EP0808311A2

EP0808311A2 - New derivatives of pyridil piperazine or pyridazinyl piperazyl, process for production thereof and medicaments containing these compounds

Info

Publication number: EP0808311A2
Application number: EP96901794A
Authority: EP
Inventors: Christos Tsaklakidis; Alfred Mertens; Gerd Zimmermann; Wolfgang Schäfer; Liesel Dörge
Original assignee: Roche Diagnostics GmbH; Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1995-02-10
Filing date: 1996-02-08
Publication date: 1997-11-26
Also published as: CA2212227A1; TW408121B; WO1996024581A3; ZA961045B; JPH10513465A; WO1996024581A2; IL117082A; IL117082A0; AU4622996A; DE19504329A1

Abstract

Compounds of formula (I), in which R1 stands for hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, a possibly substituted mono-or bi-cyclic aryl, a possibly substituted hetaryl, a possibly substituted aryl alkyl or one of the groups -OR?2, -NR3R4¿, W stands for nitrogen or -CR5, X, Z independently of each other stands for nitrogen or -CH, and where W stands for a nitrogen atom, X must be the group -CH, A stands for a valency bond or the carbonyl group, B stands for a valency bond or a C¿1?-C6 alkyl chain possibly substituted once or several times by lower alkyl or an OR?2¿ group, D stands for a valency bond, and, where X is a nitrogen atom, can also be the carbonyl group, A, B and D being unable to represent the valency bond simultaneously, R2 stands for hydrogen, lower alkyl or aryl alkyl, R3, R4 independently of each other stand for hydrogen or lower alkyl, or form a five- or six-membered heterocyclic ring together with the nitrogen atom to which they are linked, R5 stands for hydrogen or a group OR2. The invention also relates to a process for the production of these compounds, and medicaments containing them for the treatment of diseases which are attributable to thromboembolic conditions.

Description

New pyridyl or pyridazinyl-piperazine derivatives, processes for their preparation and medicaments containing these compounds

It is known that compounds carrying a basic and an acid group are able to inhibit platelet aggregation if the basic and acid group in the compounds are at a certain distance from one another (Drugs of the Future 19 (8) , 757 (1994) The patents WO 93/14077, EP-A-0 537 980, EP-A-0 542 363, WO 94/22834 and WO 94/22835 describe compounds with antiaggregatory activity on the platelets .

The present invention relates to new pyridyl or pyridazinyl piperazine derivatives, processes for their preparation and medicaments which contain these substances.

It has now been found that pyridine or pyridazine derivatives which still have a carboxylic acid function effectively inhibit the aggregation of the platelets and can therefore be used for the treatment of diseases which are attributable to thromboembolic events, such as stroke, myocardial infarction or arterial occlusive diseases, as well as inflammation, osteoporosis or tumor diseases

The present invention relates to compounds of general formula 1

in the

R 'is hydrogen, lower alkylene, lower alkenyl, cycloalkyl, cycloalkylene, an optionally substituted mono- or bicyclic aryl. an optionally substituted hetaryl. an optionally substituted arylalkyl or one of the groups

-OR ² , -NR R ⁴

means.

W means nitrogen or ^ CR ⁵ .

X. Z independently of one another are nitrogen or ^ CH, and in the event that W is a nitrogen atom. X must be the group ^, CH.

λ means a valence stitch or the carbonyl group.

B is a valence stitch or a C 1 -C 4 alkylene chain which is mono- or polysubstituted or substituted by lower alkyl or an i 0 OR ² group

D represents a valence sting, and for the case that X is a nitrogen atom. can also be the carbonyl group, where A_ B and D must not simultaneously denote the valence stitch.

-> 5

R ^{2 is} hydrogen, lower alkylene or aromatic alkylene.

R} R independently of one another are hydrogen or lower alkyl, or together with the nitrogen atom to which they are attached form a five- to six-membered heterocyclic ring,

R ^ is hydrogen or a group -OR ² . and their pharmacologically acceptable salts

In all cases, lower alkyl is said to be a straight-chain or branched C 1 -C 6 -alkyl group such as, for example, methylene. Ethnic Propyl. Isopropyl. Butvl. Isobutvl. Pentyl or hexyl, especially Methvl Ethvl. Represent propyl, isobutvl and pentvl

Lower Alkenvl means unsaturated residues with 3-6 carbon atoms such as allyl, but-2-enyl, hexa-2.4-dιenvl. especially allyl

Cvcloalkvl means an optionally substituted 3-7-ghedπgen ring, such as the

Cvclopropyl-, Cyclobutvl-. Cyclopentvl-, Cyclohexvl- or the Cycloheptylπng, in particular the Cvclopropvl. Cvclopentvl- and Cyclohexvlπng These cycloalkyl residues can be mono- or disubstituted by a C \ -C (j-alkyl group, preferably the Methvl-, ethyl or isopropyl group. As well as by Hydroxy-, Methoxy-, Benzvloxv- .Anruno-, Methvlamino- , Dimethvlamino-Benzvlaminogruppen or be substituted by chlorine or bromine

Cycloalkenyl means an optionally substituted cyclopentenyl, cyclohexenyl or cycloheptenyl ring. These rings can be mono- or disubstituted by a C 1 -C 4 -alkylene group, preferably the methyl, ethyl or isopropyl group, and also chlorine. Bromine or hvdroxy, methoxy. Benzyloxy, Armno, Methylamino, Dimethylamino or Benzvlaminogruppe be substituted

