigt (Essigsaureethylester/lsohexan= l/l ). Man erhalt so 21 1 g (75%) cis-2,3-Epoxycyclohexyltosylat als gelbliches OI, das allmählich fest wird Η-NMR (CDCl3): δ = 7.85 ppm (d, 2H); 7.35 (d, 2H); 4 .90 (m, 1H); a) The solution of 1 19.65 g of cis-2,3-epoxycyclohexanol (see Example 1c) and 188 ml of triethylamine in 400 ml of methylene chloride is at 0 ° C. with a solution of 240 g of p-toluenesulfonic acid chloride in 500 ml of methylene chloride. The reaction mixture is then stirred for 15 hours at room temperature, then the precipitated salt is filtered off and the filtrate is washed with 100 ml of saturated sodium bicarbonate solution. After drying the methylene chloride phase over sodium sulfate and the solvent is stripped off, the crude product is purified by chromatography on silica gel (ethyl acetate / isohexane = l / l). This gives 21 1 g (75%) of cis-2,3-epoxycyclohexyl tosylate as a yellowish oil, which gradually becomes solid Η-NMR (CDCl 3 ): δ = 7.85 ppm (d, 2H); 7.35 (d. 2H); 4.90 (m, 1H);
3.27 (breites s, 1H); 3 . 17 (breites s, 1 H); 2.45 (s, 3H); 1. 80 (m, 2H); 1 .65 (m, 3H); 1.22 (m, 1H). 3.27 (broad s, 1H); 3rd 17 (broad s, 1H); 2.45 (s, 3H); 1. 80 (m, 2H); 1.65 (m, 3H); 1.22 (m, 1H).
b) Die Mischung aus 1 12 g Epoxid 2a) und 1 10 ml 4-Piperidincarbonsaureethylester in 250 ml Ethanol wird in einem Mikrowellengerat 2. 75 Stunden mit einer Energie von 500 W so bestrahlt, daß die Reaktionstemperatur 65 °C. betragt Anschließend wird die Reaktionslosung auf 0 °C. abgekühlt, das Produkt abgesaugt, zweimal mit jeweils 50 ml kaltem Ethanol und dreimal mit jeweils 50 ml Diethylether gewa- sehen und im Vakuum bei 30 °C. getrocknet Man erhalt so 96 g (54%) ( 1α,2ß,3ß)- 1 -(3-p-Toluolsulfonyloxy-2-Hydroxy-cyclohexyl)-pιperidιn-4-carbon- saureethylester Fp = 135 -137 °C. m/e = 425 Η-NMR (CDCl3) δ = 7. 75 ppm (d, 2H); 7.22 (d, 2H); 4.85 (breites s, 1H); 4. 05 (q, 2H); 3 .28 (d mit Feinaufspaltung, 1H); 2. 62 (m, 2H); 2.50 (t, 1H); 2.35 (s, 3H); 2. 18 (m. 1H); 2.05 (t, 2H); 1 .75 (m, 3H); 1 .55 (m, 4H); 1.32 (m, 1H); 1 . 15 (t, 3H); 1. 10 (m. 1H). b) The mixture of 1 12 g of epoxy 2a) and 1 10 ml of 4-piperidinecarboxylic acid ethyl ester in 250 ml of ethanol is irradiated in a microwave oven for 2. 75 hours with an energy of 500 W in such a way that the reaction temperature is 65 ° C. The reaction solution is then brought to 0 ° C. cooled, the product filtered off, washed twice with 50 ml of cold ethanol and three times with 50 ml of diethyl ether see and in vacuum at 30 ° C. dried This gives 96 g (54%) (1α, 2ß, 3ß) - 1 - (3-p-toluenesulfonyloxy-2-hydroxycyclohexyl) -pιperidιn-4-carbon- acidic acid ethyl ester mp = 135 -137 ° C. m / e = 425 Η NMR (CDCl 3 ) δ = 7. 75 ppm (d, 2H); 7.22 (d, 2H); 4.85 (broad s, 1H); 4.05 (q, 2H); 3.28 (d with fine splitting, 1H); 2. 62 (m, 2H); 2.50 (t, 1H); 2.35 (s, 3H); 2. 18 (m. 1H); 2.05 (t, 2H); 1.75 (m. 3H); 1.55 (m, 4H); 1.32 (m, 1H); 1 . 15 (t, 3H); 1. 10 (m. 1H).
c) Die Mischung aus 37 g Tosylat 2b) und 34 3 g Natriumazid in 250 ml Dimethyl- formamid wird in einem Mikrowellengerat 20 min mit einer Energie von 500 W so bestrahlt, daß die Reaktionstemperatur 90 °C. betragt .Anschließend wird die Reaktionslosung auf Raumtemperatur abgekühlt, das Salz abgesaugt, das Filtrat im Vakuum bei 50 °C. zur Trockne eingedampft, der Ruckstand in 50 ml Wasser aufgenommen und die wäßrige Mischung dreimal mit je 50 ml Diethylether extrahiert Nach dem Trocknen der vereinigten organischen Phasen über Natriumsulfat undc) The 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 with an energy of 500 W for 20 min so that the reaction temperature is 90 ° C. The reaction solution is then cooled to room temperature, the salt is suctioned off and the filtrate is vacuumed at 50 ° C. evaporated to dryness, the residue taken up in 50 ml of water and the aqueous mixture extracted three times with 50 ml of diethyl ether after drying the combined organic phases over sodium sulfate and
Abziehen des Losungsmittels wird das Rohprodukt saulenchromatographisch an Kieselgel (Essigsaureethylester/lsohexan=6/4) gereinigt Man erhalt so 21 8 g (84%) der Titelverbindung als hellgraues Pulver Fp 61-63 °C. Die Titelverbindung ist nach diesem Verfahren in besserer Ausbeute und höherer Reinheit als nach dem Verfahren l h) erhaltlich. Withdrawing the solvent, the crude product is purified by column chromatography on silica gel (ethyl acetate / isohexane = 6/4). This gives 21 8 g (84%) of the title compound as a light gray powder, mp 61 ° -63 ° C. The title compound can be obtained by this process in better yield and higher purity than by process 1 h).
Beispiel 2a Example 2a
(+)-(3,R,7,R-7S)-1-[2-Oxo-3-(3,4,5.6-tetrahydro-2H-[1 ,4,]bιpyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-piperidin-4-carbonsaure (+) - (3 , R, 7 , R-7S) -1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 , ] bιpyridinyl-4-yl) octahydro - benzooxazol-7-yl] piperidine-4-carboxylic acid
Der Ersatz des racemischen cis-2,3-Epoxycyclohexanols im Beispiel 2a) durch ( 1 S,2S,3R)- 1-Hydroxy-2,3-epoxycyclohexan liefert nach der Durchführung der Reaktionsschritte 2a)-2c) die optisch aktive Verbindung ( 1R,2R,3S)- 1 -Azido-2-hydroxy- cyclohexyl)-piperidin-4-carbonsaureethylester ([a]D20 = +42° (C 1.23; CHCI3)),, aus der man analog zum Beispiel li)-ll) die Titelverbindung erhalt [a]o = +18.7 ° (C1. 2; CHCl3) . Replacing the racemic cis-2,3-epoxycyclohexanol in example 2a) with (1 S, 2S, 3R) - 1-hydroxy-2,3-epoxycyclohexane provides the optically active compound after carrying out reaction steps 2a) -2c) ( 1R, 2R, 3S) - 1-azido-2-hydroxy-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester ([a] D20 = + 42 ° (C 1.23; CHCI3)) ,, from which one analogously to example li) - ll) the title compound receives [a] o = +18.7 ° (C1. 2; CHCl 3 ).
(1 S,2S,3R)-1 -Hydroxy-2,3-epoxycyclohexan ist nach Svante T. (J. Org. Chem. , 38, 1380 ( 1973)) durch Epoxydierung des literaturbekannten (S)-Cyclohex-2-enol (Singh V. K ,et al , Synth Commun 24, 375 ( 1994)) mittels meta-Chlorperbenzoesaure erhaltlich. According to Svante T. (J. Org. Chem., 38, 1380 (1973)), (1 S, 2S, 3R) -1-hydroxy-2,3-epoxycyclohexane is epoxidized by the literature-known (S) -cyclohex-2- enol (Singh V. K, et al, Synth Commun 24, 375 (1994)) using meta-chloroperbenzoic acid.