If the radicals R- ⁵ and R together with the nitrogen atom to which they are bound form a heterocvc's ring, it is a saturated or unsaturated 5-6-membered ring, such as the pyrrolidine, pipeline, morphohn, pyrrole -, Pipeπdin-. Morpholinnng

The carbocyclic and heterocyclic rings can optionally be one or two by C i -Co alkylene groups. preferably the methyl. Ethyl or isopropyl group, and by chlorine. Bromine or hydroxyl, methoxy, benzyloxy, armno, methylamino, dimethlamino or benzvlamino groups can be substituted Arvl usually means the optionally mono- or polysubstituted phenyl radical. Hetarvi usually means a mono- or polysubstituted Pvπdin-. Pyπdazin-, Pvrrol-. Thiophene. Furan or imidazole

Bicvc's Arvl usually means an indane or naphtha radical which may be substituted one or more times. preferably the naphthalene radical aryl. Bicychic aryl and hetaryl radicals can optionally be substituted one or more times by C \ -Co-alkyl groups, preferably the Methvl-. Ethyl or isopropyl group. as well as by chlorine, bromine, fluorine, or hydroxy. Alkoxy such as methoxy, benzyloxy. Acetvloxy, carboxy, ethoxy carbonvl. Aminocarbonyl. Methvlaminocarbonyl-. Dimethvlaminocarbonvl-, Cvano-, Λmino- Methvlamino-. Dimethylamino. Benzvlamino- acetvlamino-. Benzovlamino and amidine groups can be substituted

\ rvlalkvl usually means an unsubstituted or mono- or polysubstituted Benzvl-. Phenethvl, phenylpropyl, phenylbutyl or phenylpentvlrest. preferably a Benzvl-. Phenethvl- or Phenylpentvlrest come as substituents Ci-Cg-Alkvlrestrest. preferably methyl, ethyl or isopropyl, and chlorine. Bromine. Fluorine, or hydroxy, methoxy, benzyloxy, acetyloxy, carboxy, ethoxycarbonyl, aminocarbonyl, methamine laminocarbonyl, dimethylaminocarbonyl, cyano, amino, methylamino, dimethylamino, benzvlamino, acetylamino -, Benzoylamino and amidino groups in question

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 the group ABD represents a group (CH2) ι_3 or CO- (CH2) i-3- and Z, X, W and R ^{1 have} the meaning given - -

Furthermore, compounds of the formula I are preferred in which the ring -X W represents a 1 4-Cvclohexvlιdenvl- or 1 4-pιpeπdιnvl-Rιng and Z. A-B-D- and R 'have the meaning given

In particular, compounds of the formula I are preferred in which ABD represents the group ethylene or carbon-vinyl and the ring -X ^ _^ W- is a 1,4-cyclohexviιdenyl ring and Z and R 'have the meaning given

Compounds of the general formula I are prepared by processes known per se by hydrolysis of an ester of the general formula II.

m the R 1, A, B, D, W X. and Z have the meanings given above and R ^ is a Methvl-, ethyl, tert-Butvl- or benzyl radical, prepared

Compounds of the general formula II are new and are prepared by processes known per se, preferably by

a) in the event that W is nitrogen, a compound of general formula III.

in which A_ B. D and Z have the meanings given above, with a compound of the general formula IV,

in which R 1 and R ^{6 have} the meanings given above and L is a leaving group such as, for example, shark or O-SO2-R ⁷ , where shark is chloride. Bromide or iodide and R ⁷ methyl. Phenyl, p-methylphenyl or p-nitrophenyl should be implemented.

b) in the event that W is a group CR ^ and R ^ is a group OR ² , a ketone of the general formula V.

in which A, B, D, X and Z have the meanings given above, with a carboxylic acid ester of the general formula VI.

in which R ^ and R ^ have the meanings given above and the hydroxyl group of the resulting 2-hydroxy ester of the general formula

VII.

in which R ', R ⁶ , XZA B and D have the meanings given above, optionally with an alkylating agent of the general formula VIII.

R (VIII)

in which R * - and L have the meanings given above, alkylated. or

c) in the event that W represents the CH group, a compound of the general formula VI with a compound of the general formula IX,

in which A. B, D, X. Z and L have the meanings given above, alkylated.

or

d) the olefinic double bond of a compound of the general formula X.

m the. \. B, D. R '. R ^. X, and Z have the meanings given above, katalvtisch hvdrieπ.

in the event that A and D each represent the carbon group, a dicarboxylic acid derivative of the general formula XI,

in which B has the meaning given above and Y and Q independently of one another are hydrogen, the group OR ² in which R ^{2 has} the meanings indicated above, or a halogen such as chlorine or bromine, with an amine of the general formula XII.

in which Z has the meanings given above, and an amine of the general formula XIII.

in the R '. R ^ and R ^ have the meanings given above, bπngt successively to the reaction Compounds of the general formula III are new and are prepared by processes known per se, preferably by

a compound of general formula XII with a compound of general formula XIV.

in which A_ B. and L have the meanings given and P denotes a protective group for amines such as acetyl, tert-butyloxycarbonyl, Benzvl or benzyloxycarbonyl, and then the protective group P is removed from the product formed

15 compounds of the general formula IV are prepared so that in the event that L = shark, a compound of the general formula VI is halogenated by methods known from the literature, or for the case that L in formula IV is O-Sθ2-R ^ Group means the hydroxyl group of a compound of general formula XV,

20 in which R 1 and R ^ have the meanings given above, converted into the corresponding sulfonic acid ester.

Compounds of the general formula V are new and are usually cleaved

"> the ketal group of a compound of general formula XVI.

in which A. B. D. X and Z have the meanings given above and f = 2.3

Compounds of the general formula VIII are commercially available in the case where L = shark, and in the event that L is the O-SO 2 -R ⁷ group, the hydroxyl group of commercially available alcohols of the general formula XVII.

R ² OH (XVII)

in which R ^{2 has} the meanings given above, converted into the corresponding sulfonic acid ester

Compounds of the general formula IX are new and, in the case where L is the OSO2-R group, are prepared by adding the hydroxyl group of a compound of the general formula XVIII,

(XVIII)

in which A. B, D. X, and Z have the meanings given above and are converted into the corresponding sulfonic acid esters; in the case where L = shark, the hydroxyl group of a compound of the general formula XVIII is replaced by halogen by processes known from the literature nucleophilically substituted V compounds of the general formula X are new and are known to be prepared in such a way that a ketone of the general formula V of a Wittig reaction with a phosphorane of the general formula XIX.

in which R ^ and R ^{6 have} the meanings given above and Ar is an aryl in the sense of the definition given above for aryl, or the ketone of the formula V of a Horner-Em ons reaction with a phosphonoacetic ester of the general formula XX.

in which R ¹ and R ^ have the meanings given above.

Compounds of the general formula XI are commercially available.

Compounds of the general formula XII are prepared by reacting 1-benzylpiperazine with 4-chloropyridine or -pyrazine

Compounds of the general formula XIII are prepared by a) in the event that R ^{3 is} hydrogen, the double bond of a compound of general formula XXI.

in which R ¹ and R ^{6 have} the meanings given above, are catalytically hydrogenated and

b) in the event that R ^{3 is} the group OR ² , a compound of the general

Reacts formula VI with 4-Pipeπdon and the hydroxyl group of the resulting 2-hydroxy ester of the general formula XXII.

in which R 'and R ^ have the meanings given above, alkylated with an alkylating agent of the general formula VIII

Compounds of the general formula XIV are prepared by known processes in such a way that

a) in the event that A denotes the valence line, the hydroxyl group of an alcohol of the general formula XXIII, HO (XXIII)

in which B and P have the meanings given above, correspondingly halogenated or sulfonated and

b) in the event that A denotes the carbonyl group, a carboxylic acid of the general formula XXIV.

in which B and P have the meanings given above, converted into the corresponding carboxylic acid halide

Compounds of the general formula XV can be obtained by literature processes by oxidation of the corresponding compounds of the general formula VI

Compounds of the general formula XVI are prepared by a compound of the general formula XII with a compound of the general formula XXV,

20th

in which L.A. B. D, X and f have the meanings given above, will react to the reaction

Alcohols of the general formula XVTI are commercially available

-ι 5 Compounds of the general formula XVIII are prepared by reducing the carbonyl group of a compound of the general formula V.

Some of the compounds of the general formula XIX are commercially available (Aldπch-Chemie GmbH u Co KG) and are used in special cases by known methods by reacting a 2-halocarboxylic acid derivative of the general formula IV with a tertiary phosphine of the general formula XXVI

AR ₃ P (XXVI)

in which Ar has the meanings given above, obtained

\ Compounds of the general formula XX are commercially available (Aldπch-Chemie GmbH u Co KG) and are used in special cases according to known processes by the Λrbuzov reaction between a 2-halocarboxylic acid derivative of the formula IV and a tetraalkylene phosphite of the general formula XXVII.

(OR ⁶ ) ₃ P (XXVII)

in which R> has the meanings given above

Compounds of the general formula XXI are obtainable in that a 4-Pιpeπdo of the general formula XXVIII.

P (XXVIII)

in which P has the meanings given above, is reacted with a compound of the formula XIX or the formula XX and the protective group P is removed from the product formed Compounds of the general formula XXIII are obtained by reducing the carboxyl group of a compound of the formula XXIV.

Connections of the general formula XXIV are partly commercially available. or described in the literature (Ishihara. Chem. Pharm. Bull. 4_i, 529 (1993), Merck and Co. EP 478362)

Compounds of the general formula XXV are prepared by known processes in that

a) in the event that X = CH and A are the valence line, the hydroxyl group of an alcohol of the general formula XXIX.

in which B and f have the meanings given above, converted into a halogen or a sulfonic acid ester,

b) in the event that X = CH and A represent the carbonyl group, a carboxylic acid of the general formula XXX,

in which B and f have the meanings given above, converted into the corresponding carboxylic acid halide and

c) in the event that X = N, a piperidone derivative of the general formula XXXI.

in which f has the meanings given above, with a compound of the general formula XXXII.