Beispiel 3 Example 3
(±)-(3'α,7,ß,7α)-1-( 3-[1-(2-Benzylamino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahy- dro-benzooxazol-7-yl } -piperidin-4-carbonsaure (±) - (3'α, 7 , ß, 7α) -1- (3- [1- (2-Benzylamino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahy- dro -benzooxazol-7-yl} -piperidine-4-carboxylic acid
a) Die Losung von 16 ml (0.12 Mol) 4-Piperidon-ethylenketal in 100 ml Ethanol wird unter Eiskuhlung zu einer Lösung von 18 5 g (0.12 Mol) 2,4-Dichlorpyrimidin unda) The solution of 16 ml (0.12 mol) of 4-piperidone-ethylene ketal in 100 ml of ethanol is converted into a solution of 18 5 g (0.12 mol) of 2,4-dichloropyrimidine and
17. 5 ml Triethylamin in 150 ml Ethanol zugetropft. Anschließend wird die Reaktionsmischung 2.5 Stunden bei Raumtemperatur gerührt und dann zur Trockne eingedampft. Der Rückstand wird in 50 ml Wasser aufgenommen und die wäßrige Losung dreimal mit je 20 ml Methylenchlorid extrahiert Nach dem Trocknen der vereinigten organischen Phasen über Natriumsulfat und Abziehen des Losungsmittels wird der Ruckstand aus Essigsaureethylester/Isohexan umkristallisiert Man erhalt so 21 .8 g 8-(2-Chlor-pyrimidin-4-yl)- 1,4-dioxa-8-aza-spιro- [4. 5]decan als weißes Pulver m/e = 256 1Η-NMR (CDCl3): δ = 7.92 ppm (d, 1 H, Ar-H); 6.35 (d, 1H, Ar-H); 3. 91 (s, 4H, Ketal-CH2); 3 .65 (breites s, 4H); 1. 68 (t, 4H) 17. 5 ml of triethylamine added dropwise in 150 ml of ethanol. The reaction mixture is then stirred at room temperature for 2.5 hours and then evaporated to dryness. The residue is taken up in 50 ml of water and the aqueous solution is extracted three times with 20 ml of methylene chloride. After drying the combined organic phases over sodium sulfate and stripping off the solvent, the residue is recrystallized from ethyl acetate / isohexane. 21.8 g of 8- ( 2-chloro-pyrimidin-4-yl) - 1,4-dioxa-8-aza-spιro- [4th 5] decane as a white powder m / e = 256 1 Η NMR (CDCl 3 ): δ = 7.92 ppm (d, 1 H, Ar-H); 6.35 (d, 1H, Ar-H); 3. 91 (s, 4H, ketal CH 2 ); 3.65 (broad s, 4H); 1. 68 (t, 4H)
b) Die Mischung aus 8 g 2-Chlorpyrimidin 3a) und 7 2 ml Benzvlamin wird 2 Stunden bei 150 °C. erhitzt. Man kühlt anschließend die Reaktionsmischung auf Raumtemperatur, versetzt sie mit 30 ml Wasser, extrahiert die wäßrige Losung dreimal mit je 20 ml Methylenchlorid, trocknet die vereinigten Extrakte über Natriumsulfat, zieht das Losungsmittel am Rotationsverdampfer ab und kristallisiert den Ruckstand aus Essigsaureethylester um. Man erhalt so 7 g 8-(2-Benzylamino-pyrimidin- 4-yl)- 1,4-dioxa-8-aza-spiro- [4 5]decan m/e = 326 Η-NMJR (d6-DMSO):δ = 7.88 ppm (d, 1H, Ar-H); 7. 32 (m, 5H, Ar-H); 7.25 (breites s, 1H; MH); 6. 12 (d, 1H; Ar-H); 4.45 (d, 2H, Ph-CH2) 3.98 (s, 4H, Ketal-CH2); 3 .65 (breites s. 4H); 1. 72. (breites s, 4H). b) The mixture of 8 g of 2-chloropyrimidine 3a) and 7 2 ml of benzvlamine is 2 hours at 150 ° C. heated. The reaction mixture is then cooled to room temperature, 30 ml of water are added, the aqueous solution is extracted three times with 20 ml of methylene chloride, the combined extracts are dried over sodium sulfate, the solvent is removed on a rotary evaporator and the residue is recrystallized from ethyl acetate. This gives 7 g of 8- (2-benzylamino-pyrimidin-4-yl) 1,4-dioxa-8-aza-spiro- [4 5] decane m / e = 326 Η-NMJR (d 6 -DMSO) : δ = 7.88 ppm (d, 1H, Ar-H); 7. 32 (m, 5H, Ar-H); 7.25 (broad s, 1H; MH); 6. 12 (d, 1H; Ar-H); 4.45 (d, 2H, Ph-CH 2) 3.98 (s, 4H, ketal-CH 2); 3.65 (broad see 4H); 1. 72. (broad s, 4H).
c) Analog zum Beispiel lb) erhalt man aus 7 g Ketal 3b) und 80 ml 6N Salzsaure 6 3 g 1-(2-Bernzylamino-pyrimidin-4-yl)-piperidin-4-on als braunes OI, das als Rohprodukt weiterumgesetzt wird. c) Analogously to example 1b), 6 3 g of 1- (2-bernzylamino-pyrimidin-4-yl) -piperidin-4-one are obtained from 7 g of ketal 3b) and 80 ml of 6N hydrochloric acid as a brown oil, which is further converted as a crude product becomes.
d) Analog zum Beispiel 1j) erhalt man aus 0.42 g Amin 1 i), 0 .44 g Keton 3c); 0.66 g Natriumtriacetatoborhydrid und 0. 3 ml 100%iger Essigsaure 0.77 g (±)- ( 1α,2ß,3α)- 1 -{ 2-Hydroxy-3-[ 1-(2-benzylamino-pyrirnidin-4-yl)-piperidin-4-ylamι- no]-cyclohexyl}-piperidin-4-carbonsaureethylester m/e = 537 e) Analog zum Beispiel l k) erhalt man aus 0 77 g Aminoalkohol 3d) und 0 28 g Carbonyldiimidazol 0.54 g (±)-(3,α,7'ß,7α)- 1-{3-[ 1-(2-Benzylamino-pyrimidin-4- yl)-piperidin-4-yl]-2-oxo-octahydro-benzooxazol-7-yl }-piperidin-4-carbonsaure- ethylester Pos FAß = 562. 1H-NMR (d6-DMSO); δ = 7 75 ppm (d, 1 H); 7.20 (m, 5H); 7. 12 (breites s, 1 H, NH); 6.03 (d, 1H); 4. 43 (d. 2H); 4. 39 (breites s, 1 H);d) Analogously to Example 1j), 0.42 g of amine 1 i), 0.44 g of ketone 3c) are obtained; 0.66 g of sodium triacetate borohydride and 0.3 ml of 100% acetic acid 0.77 g (±) - (1α, 2ß, 3α) - 1 - {2-hydroxy-3- [1- (2-benzylamino-pyrirnidin-4-yl) - piperidin-4-ylamι- no] -cyclohexyl} -piperidine-4-carboxylic acid ethyl ester m / e = 537 e) Analogously to example lk), from 0 77 g amino alcohol 3d) and 0 28 g carbonyldiimidazole 0.54 g (±) - ( 3 , α, 7'ß, 7α) - 1- {3- [1- (2-benzylamino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -piperidine-4-carboxylic acid ethyl ester Pos FAß = 562. 1 H-NMR (d 6 -DMSO); δ = 7 75 ppm (d, 1 H); 7.20 (m, 5H); 7. 12 (broad s, 1 H, NH); 6.03 (d, 1H); 4. 43 (i.e. 2H); 4. 39 (broad s, 1H);
4. 05 (q, 2H); 3.80 (t, 1H); 3. 69 (m, 1H); 3.25 (breites t, 1H); 2.76 (m, 5H); 2. 48 (m, 2H); 2.25 (m, 2H); 1. 95-1.20 (m, 14H); 1. 18 (t, 3H) 4.05 (q, 2H); 3.80 (t, 1H); 3. 69 (m, 1H); 3.25 (broad t, 1H); 2.76 (m, 5H); 2. 48 (m, 2H); 2.25 (m, 2H); 1. 95-1.20 (m, 14H); 1.18 (t, 3H)
f) Analog zum Beispiel 11) erhält man aus 0 .1 g Ethylester 3e) und 0.4 ml I N Natronlauge 0 065 g der Titelverbindung, m/e = 534 Fp = 180ºC. Beispiel 4 f) Analogously to Example 11), from 0 .1 g of ethyl ester 3e) and 0.4 ml of 1N sodium hydroxide solution, 0 065 g of the title compound is obtained, m / e = 534 Mp = 180 ° C. Example 4
(±)-(3,α,7'ß,7α)-l-{ 3-[1 -(2-Pyrrolidin- 1 -yl-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo- octahydro-benzooxazol-7-yl }-piperidin-4-carbonsaure (±) - (3 , α, 7'ß, 7α) -l- {3- [1 - (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-yl] -2-oxo octahydro-benzooxazol-7-yl} piperidine-4-carboxylic acid
a) Die Mischung aus 7.7 g Chlorpyrimidin-Derivat 3a) und 25 ml Pyrrolidin wird in einem Mikrowellengerat 15 Min. mit einer Energie von 500 W so bestrahlt, daß die Reaktionstemperatur 50 °C. beträgt. Anschließend wird die Reaktionslösung zur a) The mixture of 7.7 g of chloropyrimidine derivative 3a) and 25 ml of pyrrolidine is irradiated in a microwave oven for 15 minutes with an energy of 500 W in such a way that the reaction temperature is 50 ° C. is. The reaction solution then becomes
Trockne eingedampft, der Rückstand in 20 ml Wasser aufgenommen und die wäßrige Losung viermal mit je 20 ml Methylenchlorid extrahiert Nach dem Trocknen der vereinigten Extrakten über Natriumsulfat und Abziehen des Losungsmittels wird der Rückstand mittels prap HPLC (Merck. Select B, Methanol/Puffer (pH=7.5) 75/25) gereinigt. Man erhält so 7 .8 g 8-(2-Pyrrolidin- 1 -yl-pyrimidin-4- yl)-1 ,4-dioxa-8-aza-spiro- [4 .5]decan.. m/e = 290. Evaporated to dryness, the residue was taken up in 20 ml of water and the aqueous solution was extracted four times with 20 ml of methylene chloride. After the combined extracts had been dried over sodium sulfate and the solvent had been stripped off, the residue was removed using prap HPLC (Merck. Select B, methanol / buffer (pH = 7.5) 75/25) cleaned. This gives 7.8 g of 8- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -1, 4-dioxa-8-aza-spiro- [4 .5] decane. M / e = 290 .