L-A-B-D-L (XXXII)

in which L.A. B and D have the meanings given above, will react to the reaction

Tπarvlphosphine of formula XXVI. Trialkyl phosphites of the formula XXVII and 4-Pιpeπdon of the formula XXVIII are commercially available

Compounds of the general formula XXIX are obtained by reducing the carbonyl group of a compound of the formula XXX

Compounds of the general formula XXX are obtained by hydrolysis of an ester of the general formula XXXIII.

(XXXIII)

in which R ^, B and f have the meanings given above

Compounds of the general formula XXXI are commercially available Compounds of the general formula XXXII are commercially available if L = shark. in the event that L is a sulfonic acid residue, commercially available 1-omegadiols are sulfonated accordingly. in the event that A or D represent the carbonyl group and L = shark, commercially available omega-halocarboxylic acids are converted into the corresponding carboxylic acid halo and in the event that A and D represent the carbonyl group, these are compounds of the general formula XI

Compounds of the general formula XXXIII are commercially available and are in special cases by catalytic hydrogenation of the double bond of a compound of the general formula XXXIV.

(XXXIV)

in which B, R ^ and f have the meanings given above, obtained.

Compounds of the general formula XXXIV can be prepared by known processes by reacting a 1,4-cyclohexanedione derivative of the general formula XXXV,

in which f has the meanings given above, with a phosphorane of the general formula XXXVI. (XXXVI)

in the R ^. B and Ar have the meanings given above, obtained

Compounds of the general formula XXXVI are obtained by reacting a triarylphosphine of the formula XXVI with a commercially available omega-halocarboxylic acid ester

The hydrolysis of an ester of the general formula II or the formula XXXIII to the corresponding carboxylic acid of the general formula I or XXX is carried out by customary processes, in which a carboxylic acid ester of the general formula II 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 and at temperatures between room temperature and 80 ° C. preferably treated at room temperature

The reaction of a compound of general formula III with a compound of formula IV or a compound of formula VII with a compound of formula VIII or a compound of formula VI with a compound of formula IX or a compound of formula XXII with a compound VIII or a compound of the formula XII with a compound of the formula XIV or a compound of the formula XII with a compound of the formula XXV or a compound of the formula XXXI with a compound of the formula XXXII or the reaction of 4-chloropiridine or pyridazine with 1-benzylpiperazine usually takes place in an aprotic solvent such as toluene. Tetrahydrofuran. Diethyl ether or dimethylformamide. 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 The reaction of a ketone of the general formula V with an ester of the general formula VI or the reaction between 4-piperidone and an ester of the formula VI takes place under the conditions of the aldol reaction. in a solvent such as methanol, ethanol, toluene. Tetrahvdrofuran. 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 hexamethyl disilazide. preferably sodium hydride or lithium diisopropylamide and at temperatures between -78 ° C. and 90 ° C. but preferably at -78 ° C. and room temperature.

The catalytic hydrogenation of the olefinic double bond of a compound of general formula X or formula XXI or formula XXXIV is carried out analogously to processes known from the literature (A Nose. Chem Pharm Bull. 38. 2097 (1990). Tamura M Bull Chem Soc Jpn 53, 561 (1980); Liu H -J. Synth Commun 15, 965 (1985). Chido N. J Chem soc Chem Commun. 994 (1990). Buchi G. J Amer Chem Soc 89, 6745 (1967), Ernst I. , Coll Czech Chem Comm 24, 3341 (1959), Johnson WS. J Amer chem Soc 79, 1995 (1957), Muchowski J. M, Can. J Chem 47, 857 (1969))

The protective group P can, if necessary, be removed from compounds which carry the protective group P and which are described or included in this patent specification by a compound carrying the protective group P having aqueous mineral acids or bases. treated as hydrochloric acid, sulfuric acid or trifluoroacetic acid or sodium or potassium hydroxide solution or this catalytic hydrogenation, such as. B. with palladium / carbon hydrogen

The halogenation of a compound of the general formula VI or the formula XVIII, or of the formula XXIII, or of the formula XXIV, or of the formula XXIX, or of the formula XXX is carried out by reaction with molecular halogen (chlorine, bromine, iodine), preferably bromine without solvent or in an inert solvent such as methylene chloride. Chloroform or carbon tetrachloride, preferably carbon tetrachloride and with the addition of red phosphorus, phosphorus trichloride or phosphorus tribormid and at a temperature between room temperature and 100 ° C., preferably at 90 ° C. (K Stoh. Chem Pharm Bull 34, 2078 (1986); HJ Ziegler. Synthesis 1969. 39)) Furthermore, compounds of the general formula VI can be halogenated by being treated in an aprotic solvent. solvents such as tetrahydrofuran and at a low temperature, preferably at -78 ° C., with a lithium amide such as lithium diisopropylamide and then the α-position metalated compounds of the general formula XVI with bromine. Iodine. Carbon tetrachloride or carbon tetrabromide (M Hesse. Helv Chim Acta 72, 847 (1989) RT. Arnold, J Org Chem 43, 3687 (1978)) or with N-chloro- or N-bromosuccinimide (W Oppolzer, Tetrahedron Leu 26. 5037 (1985)

Conversion of the hydroxyl group of a compound of general formula XV. XVII, XVIII. XXIII. or XXIX in a sulfonic acid ester is carried out by customary methods, such as, for example, by condensation with a sulfonic acid chloride. like methane. Benzene, p-toluene or p-nitrobenzenesulfonic acid chloride. preferably methane or p-toluenesulfonic acid chloride. in an inert solvent such as methylene chloride. Tetrahydrofuran or diethyl ether. preferably methylene chloride using an auxiliary base such as Tπmethvl- or Tπethytamin or pyridine, preferably Triethvlamin and at a temperature between 0 ° C and room temperature

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

The Wittig reaction between a ketone of the general formula V and a phosphorane of the general formula XIX. or a ketone of formula XXVIII and a phosphorane of formula XIX. or a ketone of the formula XXXV with a phosphorane of the formula XXXVI is carried out according to known processes by refluxing the reactants in an aprotic solvent such as benzene. Toluene or xylene, preferably toluene

The Horner-Emmons reaction between a ketone of the general formula V and a phosphonoacetic ester of the general formula XX. or a ketone of the formula XXVIII and a phosphonoacetic ester of the formula XX are usually carried out in a solvent such as dimethylformamide, tetrahydrofuran. Diethyl ether or 1,4-dioxane, preferably dimethylformamide or tetrahydrofuran using a base such as sodium hydride. Butyllithium. Lithiumdiisopropylamid or Natπumhexamethyldisilazid. in front- preferably sodium hydride or lithium diisopropylamide and preferably at -78 ° C or 100 ° C at -78 ° C or room temperature.

The oxidation of a compound of general formula VI to a compound of general formula XV is generally carried out in a solvent such as tetrahydrofuran by adding a base such as lithium diisopropylamide or lithium N-isopropyl-N-cyclohexvlamide using an oxidizing agent such as an oxaziridine derivative. Molybdenum peroxide or atmospheric oxygen and at temperatures between -78 ° C and room temperature, preferably at 50 ° C by (C. Tamm. Tetrahedron Lett. 26, 203 (1085); FA Davis I Org Chem 51, 2402 (1986). C Wintoai Synth Commun 18, 2141 (1988))

The reaction of a compound of general formula IV with a triarylphosphine of general formula XXVI. or a compound of the formula XXXVI with a triarylphosphine of the formula XXVI is carried out 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 Deutsch Chem Ges. 88, 1654 (1955)

The reaction between a compound of general formula IV and a compound of general formula XXVII generally takes place without solvent at temperatures between room temperature and 150 ° C., preferably at 130 ° C. with a reaction time between 30 minutes and 30 hours, preferably 18 hours.

The reduction of a carboxylic acid of the general formula XXTV or XXX to an .Alcohol of the formula XXIII or XXIX is generally carried out in a solvent such as tetrahydrofuran or diethyl ether with a reducing agent such as lithium aluminum hydride and at a reaction temperature between 0 ° C. and the reflux temperature of the solvent used, preferably carried out at 40 ° C.

The acylation of an A in the general formula XII or formula XIII. or the formula XXXI with a carboxylic acid derivative of the formula XI, or the formula XXV. or the formula XXXII. or the formula XIV is usually carried out in a solvent like Methvlenchloπd. Dimethvlformamid or Pvπdm preferably Methvlenchloπd or Pvπdin with the addition of an auxiliary base such as Tπethvlamin or 4-Dιmethvlamιnopyπdιn and preferably at a temperature between - 10 ° C and 50 ° C at room temperature

The reduction of a ketone of the general formula V to an alcohol of the formula XVIII is usually carried out in a solvent such as methanoi. Ethanol. Tetrahydrofuran or diethyl ether preferably methanol with a reducing agent such as Natπumborhvdπd, Lithiumborhvdπd, or Lithiumaluminiumhvdπd. preferably Natπumborhvdπd and at a temperature between - 10 ° C and -ι-30 ° C, preferably at room temperature

Alkaline salts are the main pharmacologically acceptable salts. Ammonium salts. Tπfluoracetate or Hvdrochloπde used, which is usually done, for example, by titration of the compounds with inorganic or organic bases or acids such as, for example, sodium or potassium bicarbonate. Caustic soda. Potash lye, water ammonia or nurse such as Tπmethvl- or Tπethvlamin. Tπfluoroacetic acid or hydrochloric acid produces The salts are usually cleaned by falling over from water / acetone

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 application are possible here, for example tablets, capsules. Dragees, syrups, solutions, suspensions, etc. Water is preferably used as the injection medium, which contains the additives, such as stabilizers, which are customary for injection solutions. Solution broker and buffer included

Such additives are eg tartrate and citrate buffers. Ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high-molecular polymers (such as liquid polyethylene oxide) for regulating the viscosity. Liquid carrier substances for injection solutions must be rigid and are preferably filled into ampoules. Solid carrier substances are, for example, strong, lactose. Manrut. Methyl cellulose. Talc, highly disperse silicas, high molecular weight fatty acids (such as stearic acid). Gelatin, agar. Calcium phosphate. Magnesium stearate and vegetable fats, solid high-molecular polymers (ie 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. Species. Depend on age and / or individual condition. The daily doses to be administered are about 10-1000 mg / person, preferably 100-500 mg / person and can be taken in one or more times distributed

For the purposes of the present invention, preference is given to the following pyridine or pyridazine derivatives, in addition to the compounds mentioned in the examples and by combining all the meanings of the substituents mentioned in the claims:

1 [4- (4-pyridin-4-yl-piperazin-1-ylmethyl) cyclohexyl] acetic acid

2! 4- [2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] cyclohexyl} acetic acid