b) Analog zum Beispiel 1b) erhält man aus 7.8 g Ketal 4a) und 72 ml 6N Salzsaure 5 9 g 1-(2-Pyrrolidin- 1-yl-pyrimidin-4-yl)-piperidin-4-on, das als Rohprodukt weiterumgesetzt wird. b) Analogously to Example 1b), 7.8 g of ketal 4a) and 72 ml of 6N hydrochloric acid give 5 9 g of 1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-one, which is the crude product is implemented further.
c) Analog zum Beispiel 1j) erhält man aus 2.46 g Keton 4b), 2.7 g Amin 1i), 3.2 g Natriumtriacetatoborhydrid und 6 ml 100%iger Essigsaure 3.4 g (±)-( 1α,2ß,3α)-1 -c) Analogously to Example 1j), 2.46 g of ketone 4b), 2.7 g of amine 1i), 3.2 g of sodium triacetate borohydride and 6 ml of 100% acetic acid give 3.4 g (±) - (1α, 2ß, 3α) -1 -
{2-Hydroxy-3-[1-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-piperidin-4-ylaminoj-cyclo- hexyl}-piperidin-4-carbonsäureethylester als gelbes Öl. Η-NMR (d6-DMSO +{2-Hydroxy-3- [1- (2-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-4-ylaminoj-cyclohexyl} -piperidine-4-carboxylic acid ethyl ester as a yellow oil. Η NMR (d 6 -DMSO +
AcOH): δ = 7.92 ppm (d, 1H); 6.29 (d, 1H); 4.52 (breites d, 2H); 4. 15 (q, 2H); 3,79 (t, 1H); 3.53 (m, 4H); 3.20 (m, 3H); 3.00 (m, 3H); 2.55 (m, 2H); 2.20-170 (m, 13H); 1.62-1.35 (m.5H); 125 (t, 3H) AcOH): δ = 7.92 ppm (d, 1H); 6.29 (d, 1H); 4.52 (broad d, 2H); 4. 15 (q, 2H); 3.79 (t, 1H); 3.53 (m, 4H); 3.20 (m, 3H); 3.00 (m, 3H); 2.55 (m. 2H); 2.20-170 (m, 13H); 1.62-1.35 (m.5H); 125 (t, 3H)
d) Analog zum Beispiel 1k) erhalt man aus 33 g Aminoalkohoi 4c) und 1.6 g Carbonyldiimidazol 2.5g (±)-(3'α,7'ß,7α)-1-{3-[1-(2-Pyrrolidin-1-yl-pyrimidιn-4-yl)-pι- peridιn-4-yl]-2-oxo-octahydro-benzooxazol-7-yl}-pιperidιn-4-carbonsaure-ethyl- ester als hellgraues Pulver Fp = 140 °C. m/e = 526 Η-NMR (d6-DMSO) δ = 801 ppm (d, 1H); 6.21 (d, 1H); 4.62 (breites t, 2H); 4.20 (q, 2H); 3.99 (t, 1H); 3.88 (m, 1H); 3.55 (m, 5H); 2.98 (m, 5H); 2.65 (m, 1H); 2.45 (m, 2H); 2.13 (m, 1H); 2.08-1.40 (m, 18H); 1.33 (t, 3H). d) Analogously to Example 1k), from 33 g of amino alcohol 4c) and 1.6 g of carbonyldiimidazole, 2.5 g (±) - (3'α, 7'ß, 7α) -1- {3- [1- (2-pyrrolidine 1-yl-pyrimidιn-4-yl) -pι- peridιn-4-yl] -2-oxo-octahydro-benzooxazol-7-yl} -pιperidιn-4-carboxylic acid ethyl ester as a light gray powder, mp = 140 ° C. . m / e = 526 Η NMR (d 6 -DMSO) δ = 801 ppm (d, 1H); 6.21 (d, 1H); 4.62 (broad t, 2H); 4.20 (q, 2H); 3.99 (t, 1H); 3.88 (m, 1H); 3.55 (m, 5H); 2.98 (m, 5H); 2.65 (m, 1H); 2.45 (m. 2H); 2.13 (m, 1H); 2.08-1.40 (m, 18H); 1.33 (t, 3H).
e) Analog zum Beispiel 1l) erhalt man aus 0.4 g Ethylester 4d) und 0.9 ml IN Natronlauge 0.16 g der Titelverbindung m/e = 498 1Η-NMR (d6-DMSO+AcOH) δ = 7.60 ppm (d, 1H); 6.25 (d, 1H); 4.35 (breites s, 2H); 3.78 (t, 1H); 3.59 (breites t, 1H); 3.25 (m, 5H); 3.05-2.70 (m, 5H); 2.60 (breites t.1H); 2.42 (breites t, 1H); 2.15 (m, 1H); 1.80-1.38 (m, 14H); 1.20 (m, 4H). e) Analogously to Example 1l), 0.46 g of the title compound is obtained from 0.4 g of ethyl ester 4d) and 0.9 ml of 1N sodium hydroxide solution m / e = 498 1 Η-NMR (d 6 -DMSO + AcOH) δ = 7.60 ppm (d, 1H) ; 6.25 (d, 1H); 4.35 (broad s, 2H); 3.78 (t, 1H); 3.59 (broad t, 1H); 3.25 (m, 5H); 3.05-2.70 (m, 5H); 2.60 (broad t.1H); 2.42 (broad t, 1H); 2.15 (m, 1H); 1.80-1.38 (m, 14H); 1.20 (m, 4H).