3 {4- [3- (4-Pyridin-4-yl-piperazin-1-yl) propyl] cyclohexyl} acetic acid

4 {4- [4- (4-Pyridin-4-yl-piperazin-1-yl) butyl] cyclohexyl} acetic acid

5 {4- [6- (4-Pyridin-4-yl-piperazin-1-yl) hexyl] cyclohexyl} acetic acid

6 [4- (4-pyridin-4-yi-piperazin-1-carbonyl) cyclohexyl] acetic acid

7 {4- [2-Oxo-2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] cyclohexyl ^ acetic acid

8 {4- [3 -Oxo-3 - (4-pyridin-4-yl-piperazin-1-yl) propyl] cyclohexyl} acetic acid

9 {4- [4-Oxo-4- (4-pyridin-4-yl-piperazin-l-yl) butyl] cyclohexyl} acetic acid

10 14- [6-Oxo-6- (4-pyridin-4-yl-piperazin-1-yl) hexyl] cyclohexyl} acetic acid

1 1 {1 - [2-Oxo-2- (4-pyridin-4-yl-piperazin-1-yl) acetyl] piperidin-4-yl ^ -acetic acid

12. {l - [4-Oxo-4- (4-pyridin-4-yl-piperazin-l-yl) butyryl] piperidin-4-yl} acetic acid 1- [5-Oxo-5- (4-pyridin-4-yl-piperazin-l-yl) pentanoyl] piperidin-4-yl} -essιgsaure

1 - [6-Oxo-6- (4-pyridin-4-yl-piperazin-1-yl) hexanoyl] piperidin-4-yl acetic acid

1 - [8-Oxo-8- (4-pyπdin-4-yl-piperazin-1-yl) octanoyl] piperidin-4-yl} acetic acid

1- [3. (4-pyridin-4-yl-piperazin-l-yl) propionyl] piperidin-4-yl} acetic acid

l - [4- (4-Pvridin-4-yl-piperazin-l-yl) butyryl] -pipeπdin-4-yl} acetic acid

l - [5- (4-Pvridin-4-vl-piperazιn-l-vl) -pentanoyi] -piperidin-4-yl> -acetic acid

1. [2- (4-Pvridin-4-yl-piperazin-1-yl) acetyl] piperidin-4-yl} acetic acid

15

20 [4- (4-pyridin-4-yl-piperazin-1-carbonyl) -pιperidin-1 -yl] -acetic acid

21 {4- [2-Oxo-2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] piperidin-1-yl} acetic acid

-> n -> "> {4- [3-oxo-3- (4-pyridin-4-yl-piperazin-1-yl) -propyl] -piperidin-1-yl} -acetic acid

23 {4- [5-Oxo-5- (4-pyridin-4-yl-piperazin-1-yl) pentyl] piperidin-1-yl} acetic acid

24 {4- [7-Oxo-7- (4-pyridin-4-yl-piperazin-l-yl) -heptyl) -piperidin-l-yl} -essιgsaure

25 [1-Hydroxy-4- (4-pyridin-4-yl-piperazin-1-carbonyl) cyclohexyl] acetic acid

26 [1-Hydroxy-4- (4-pyridin-4-yl-piperazin-1-ylmethyl) cyclohexyl] acetic acid

30 {1-Hvdroxv-4- [2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] cyclohexyl} acetic acid

28 {1 -hydroxv-4- [3- (4-pyridin-4-yl-piperazin-1-yl) propyl] cyclohexyl} acetic acid - 2 -

29! l-Hvdroxv-4- [5- (4-pyπdin-4-yl-piperazin-l-yi) pentyl] cyciohexyl> acetic acid

30 | 1-Hydroxy-4- [6- (4-pyridin-4-yl-piperazin-1-yl) hexyl] cyclohexyl} acetic acid

1-Hvdroxv-4- [2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] cyclohexyl} acetic acid

1 -hydroxy -4- [3-oxo-3- (4-pyridin-4-yl-piperazin-l-yl) propyl] cyclohexyl} acetic acid

33 | l-Hydroxy-4- [4-oxo-4- (4-pyridin-4-yl-piperazin-l -yl) butyl] cyclohexyU-acetic acid

34 j 1 -hydroxv-4- [6-oxo-6- (4-pyridin-4-yl-piperazin-1-yl) hexyl] cyclohexyi} - acetic acid

35 {l-Hydroxy-4- [7-oxo-7- (4-pyridin-4-yl-piperazin-l-yl) heptyl] cyclohexyl} acetic acid

36 {4-Hydroxy-1 - [2-oxo-2- (4-pyridin-4-yl-piperzain-1-yl) acetyl] piperidin-4-yl} acetic acid

37 {4- Hydroxy-1 - [4-oxo-4- (4-pyτidin-4-yl-piperazin-1-yl) -butyryi] -piperidin-4-yl} - acetic acid

38 {l- [2,3-Dihydroxy-4-oxo-4- (4-pyridin-4-yl-piperazin-l-yl) butyryl] -4-hydroxy-piperidin-4-yl} acetic acid

39 {l- [2,3-Dihydroxy-4-oxo-4- (4-pyridin-4-yl-piperazin-1-yl) -butyryl] -piperidin-4-yl} - acetic acid

40 {4-Hydroxy-1 - [7-oxo-7- (4-pyridin-4-yl-piperazin-1-yl) -heptanoyl] -piperidin-4-yl (- acetic acid 41 Hvdroxv- [4- (4-pyπdin-4-yl-piperazin-1-ylmethyl) cyclohexyl] acetic acid

42 Phenvl- [4- (4-pyπdin-4-yl-piperazιn-l-ylmethyl) -cyclohexyl] -essιgsaure

43. \ Mιno- [4- (4-pyπdin-4-yl-piperazin-1 -ylmethyl) -cyciohexyl] -essιgsaure

44 (butane-1-sulfone-vlamino) - [4- (4-pyπdin-4-yl-pιperaz - 1 -ylmethyl) -cvclohexyl] - acetic acid

45 (butane-1-sulfone-vlamino) - [1 -hydroxy-4- (4-pyπdin-4-yl-piperazιn-1-vinylmethyl) cyclohexyl] -essioic acid

46 [1 -Methoxv-4- (4-pyridιn-4-yl-pιperazιn-l -ylmethyl) -cyclohexyl] -essιgsaure

47 (butane-1-sulfone-vlamino) - {l-hydroxy-4- [2- (4-pyπdin-4-yl-pιperazin-l-yl) -ethyl] - cyclohexyl]} acetic acid

48 (Butane-1-sulfone-vlamino) - {4- [2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] cyclohexyl} ■ acetic acid

49 2- [4- (4-pyridin-4-yl-piperazin-1-ylmethyl) cyclohexyl] propionic acid

50 (butane-1 sulfonvlamino -) -! l-hydroxy-4- [2-oxo-2- (4-pyridin-4-yI-pιperazιn-l-yl) - ethylj-cyclohexyU-acetic acid

51 (butane-1-sulfone-vlamino- {1 -hydroxy-4- [4-oxo-4- (4-pyridin-4-yl-pιperazιn-1 -yl) butyl] cyclohexyl} acetic acid

52 [4- (4-pyridazin-4-yl-piperazιn-1-ethylmethyl) cyclohexyl] acetic acid

53 [4- (4-Pyridazιn-4-yl-pιperazιn-1-carbonyl) -cyclohexyl] -essιgsaure

54 {l - [6- (4-Pvridazin-4-yl-piperazin-l -yl) -hexyl] -pipeπdin-4-yl} acetic acid 55; 4- [2-oxo-2- (4-pyridazin-4-yl-piperazm-1-yl) ethyl] cyclohexyl

56! 4- [3-Oxo-3- (4-pyridazin-4-yl-piperazιn-1-yl) propyl] cyclohexyl [acetic acid

{l - [2-Oxo-2- (4-pyπdazin-4-yl-piperazin-l-yl) -acetyl] -piperidin-4-yl} -essιgsaure

8th ! 1 - [4-Oxo-4- (4-pyπdazin-4-y l-piperazin-1 -yl) butyryl] piperidin-4-yl} acetic acid

59 {l- [6-Oxo-6- (4-pyridazin-4-yl-pιperazιn-l-yl) -hexanoyl] -piperidin-4-yl} acetic acid

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 determined by Η. and if necessary by l and secured by mass spectrometry. The purity of the substances was determined by means of C. H, N and by thin layer chromatography

example 1

.4-f2-Oxo-2- (4-pyridin-4-yl-piperazin-l-yl) ethyl ^' | -cyclohexl} acetic acid

l a) 76 g (4-hydroxy-cyclohexyl) - ethyl acetate. prepared from 4-hydroxyphenylacetic acid ethyl ester by catalytic hydrogenation (Raney-NL / H2 / 160 ° C / 200 bar / 72 h / ethanol) are dissolved in 130 ml of methylene chloride and with 20 6 g

Dess-Martin periodinan offset. The reaction solution is then stirred at room temperature for 30 h. The precipitate which has precipitated is then filmed, the methylene chloride solution is washed in succession with saturated sodium thiosulfate solution and water and dried over sodium sulfate. After removing the solvent, 16 5 g (4-oxocyclohexyl) are obtained. ethyl acetate as a colorless

Ol 1H-NMR (DMSO-d ⁶ ) δ = 4 05 ppm (q. 2H), 2 48-2 25 (m. 8 lines. 3H). 2 15 (m, 3H), 1 92 (m, 2H), 1 90 (sextet. 2H). 1.15 (t, 3H) b) The solution of 3 6 (4-oxo-cvclohexyl) -essιgsaureethvlester and 8 g (tert-Butoxvcarbonvimethylen) -tπphenylphosphoran (Aldπch GmbH u Co KG) in 100 ml of toluene is heated at reflux for 40 h. Then the toluene is removed in vacuo and the product is purified by column chromatography (ethyl acetate / isohexane = 1/10). The (4-ethoxvcarbonvlmethvl- cvclohexvlιden) -essιgsaure-tert-butvlester (2 7 g) thus obtained is dissolved in 40 ml of tetrahvdrofuran, with 300 mg lOprocess palladium / Charcoal added and hydrogenated at normal pressure and room temperature for 20 hours. The catalyst is then filtered off. the tetrahydrofuran was drawn off on a rotary evaporator and the residue (2 8 g) was taken up in 5 ml of methylene chloride