Beispiel5 Example 5
(±)-(3'α,7'ß.7α)-1-{3-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-2-oxo-octahydro- benzooxazol-7-yl)-piperidin-4-carbonsaure (±) - (3'α, 7'ß.7α) -1- {3- [1- (2-Amino-pyrimidin-4-yl) piperidin-4-yl] -2-oxo-octahydro-benzooxazole -7-yl) -piperidine-4-carboxylic acid
ln einem 11 Autoklaven wird die Losung aus 26 g Chlorpyrimidin 3a) und 120 ml flussigem Ammoniak in 500 ml Ethanol 60 Stunden bei 5 bar und 90 °C. gehalten Anschließend wird die Reaktionsmischung zur Trockne eingedampft, der Ruckstand in 20 ml Wasser aufgenommen und die wäßrige Losung fünfmal mit je 20 ml Methylenchlorid extrahiert Nach dem Trocknen der vereinigten organischen Phasen über Natriumsulfat und Abziehen des Losungsmittels wird der feste Ruckstand mit 40 ml Essigsaureethylester ausgeruhrt Man erhalt so 5 .7 g 8-(2- Amino-pyrimidin-4-yl)-1 ,4-dioxa-8-aza-spiro- [4 5]decan als gelbliches Pulver m/e = 236. In an 11 autoclave, the solution of 26 g of chloropyrimidine 3a) and 120 ml of liquid ammonia in 500 ml of ethanol is mixed for 60 hours at 5 bar and 90 ° C. The reaction mixture is then evaporated to dryness, the residue is taken up in 20 ml of water and the aqueous solution is extracted five times with 20 ml of methylene chloride. After drying the combined organic phases over sodium sulfate and removing the solvent, the solid residue is extracted with 40 ml of ethyl acetate this gives 5 .7 g of 8- (2-aminopyrimidin-4-yl) -1, 4-dioxa-8-aza-spiro- [4 5] decane as a yellowish powder m / e = 236.
b) Analog zum Beispiel 1b) erhalt man aus 6 g Ketal 5a) und 65 ml 6N Salzsaure 5. 5 g (2-Amino-pyrimidin-4-yl)-piperidin-4-on als gelblichen Feststoff m/e = 192 b) Analogously to Example 1b), 5 g (2-amino-pyrimidin-4-yl) -piperidin-4-one are obtained from 6 g of ketal 5a) and 65 ml of 6N hydrochloric acid as a yellowish solid m / e = 192
c) Analog zum Beispiel 1j) erhalt man aus 1 g Amin 1i), 0.7 g Keton 5b), 1. 6 g Na- triumtriacetatoborhydrid und 0 8 ml 100%iger Essigsaure 1 5 g (±)-( 1α,2ß,3α)- 1 - {2-Hydroxy-3-[ 1 -(2-amino-pyrimidin-4-yl)-piperidin-4-ylamino]-cyclohexyl}-pipe- ridin-4-carbonsaureethylester als gelbes OI m/e = 446 Η-NMR (d6-DMSO) δ - 7. 80 ppm (d, 1H); 6. 08 (d, 1H); 6.00 (s, 1H, MH); 4.24 (d, 2H); 4. 15 (m, 4H);c) Analogously to Example 1j), 1 g of 1 g), 0.7 g of ketone 5b), 1. 6 g of sodium triacetate borohydride and 0 8 ml of 100% acetic acid give 1 5 g (±) - (1α, 2ß, 3α ) - 1 - {2-Hydroxy-3- [1 - (2-aminopyrimidin-4-yl) -piperidin-4-ylamino] -cyclohexyl} -piperidin-4-carboxylic acid ethyl ester as yellow OI m / e = 446 Η NMR (d 6 -DMSO) δ - 7. 80 ppm (d, 1H); 6. 08 (d, 1H); 6.00 (s, 1H, MH); 4.24 (d, 2H); 4. 15 (m, 4H);
3. 12 (t, 1H); 2.90 (m, 4H); 2. 72 (breites d, 1H); 2,60 (m, 3H); 2.30 (breites t, 3H); 1 .88 (m, 5H); 1.70 (m, 5H); 1.25 (t, 3H); 1. 15 (m, 3H) d) Analog zum Beispiel 1k) erhalt man aus 1 . 1 g Aminoalkohoi 5c) und 0. 5 g Carbo- nyldiimidazol 0 3 g (±)-(3'α,7,ß,7α)- 1-{ 3-[ 1 -(2-Amino-pyrimidin-4-yl)-pιperi din-3. 12 (t, 1H); 2.90 (m, 4H); 2. 72 (broad d, 1H); 2.60 (m, 3H); 2.30 (broad t, 3H); 1.88 (m, 5H); 1.70 (m, 5H); 1.25 (t, 3H); 1. 15 (m, 3H) d) Analogously to example 1k) one obtains from 1. 1 g of amino alcohol 5c) and 0.5 g of carbonyldiimidazole 0.3 g (±) - (3'α, 7 , ß, 7α) - 1- {3- [1 - (2-aminopyrimidin-4-yl ) -pιperi din-
4-yl]-2-oxo-octahydro-ben zooxazol-7-yl}-piperidin-4-carbonsaure-ethylester als hellgraues Pulver. m/e = 472. Fp = 120-122 °C. 4-yl] -2-oxo-octahydro-ben zooxazol-7-yl} -piperidine-4-carboxylic acid ethyl ester as a light gray powder. m / e = 472. Mp = 120-122 ° C.
e) Analog zum Beispiel 1l) erhalt man aus 0. 1 1g Ethylester 5d) und 0 25 ml IN Natronlauge 0. 07 g der Titeiverbindung m/e = 444 Fp > 200 °C.. Beispiel 6 e) Analogously to Example 1l), 0.1 g of ethyl ester 5d) and 0 25 ml of 1N sodium hydroxide solution give 07.07 g of the titanium compound m / e = 444 bp> 200 ° C. Example 6
(±)-(3 'α,7'ß.7α)-{1-[2-Oxo-3-(3.4.5.6-tetrahvdro-2H-[ 1.4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-piperidin-4-yl }-essigsaure (±) - (3 'α, 7'ß.7α) - {1- [2-Oxo-3- (3.4.5.6-tetrahvdro-2H- [1.4'] bipyridinyl-4-yl) -octahydro-benzooxazole- 7-yl] piperidin-4-yl} acetic acid
Die Titelverbindung erhalt man analog zu den Beispielen 2b). 2c) und 1i)- 1 l), indem man im Beispiel 2b) den 4-Piperidincarbonsaureethylester gegen 4-Piperidin-essigsaureethyl- ester ersetzt Fp = 135 °C. (Zersetzung) m/e (Ei-Spektrum) = 514 (gemessen als The title compound is obtained analogously to Examples 2b). 2c) and 1i) - 1 l) by replacing the 4-piperidinecarboxylic acid ethyl ester with 4-piperidine-acetic acid ethyl ester in Example 2b), mp = 135 ° C. (Decomposition) m / e (egg spectrum) = 514 (measured as
Trimethylsilylderivat) Trimethylsilyl derivative)
Beispiel 7 Example 7
(=)-(3'α,7'ß,7α)-( 1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[ 1 ,4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-4-(2-phenylethyl)-piperidin-4-carbonsaureethylester (=) - (3'α, 7'ß, 7α) - (1- [2-Oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyl-4-yl ) -octahydro-benzooxazol-7-yl] -4- (2-phenylethyl) -piperidine-4-carboxylic acid ethyl ester
Die Titelverbindung erhalt man analog zu den Beispielen 2b), 2c) und 1i)-1k), indem man im Beispiel 2b) den 4-Piperidincarbonsaureethylester gegen 4[4-(2-Phe-nylethyl)]- Piperidin-carbonsaureethylester (Gilligan et al., J. Med., Chem. ,37, 364 (1994)) ersetzt m/e = 560. Η-NMR (d6-DMSO) : δ = 8. 13 ppm (d, 2H); 7 .25 (m, 2H); 7. 15 (m, 3H); 6.80 (d, 2H); 4.12 (q, 2H); 4.01 (m, 2H); 3.80 (t, 1H), 3.70 (m, 1H), 3.60 (m, 4H);3.28 (m, 1H);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). The title compound is obtained analogously to Examples 2b), 2c) and 1i) -1k) by, in Example 2b), the 4-piperidinecarboxylic acid ethyl ester against 4 [4- (2-phenylethyl)] - piperidinecarboxylic acid ethyl ester (Gilligan et al., J. Med., Chem., 37, 364 (1994)) replaces m / e = 560. Η NMR (d 6 -DMSO): δ = 8. 13 ppm (d, 2H); 7.25 (m, 2H); 7. 15 (m, 3H); 6.80 (d. 2H); 4.12 (q, 2H); 4.01 (m, 2H); 3.80 (t, 1H), 3.70 (m, 1H), 3.60 (m, 4H); 3.28 (m, 1H); 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).
Beispiel 8 Example 8
(±)-(3'α,7'ß.7α)- 1 -[2-Thiooxo-3-(3,4,5,6-tetrahvdro-2H-[1,4']bipyridinyl-4-yl)- octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaure (±) - (3'α, 7'ß.7α) - 1 - [2-Thiooxo-3- (3,4,5,6-tetrahvdro-2H- [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] piperidine-4-carboxylic acid
a) Analog zum Beispiel 1 k) erhalt man aus 0. 3 g Aminoalkohoi lj) und 0.21 g Thiocarbonyldiimidazol 0. 2 g (±)-(3 'α,7'ß,7α)-1 -[2-Thιooxo-3-(3,4,5,6-tetrahydro- 2H-[ 1,4']bipyridinyl-4-yl)-octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaure- ethylester. Pos. FAB = 472. a) Analogously to Example 1 k), 0.3 g of amino alcohol lj) and 0.21 g of thiocarbonyldiimidazole are used to obtain 0.2 g (±) - (3 'α, 7'ß, 7α) -1 - [2-thiooxo-3 - (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) -octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid, ethyl ester. Pos. FAB = 472.
b) Analog zum Beispiel 11) erhalt man aus 0. 14g Ethylester 8a) und 0. 35 ml 1 N Natronlauge 0. 1 g des Produktes, aus dem man nach Zusatz von 0. 6 ml 1 Nb) Analogously to Example 11), 0. 14 g of ethyl ester 8a) and 0. 35 ml of 1 N sodium hydroxide solution give 0.1 g of the product from which, after addition of 0. 6 ml of 1 N,
Salzsaure 143 mg der Titelverbindung als HCl-Salz isoliert Pos FAB = 472. Fp = 180 °C. Beispiel 9 Hydrochloric acid 143 mg of the title compound as HCl salt isolated Pos FAB = 472. Mp = 180 ° C. Example 9
(±)-(3'α,7'ß,7α)- 1 -[3-( 1-Benzyl-[ 1 ,4']bipiperidinyl-4-yl)-2-oxo-octahydro-benzooxazol- 7-yl]-piperidin-4-carbonsaure (±) - (3'α, 7'ß, 7α) - 1 - [3- (1-Benzyl- [1, 4 '] bipiperidinyl-4-yl) -2-oxo-octahydro-benzooxazol-7-yl ] -piperidine-4-carboxylic acid
a) Die Mischung von 15 g Pyridin-Derivat 1 a) und 4 g Rutheniumoxid wird solange hydriert, bis die Wasserstoffaufnahme beendet ist (30 Stunden) Anschließend wird der Katalysator abfiltriert, das Fiitrat im Vakuum eingeengt, der Ruckstand in 120 ml 1,4-Dioxan aufgenommen und die so erhaltene Losung mit 18 ml Benzylchlorid und 15 g Kaliumkarbonat versetzt Die Reaktionsmischung wird dann 5 Stunden am Rückfluß erhitzt, danach abgekühlt, der Niederschlag abfiltriert und das Fiitrat zur Trockne eingedampft Das Rohprodukt wird saulenchromatographisch an Kieselgel (Essigsaureethylester + 10% gesättigtes ammoniakalisches Methanol) gereinigt Man erhalt so 3. 4 g 8-( 1-Benzyl-piperidin-4-yl)- 1 ,4-dioxa-8-aza-spι- ro[4.5]decan. 1H-NMR (d6-DMSO) δ = 7.30 ppm ( m, 5H); 3.85 (s, 4H);3.45 (s, 2H); 2.84 (d, 2H); 2.52 (m, 4H); 2.25 (m, 1H); 1. 88 (t, 2H); 1.63 (m, 6H); 1.42 (q mit Feinaufspaltung, 2H) a) The mixture of 15 g of pyridine derivative 1 a) and 4 g of ruthenium oxide is hydrogenated until the hydrogen uptake has ended (30 hours). The catalyst is then filtered off, the filtrate is concentrated in vacuo, the residue in 120 ml of 1.4 -Dioxane is added and the solution thus obtained is mixed with 18 ml of benzyl chloride and 15 g of potassium carbonate. The reaction mixture is then heated under reflux for 5 hours, then cooled, the precipitate is filtered off and the filtrate is evaporated to dryness. The crude product is purified by column chromatography on silica gel (ethyl acetate + 10%) saturated ammoniacal methanol). This gives 3. 4 g of 8- (1-benzyl-piperidin-4-yl) - 1,4-dioxa-8-aza-spι- ro [4.5] decane. 1 H NMR (d 6 -DMSO) δ = 7.30 ppm (m, 5H); 3.85 (s, 4H); 3.45 (s, 2H); 2.84 (d, 2H); 2.52 (m, 4H); 2.25 (m, 1H); 1. 88 (t, 2H); 1.63 (m, 6H); 1.42 (q with fine splitting, 2H)
b) Analog zum Beispiel 1b) erhalt man aus 1.5 g Ketal 9a) und 10 ml 6N Salzsaure 1.2 g 1'-Benzyl-[144']bipiperidinyl-4-on. m/e = 272 1H -NMR (d6-DMSO) δ = 7 35 ppm ( m, 5H); 4.01 (s, 2H); 3.22 (d, 2H); 3.01 (m, 1H); 2.84 (d, 3H); 2.65 (q,b) Analogously to Example 1b), 1.2 g of 1'-benzyl- [144 '] bipiperidinyl-4-one is obtained from 1.5 g of ketal 9a) and 10 ml of 6N hydrochloric acid. m / e = 272 1 H -NMR (d 6 -DMSO) δ = 7 35 ppm (m, 5H); 4.01 (s, 2H); 3.22 (d, 2H); 3.01 (m, 1H); 2.84 (d, 3H); 2.65 (q,
3H); 2.33 (t, 3H); 1. 80 (m, 5H). c) Analog zum Beispiel 1j) erhalt man aus 1.2 g Amin 1i), 1.2 g Keton 9b) und 1.9 g Natriumtriacetatoborhydrid 1.4 g 1-[3-( 1-Benzyl-[ 1.4']bipιperidinyl-4-ylamιno)-2- hydroxy-cyclohexyl]-pιperidιn-4-carbonsaure-ethylester als hellgrauen Feststoff Fp= 92 °C.. 3H); 2.33 (t, 3H); 1.80 (m, 5H). c) Analogously to example 1j), 1.2 g of amine 1i), 1.2 g of ketone 9b) and 1.9 g of sodium triacetate borohydride give 1.4 g of 1- [3- (1-benzyl- [1.4 '] bipιperidinyl-4-ylamιno) -2- hydroxy-cyclohexyl] -pιperidιn-4-carboxylic acid ethyl ester as a light gray solid, mp = 92 ° C.
d) Analog zum Beispiel l k) erhalt man aus 0 99 g Aminoalkohoi 9c) und 0 45 g Carbonyldiimidazol 0 51 g (±)-(3'α,7'ß,7α)-1-[3-(1 '-Benz yl-[1 ,4']bιpιperidιnyl-4-yl)- 2-oxo-octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaure-ethylester als weißes Pulver Fp = 148 - 150 °C.. d) Analogously to example lk), from 0 99 g of amino alcohol 9c) and 0 45 g of carbonyldiimidazole, 0 51 g (±) - (3'α, 7'ß, 7α) -1- [3- (1 '-Benz yl- [1, 4 '] bιpιperidιnyl-4-yl) - 2-oxo-octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid ethyl ester as white powder Mp = 148 - 150 ° C ..
e) Analog zum Beispiel 1 l) erhalt man aus 0. 25 g Ethylester 9d) und 0. 5 ml 1 N Natronlauge 0. 12 g der Titelverbindung m/e = 524. 1H-NMR (D2O) : δ = 7. 25 ppm (m, 5H); 3.92 (t, 1H); 3 60 (s, 2H); 3.45 (m, 2H); 3.01 (d, 4H); 2 82 (m, 3H); 2.48e) Analogously to Example 1 l), 0.25 g of ethyl ester 9d) and 0.5 ml of 1 N sodium hydroxide solution give 0. 12 g of the title compound m / e = 524. 1 H-NMR (D 2 O): δ = 7. 25 ppm (m, 5H); 3.92 (t, 1H); 3 60 (s, 2H); 3.45 (m. 2H); 3.01 (d, 4H); 2 82 (m, 3H); 2.48
(t, 2H); 2.38-2.00 (m, 7H); 1. 95-1.60 (m, 10H); 1. 35 (m, 7H). (t, 2H); 2.38-2.00 (m, 7H); 1. 95-1.60 (m, 10H); 1. 35 (m, 7H).
Beispiel 10 Example 10
( ± )-(3'α,7'ß,7α)-l -(3-[ 1 ,4']Bipiperidinyl-4-yl-2-oxo-octahydro-benzooxazol-7-yl)- piperidin-4-carbonsaure (±) - (3'α, 7'ß, 7α) -l - (3- [1, 4 '] bipiperidinyl-4-yl-2-oxo-octahydro-benzooxazol-7-yl) - piperidin-4- carboxylic acid
a) Die Mischung von 0. 74 g N-Benzylderivat 9d) und 0. 3 g 10%iger Palladium/Kohle in 20 ml Ethanol wird bei 50 °C/4 bar solange hydriert, bis die Wasserstoffaufnahme beendet ist (2 Stunden). Danach wird der Katalysator abfilmen und das Filtrat zur Trockne eingedampft. Man erhält so 0. 355 g (±)-(3'α,7'ß,7α)- 1-(3- [1 ,4']Bipiperidinyl-4-yl-2-oxo-octahydro-benzooxazol-7-yl)-piperidin-4-carbon- saure-ethylester. Pos FAB - 524 Fp > 200 °C.. a) The mixture of 0.74 g of N-benzyl derivative 9d) and 0.3 g of 10% palladium / carbon in 20 ml of ethanol is hydrogenated at 50 ° C./4 bar until the hydrogen uptake has ended (2 hours). Then the catalyst will film and that The filtrate was evaporated to dryness. This gives 0. 355 g (±) - (3'α, 7'ß, 7α) - 1- (3- [1, 4 '] bipiperidinyl-4-yl-2-oxo-octahydro-benzooxazol-7- yl) -piperidine-4-carbon-acidic ethyl ester. Pos FAB - 524 Fp> 200 ° C ..
b) Analog zum Beispiel 1l) erhält man aus 0. 2 g Ethylester 10a) und 0.7 ml IN Natronlauge 0. 13 g der Titelverbindung Pos FAB (MH ) = 435. Fp > 200 °C. b) Analogously to Example 1l), 0.2 g of ethyl ester 10a) and 0.7 ml of 1N sodium hydroxide solution give 0. 13 g of the title compound Pos FAB (MH) = 435. mp> 200 ° C.
Beispiel 11 Example 11
(±)-(3'ß,7'α,7α)- 1 -[2-Oxo-3-(3,4,5,6-tetrahvdro-2H-[ 1.4']bipyridinyl-4-yl)-octahydro- benzooxazol-7-yl]-piperidin-4-carbonsaure (±) - (3'ß, 7'α, 7α) - 1 - [2-Oxo-3- (3,4,5,6-tetrahvdro-2H- [1.4 '] bipyridinyl-4-yl) octahydro - benzooxazol-7-yl] piperidine-4-carboxylic acid
a) Die Mischung aus 1.77 g trans-3-Brom- 1 ,2-epoxycyclohexan (Lier E. et al , Ηelv Chim Acta, 62, 932 ( 1979)), 1. 7 ml 4-Piperidincarbonsaureethylester und 1.8 g Kaliumcarbonat in 30 ml Dimethylformamid wird 24 Stunden bei Raumtemperatur gerührt. Anschließend wird die Reaktionsmischung mit 400 ml Wasser versetzt und die wäßrige Lösung dreimal mit je 40 ml Diethylether extrahiert Nach Trocknen der vereinigten organischen Phasen über Natriumsulfat und Abziehen des Losungsmittels wird das Rohprodukt saulenchromatographisch an Kieselgel (Essigsäureethylester + 1% gesättigtes ammoniakalisches Methanol) gereinigt Man erhält so 0.6 g (±)-cis-1-(2,3-Epoxy-cyclohexyl)-piperidin-4-carbonsaure- ethylester 1H-NMR (CDCI3): δ - 4.05 ppm (q, 2Η); 3.20 (d, 1H); 3.05 (t, 1H); 2.98 (m, IH); 2.82 (m, 2H); 2.40 (m, 12 Linien, 2H); 2.18 (m, 1H); 1. 85 (m, 2H); 1.70 (m, 6H); 1.50 (m, 1H); 1.36 (m, 1H); 1. 19 (t, 3H). b) Analog zum Beispiel 2c) erhalt man aus 0 6 g Epoxid 1 1a) und 0. 23 g Natriumazid 0. 6 g (±)-(1α,2α,3ß)-1 -(3-Azido-2-hydroxy-cyclohexyl)-pιperidin-4-carbonsau- reethylester als grauen Feststoff m/e = 296 Fp = 90 °C. a) The mixture of 1.77 g of trans-3-bromo-1,2-epoxycyclohexane (Lier E. et al, Ηelv Chim Acta, 62, 932 (1979)), 1.7 ml of 4-piperidinecarboxylic acid ethyl ester and 1.8 g of potassium carbonate in 30 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is then mixed with 400 ml of water and the aqueous solution is extracted three times with 40 ml of diethyl ether. After drying the combined organic phases over sodium sulfate and removing the solvent, the crude product is purified by column chromatography on silica gel (ethyl acetate + 1% saturated ammoniacal methanol) so 0.6 g (±) -cis-1- (2,3-epoxy-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester 1 H-NMR (CDCI 3 ): δ - 4.05 ppm (q, 2Η); 3.20 (d, 1H); 3.05 (t, 1H); 2.98 (m, IH); 2.82 (m, 2H); 2.40 (m, 12 lines, 2H); 2.18 (m, 1H); 1. 85 (m, 2H); 1.70 (m, 6H); 1.50 (m, 1H); 1.36 (m, 1H); 1. 19 (t, 3H). b) Analogously to example 2c), 0 6 g of epoxy 1 1a) and 0.23 g of sodium azide 0. 6 g (±) - (1α, 2α, 3ß) -1 - (3-azido-2-hydroxy- cyclohexyl) -pιperidin-4-carbonsau- reethylester as a gray solid m / e = 296 mp = 90 ° C.
c) Analog zum Beispiel 1i) erhalt man aus 0. 44 g Azid 1 1b) 0. 2 g (±)-( 1α,2α,3ß)-1-c) Analogously to example 1i), from 0. 44 g of azide 1 1b) 0.2 g (±) - (1α, 2α, 3ß) -1-
(3-Amιno-2-hydroxy-cyclohexyl)-pιperidin-4-carbonsaureethylester Pos FAB =(3-Amιno-2-hydroxy-cyclohexyl) -pιperidin-4-carboxylic acid ethyl ester Pos FAB =
270. 1H-NMR (CDCh) δ = 4.05 ppm (q, 2H); 3.60 (t, 1H); 3.15 (q, 1H); 3.00 (m,270. 1 H NMR (CDCh) δ = 4.05 ppm (q, 2H); 3.60 (t, 1H); 3.15 (q, 1H); 3.00 (m,
2H); 2.50 (m, 1H); 2.28-2.00 (m, 5H); 1.90-1.40 (m, 1 1 H); 1.25 (m, I H); 1. 18 (t, 3H). 2H); 2.50 (m, 1H); 2.28-2.00 (m, 5H); 1.90-1.40 (m, 1 1 H); 1.25 (m, IH); 1.18 (t, 3H).
d) Analog zum Beispiel 1j) erhalt man aus 0. 2 g Amin 1 1 c), 0. 13 g Keton 1 b) und 0. 31 g Natriumtriacetatoborhydrid 0. 12 g (±)-( 1α,2α,3ß)-1-[2-Hydroxy-3- (3,4,5,6-tetrahydro-2H-[ 1 ,4']bιpyridinyl-4-ylamιno)-cyclohexyl]-pιperidm-4-car- bonsaureethylester Pos FAB = 430. d) Analogously to example 1j), 0.2 g of amine 1 1 c), 0.13 g of ketone 1 b) and 0.31 g of sodium triacetate borohydride 0. 12 g (±) - (1α, 2α, 3ß) - 1- [2-Hydroxy-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bιpyridinyl-4-ylamιno) -cyclohexyl] -pιperidm-4-carboxylic acid ethyl ester Pos FAB = 430.
e) Analog zum Beispiel 1 k) erhalt man aus 0. 42 g Aminoalkohoi 1 1 d) und 0. 24 g Carbonyldiimidazol 0. 35 g (±)-(3'ß,7'α,7α)- 1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-e) Analogously to Example 1 k), 0. 42 g of amino alcohol 1 1 d) and 0. 24 g of carbonyldiimidazole 0. 35 g (±) - (3'ß, 7'α, 7α) - 1- [2 -Oxo-3- (3,4,5,6-tetrahydro-2H-
[ 1,4']bipyridinyl-4-yl)-octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaureethyl- ester m/e = 456. 1H-NMR (d6-DMSO): δ = 8. 20 ppm (d, 2H); 6.85 (d, 2H); 4.05 (q+m, 5H); 3.75 (m, 1H); 3.20 (breites d, 1H); 2.90 (m, 3H); 2.30 (m, 1H); 2.04 (m, 4H); 1. 80 (m, 5H); 1. 65-1. 35 (m, 9H); 1.20 (t, 3H). [1,4 '] bipyridinyl-4-yl) octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid ethyl ester m / e = 456. 1 H-NMR (d 6 -DMSO): δ = 8. 20 ppm (d, 2H); 6.85 (d. 2H); 4.05 (q + m, 5H); 3.75 (m, 1H); 3.20 (broad d, 1H); 2.90 (m, 3H); 2.30 (m, 1H); 2.04 (m, 4H); 1. 80 (m, 5H); 1. 65-1. 35 (m, 9H); 1.20 (t, 3H).
f) Analog zum Beispiel 1l) erhalt man aus 0. 3 g Ethylester 1 1e) und 1 ml 4N f) Analogously to Example 1l), 0.3 g of ethyl ester 11e) and 1 ml of 4N are obtained
Natronlauge 0. 26 g der Titelverbindung Pos FAB = 428. Beispiel 12 Sodium hydroxide solution 0.26 g of the title compound Pos FAB = 428. Example 12
(±)-(3'ß,7'ß,7α)- 1 -[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[ 1 ,4'lbιpyridιnyl-4-yl)-octahydro- benzooxazol-7-y l]-pιperidιn-4-carbonsaure (±) - (3'ß, 7'ß, 7α) - 1 - [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1, 4'lbιpyridιnyl-4-yl) - octahydro-benzooxazol-7-yl] -pιperidιn-4-carboxylic acid
a) Analog zum Beispiel 1d) erhalt man aus 0. 65 g cιs-3-Benzvloxycarbonylamιno- 4 ,2- epoxycyclohexan (Brouillette W. J. et al , J. Org. Chem. , 59, 4297 (1994)) und 0. 6 ml 4-Piperidιncarbonsaureethylester 0. 9 g (±)-( 1α,2ß,3ß)-1-(3-Benzyloxycarbonyl- amιno-2-hydroxy-cyclohexyl)-pιperidin-4-carbonsaureethylester als zähes OI, das als Rohprodukt weiterumgesetzt wird. a) Analogously to Example 1d), 0.65 g of cιs-3-benzvloxycarbonylamιno- 4,2-epoxycyclohexane (Brouillette WJ et al, J. Org. Chem., 59, 4297 (1994)) and 0. 6 ml 4-Piperidιncarbonsaureethylester 0. 9 g (±) - (1α, 2ß, 3ß) -1- (3-Benzyloxycarbonyl- amιno-2-hydroxy-cyclohexyl) -pιperidin-4-carboxylic acid ethyl ester as a tough OI, which is further converted as a crude product.
b) Die Losung von 0. 9 g des unter 12a) hergestellten N-Benzyloxycarbonylamins in 15 ml Ethanol wird mit 0 8 g 10%ιger Palladium/Kohle versetzt, und die Mischung bei Normaldruck und Raumtemperatur solange hydriert, bis die Wasserstoffaufnahme beendet ist ( 12 Stunden) Anschließend wird der Katalysator abfiltriert und die Losung am Rotationsverdampfer eingeengt Man erhalt so 0. 5 g (±)- (1α,2ß,3ß)- 1 -(3-Amιno-2-hydroxy-cyclohexyl)-pιperidin-4-carbonsaureethylester m/e = 270. 1H-NMR (d6-DMSO) δ = 4.05 ppm (q, 2H); 3.48 (dd, 1H); 3.20 (q, 1H); 2.80 (dt, 1H);2. 68 (dt, 1H); 2.58 (t mit Feinaufspaltung, 1H); 2.42 (t mit Feinaufspaltung, 1H); 2.25 (m, 1H); 2.13 (t mit Feinaufspaitung, 1H); 1. 78 (m, 2H); 1. 63 (m, 2H); 1. 55 (m, 4H); 1. 38 (m, 2H); 1. 19 (t, 3H); 1. 15 (m, 2H). b) The solution of 0. 9 g of the N-benzyloxycarbonylamine prepared 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 and room temperature until the hydrogen uptake has ended ( 12 hours) The catalyst is then filtered off and the solution is concentrated on a rotary evaporator. This gives 0.5 g (±) - (1α, 2ß, 3ß) - 1 - (3-amino-2-hydroxy-cyclohexyl) -pιperidin-4 -carboxylic acid ethyl ester m / e = 270. 1 H-NMR (d 6 -DMSO) δ = 4.05 ppm (q, 2H); 3.48 (dd, 1H); 3.20 (q, 1H); 2.80 (German, 1H); 2. 68 (dt, 1H); 2.58 (t with fine splitting, 1H); 2.42 (t with fine splitting, 1H); 2.25 (m, 1H); 2.13 (t with fine machining, 1H); 1. 78 (m, 2H); 1. 63 (m, 2H); 1. 55 (m, 4H); 1. 38 (m, 2H); 1. 19 (t, 3H); 1.15 (m, 2H).
c) Analog zum Beispiel 1j) erhalt man aus 0. 4 g Amin 12b), 0. 26 g Keton 1b) und 0. 42 g Natriumtriacetatoborhydrid 0. 33 g (±)-( 1α,2ß,3ß)- 1-[2-Hydroxy-3- (3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-4-ylamino)-cyclohexyl]-piperidin-4-car- bonsaureethylester.Die anschließende Umsetzung des so hergestellten Aminoalkohols mit 0. 17 g Carbonyldiimidazol analog zum Beispiel 1k) lieferte 0. 22 g Ethylester (±)-(3'ß,7'ß,7α)-1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-4-yl)- octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaureethylester, dessen Versei- füng. mit 0 6 ml IN Natronlauge analog zum Beispiel 11) 0. 1 1 g der Titelverbindung ergab. Fp = 150 °C. (Zersetzung), m/e = 428. 1H-NMR (d6-DMSO+AcOH) δ = 4.05 ppm 8. 15 (d, 2H); 7. 10 (d, 2H); 4.65 (t, 1H); 4.25 (breites d, 2H); 3.98 (breites d, 1H); 3.61 (m, 1H); 30.5 (m, 4H); 2.70 (m, 2H); 2.35 (m, 1H); 2.10 (m, 1H); 2.0- 1.10 (m, 16). c) Analogously to Example 1j), 0.4 g of amine 12b), 0.26 g of ketone 1b) and 0.42 g of sodium triacetate borohydride 0. 33 g (±) - (1α, 2ß, 3ß) - 1- [ 2-hydroxy-3- (3,4,5,6-tetrahydro-2H- [1, 4 '] bipyridinyl-4-ylamino) cyclohexyl] piperidine-4-carboxylic acid ethyl ester. The subsequent reaction of the amino alcohol thus prepared with 0.17 g of carbonyldiimidazole analogous to example 1k) gave 0.22 g of ethyl ester (±) - (3'ß, 7'ß, 7α) -1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [ 1, 4 '] bipyridinyl-4-yl) - octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid ethyl ester, the Versei- five. with 0 6 ml IN sodium hydroxide solution analogously to Example 11) 0.1 1 g of the title compound gave. Mp = 150 ° C. (Decomposition), m / e = 428. 1 H NMR (d 6 -DMSO + AcOH) δ = 4.05 ppm 8. 15 (d, 2H); 7. 10 (d, 2H); 4.65 (t, 1H); 4.25 (broad d, 2H); 3.98 (broad d, 1H); 3.61 (m, 1H); 30.5 (m, 4H); 2.70 (m, 2H); 2.35 (m, 1H); 2.10 (m, 1H); 2.0-1.10 (m, 16).
Beispiel 13 Assay Example 13 Assay
Mikrotiterplatten wurden über Nacht mit 2 μg/ml isoliertem aktiviertem GplIb/IIla- Rezeptor beschichtet Nachdem der ungebundene Rezeptor durch einige Waschschritte entfernt wurde, wurde die Oberflache der Platte mit 1 % Kasein blockiert und nochmals gewaschen Die Testsubstanz wurde in den notwendigen Konzentrationen dazugegebenen, anschließend wurden die Platten für 10 Minuten unter Schuttein in einem Linearschuttier inkubiert. Der naturliche Ligand des gpIIb/IIIa-Rezeptors, Fibronogen, wurde dazugegeben Nach 1 stundigem Inkubieren wurde das ungebundene Fibrinogen durch mehrere Waschschritte entfernt, und das gebundene Fibronogen wurde bestimmt, indem die optische Dichteänderung bei 405 nm durch einen Peroxidase- konjugierten monoklonaler Antikörper in einem ELISA-Ableser bestimmt wurde Inhibierung der Fibrinogen-GpIIb/IIIa-Wechselwirkung fuhrt zu niedrigen optischen Dichten Der ICso-Wert wurde anhand einer Konzentration-Effekt-Kurve bestimmt. Literatur : Microtiter plates were coated overnight with 2 μg / ml isolated activated GplIb / IIla receptor. After the unbound receptor was removed by a few washing steps, the surface of the plate was blocked with 1% casein and washed again. The test substance was added in the required concentrations, then the plates were incubated under rubble in a linear shaker for 10 minutes. The natural ligand of the gpIIb / IIIa receptor, fibronogen, was added. After 1 hour of incubation, the unbound fibrinogen was removed by several washes and the bound fibronogen was determined by measuring the optical density change at 405 nm by a peroxidase-conjugated monoclonal antibody in one Inhibition of the fibrinogen-GpIIb / IIIa interaction leads to low optical densities. The IC 50 value was determined on the basis of a concentration-effect curve. Literature:
Der GpIIb/IIla-Fibrinogen-ELISA ist eine Modifikation des Assays, der in folgenden Referenzen beschrieben ist. The GpIIb / IIla fibrinogen ELISA is a modification of the assay described in the following references.
Nachman, R.L. & Leung, L.L.K (1982) Complex formation of platelet membrane gly- coproteins Ilb and lila with fibrinogen J. Clin. Invest 69 263-269. Nachman, R.L. & Leung, L.L.K (1982) Complex formation of platelet membrane glycoproteins Ilb and lila with fibrinogen J. Clin. Invest 69 263-269.
Wright, P. S . et al. ( 1993): An echistatin C-terminal peptide activated GpIIbllla binding to fibrinogen, fibronectin, vitronectin and collagen type I and type IV Biochem. J. 293 :263-267.  Wright, P. S. et al. (1993): An echistatin C-terminal peptide activated GpIIbllla binding to fibrinogen, fibronectin, vitronectin and collagen type I and type IV Biochem. J. 293: 263-267.

Claims

Patentansprüche 1. Verbindungen der allgemeinen Formel 1, 1. Compounds of general formula 1,
in der E einen Rest der Formel (a) oder (b) in which E is a radical of the formula (a) or (b)
bedeutet,  means
M Sauerstoff, Schwefel oder NR00 bedeutet, M represents oxygen, sulfur or NR 00 ,
X Wasserstoff oder NR1 R2 bedeutet, X represents hydrogen or NR 1 R 2 ,
W Stickstoff bzw NH oder CH bzw. CH2 bedeutet, W denotes nitrogen or NH or CH or CH 2 ,
Q Stickstoff oder CH bedeutet, Q represents nitrogen or CH,
Y Stickstoff oder CH bedeutet,  Y represents nitrogen or CH,
Z Stickstoff, CH oder C-OH bedeutet,  Z is nitrogen, CH or C-OH,
A eine gegebenenfalls substituierte Alkylenkette -(CH2)p- bedeutet, A denotes an optionally substituted alkylene chain - (CH 2 ) p -,
D eine Seitenkette der Form -(CHR3)m-COO-R8 oder =CR3-COO-R8 bedeutet, n = 1-3 bedeutet, D is a side chain of the form - (CHR 3 ) m -COO-R 8 or = CR 3 -COO-R 8 , n = 1-3 means
m = 0 oder 1 bedeutet, m = 0 or 1 means
p = 0-3 bedeutet, R1 , R2 unabhängig voneinander Wasserstoff, niederes Alkyl Aryl, Arylalkyl, Het- aryl,Acyl oder einen gegebenenfalls substituierten carbocvclischen oder heterocy- clischen Ring bedeuten, oder zusammen mit dem Stickstoff an dem sie gebunden sind, einen gegebenenfalls substituierten fünf- oder sechsgliedrigen Ring bilden, der noch 1 bis 3 weitere Heteroatome enthalten kann, oder eine Gruppe (c) p = 0-3 means R 1 , R 2 independently of one another are 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, an optionally substituted five- or six-membered ring Form a ring, which may also contain 1 to 3 further heteroatoms, or a group (c)
bedeuten,  mean,
R3 Wasserstoff oder eine Gruppe -OR5 oder -NR6R7 bedeutet, R 3 represents hydrogen or a group -OR 5 or -NR 6 R 7 ,
R4 Wasserstoff, niederes Alkyl, Aryl, Arylalkyl Hetaryl oder eine Gruppe -OR5 R 4 is hydrogen, lower alkyl, aryl, arylalkyl hetaryl or a group -OR 5
bedeutet,  means
R5 Wasserstoff, niederes Alkyl, Aryl oder Arylalkyl bedeutet, R 5 denotes hydrogen, lower alkyl, aryl or arylalkyl,
R6 Wasserstoff, niederes Alkyl oder Arylalkyl bedeutet, R 6 represents hydrogen, lower alkyl or arylalkyl,
R7 Wasserstoff, niederes Alkyl, Arylalkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl R 7 is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl
bedeutet,  means
R8 Wasserstoff, Methyl, Ethyl, Isopropyl, tert -Butyl, Phenyl oder Benzyl R 8 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, phenyl or benzyl
insbesondere Wasserstoff, Ethyl, Phenyl oder Isopropyl bedeutet,  is in particular hydrogen, ethyl, phenyl or isopropyl,
R10 Wasserstoff, niederes Alkyl, Arylalkyl, Acyl. Alkylsulfonyl Arylsulfonyl oder eineR 10 is hydrogen, lower alkyl, arylalkyl, acyl. Alkylsulfonyl arylsulfonyl or a
Gruppe (c) bedeutet, R0 Wasserstoff, niederes Alkyl, Arylalkyl oder eine Gruppe -NHR00 bedeutet, Group (c) means R 0 is hydrogen, lower alkyl, arylalkyl or a group -NHR 00 ,
R00 Wasserstoff, niederes Alkyl, Arylalkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl R 00 is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl
bedeutet, sowie deren Konformations- und Konfigurationsisomere und deren pharmakologisch unbedenklichen Salze  means, as well as their conformational and configuration isomers and their pharmacologically acceptable salts
2. Verbindungen der allgemeinen Formel I gemäß Anspruch 1, dadurch gekennzeichnet, daß n den Wert 1, 2 oder 3 und p den Wert 0, 1 oder 3 annimmt. 2. Compounds of general formula I according to claim 1, characterized in that n assumes the value 1, 2 or 3 and p assumes the value 0, 1 or 3.
3. Die Verbindungen 3. The connections
(±)-(3 ,α,7,ß,7α)- 1-[2-Oxo-3-(3,4,5,6-tetrahydro-2-7-[ 1 ,4']bipyridinyl-4-yl)- octahydro-benzooxazol-7-yl]-pιperidin-4-carbonsaure (±) - (3 , α, 7 , ß, 7α) - 1- [2-oxo-3- (3,4,5,6-tetrahydro-2-7- [1, 4 '] bipyridinyl-4- yl) - octahydro-benzooxazol-7-yl] -pιperidin-4-carboxylic acid
(±)-(3'α,7'ß,7α)-1-[2-Oxo-3-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)- octahydro-benzooxazol-7-yl]-piperidin-4-carbonsaureethylester (±) - (3'α, 7'ß, 7α) -1- [2-oxo-3- (3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl) - Octahydro-benzooxazol-7-yl] -piperidine-4-carboxylic acid ethyl ester
sowie deren Konformations- und Konfigurationsisomere und deren pharmakolo- gisch unbedenklichen Salze. and their conformational and configuration isomers and their pharmacologically acceptable salts.
4. Pharmazeutische Zusammensetzung, enthaltend mindestens eine Verbindung gemäß Formel I nach einem der Ansprüche 1-3 neben üblichen Trager- und Hilfs- Stoffen. 4. Pharmaceutical composition containing at least one compound according to formula I according to any one of claims 1-3 in addition to conventional carriers and auxiliary substances.
5. Verwendung von Substanzen nach einem der Ansprüche 1-3 zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten, die auf eine Blutplattchenaggrega- tion zurückzuführen sind. 5. Use of substances according to any one of claims 1-3 for the manufacture of medicaments for the treatment of diseases which are due to blood platelet aggregation.
EP97916395A 1996-03-30 1997-03-26 Novel oxazolidine derivatives, process for their production and medicaments containing them Ceased EP0891359A1 (en)

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DE19612827A DE19612827A1 (en) 1996-03-30 1996-03-30 New (pyridyl-piperidinyl)-(carboxy-cycloalkyl)cycloalkano:oxazolidinone
DE19654479 1996-12-27
DE1996154479 DE19654479A1 (en) 1996-12-27 1996-12-27 Oxazolidine derivs. to inhibit blood platelet aggregation,
PCT/EP1997/001542 WO1997036899A1 (en) 1996-03-30 1997-03-26 Novel oxazolidine derivatives, process for their production and medicaments containing them

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