After addition of 5 ml of tetrafluoroacetic acid, the reaction solution is left to stir at room temperature for 2 h and then evaporated to dryness. 2 7 g (4-ethoxvcarbonvlmethvl-cvclohexvl) -essιgsaure FAB 228 are ^{obtained. Ϊ} H-NMR (CDCI3) δ = 7 70 ppm (broad see 1H), 4 15 (q, 2H), 2 20 (d, 2H), 2 17 (d, 2H). 1 75 (m 5H),

1 60 (. 1H), 1 40 (m. 1H). 1 25 (d.3H), 1 05 (m, 3H)

c) The solution of 690 mg (4-ethoxycarbonylmethyl-cyclohexyl) -essιgsaure. 490 mg l- (4-pyπdyl) -pιperazιn and 680 mg dicyclohexylcarbodiimide in 10 ml dimethylformamide is stirred for 48 hours at room temperature. The dimethylformamide is then stripped off on a rotary evaporator, the residue is taken up in 10 ml water and the water mixture extracted three times with 10 ml of methylene chloride After drying the combined organic phases over sodium sulfate and stripping off the solvent, the product is purified by means of preparative HPLC (RP-18, methanol / buffer [pH 6 8] = 7/3) 770 mg {4- [2-Oxo-2- (4-Pvπdιn-4-vl- pιperazιn-l-yl) -ethyl] -cyclohexyl} -essιgsaureethylester m / e = 373, 1H-NMR (DMSO-d ⁶ ) δ = 8 18 ppm (d, 2H), 6 82 (d, 2H), 4 05 (q, 2H), 3 60 (broad s 4H) 3 42 (broad s, 4H), 2 31 (dd. 2H), 2 15 (dd 2H), 1 55 (m, 5H), 1.45 (m, 1H), 1 40 (m, 1H). 1 15 (d.3H), 0 95 (broad d.3H)

d) The solution of 730 mg of the ethyl ester prepared in 1 c) in 6 ml of methanol and 2 ml of 1N sodium hydroxide solution is stirred for 3 hours at 50 ° C. The methanol is then stripped off in vacuo and the residue is taken up in 10 ml of water and the product was purified by ion chromatography (DOWEX 50 H form. Eluenr water ammonia). This gave 300 mg of the title compound as a white powder FAB 345, 1H-NMR (DMSO-d ⁶ ) δ 8.20 ppm (d. 2H), 3 60 (broad see 4H), 3.35 (broad see 4H). 2 30 (dd. 2H); 2 10 (dd. 2H). 1 90 (m. 1H), 1.65 (m. 4H). 1 55 (m. 1H), 1 40 (m. 1H). 0 95 (m, 3H)

Example 2

10 I 1 -Hydroxy-4-f 2-oxo-2- (4-pyπdin-4-yl-piperazιn-1 -yl) -ethyl] -cvclohexyl 1 -acetic acid

2 a) 1 5 3 g of the ketone prepared under 1 a) are dissolved in 200 ml of toluene and mixed with 6 ml of ethylene glycol and 30 mg of p-toluenesulfonic acid. The reaction solution is then heated at 140 ° C. for 4 h on a water separator, then cooled and

15 washed with 50 ml of saturated sodium bicarbonate solution. The aqueous phase is then extracted twice with 30 ml of methylene chloride each time, the combined organic phases are dried over sodium sulfate and the solvent is evaporated on a rotary evaporator. The remaining ketal (19 3 g) is taken up in 100 ml of tetrahydrofuran and the solution 100 ml of 1 N sodium hydroxide solution are added

20 now heats the reaction solution at 50 ° C. for 24 h, then pulls the tetrahydrofuran in

Vacuum off. acidifies the aqueous solution with 1 N hydrochloric acid and extracts it three times with 50 ml of methylene chloride. After drying the combined extracts over sodium sulfate and stripping off the solvent, 13 g of (1,4-dioxa-spιro- [4,5] dec-8-yl) acetic acid FAB are obtained. 200

-> ς

2 b) In analogy to 1 c), 13 g (1,4-dioxa-spiro [4,5] -dec-8-yl) acetic acid are obtained. 10.6 g of 1 - (4-pyridyl) piperazine and 15.6 g of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride 1 1.3 g of 2- (1,4-dioxa-spiro [4,5] dec-8-yl ) -l- (4-pyridin-4-yl-piperazιn-l-yl) -ethanone Η-NMR (CDC1 ₃ ) δ = 8 25 ppm (d. 2H), 6 58 (d. 2H). 3 38 (see 4H), 3 70 (t 2H), 3 58 (t, 2H); 3 30 (q, 4H), 2.25 (d, 2H), 1 85 (m. 1H). 1 70 (m, 4H). 1 52 (sextet. 2H), 1.25 (m. 2H) c) The solution of 15 g of the product prepared under 2 b) in 10 ml of tetrahydrofuran and 5 ml of 6 N hydrochloric acid is stirred for 30 min at room temperature. The tetrahydrofuran is then removed in vacuo and the hydrochloric acid solution is concentrated with ammonia brought to pH 9 and extracted three times with 5 ml each of methylene chloride. After drying the combined organic phases over sodium sulfate and removing the solvent, the residue is purified by column chromatography (eluent ethyl acetate / methanolic ammonia = 9/1). This gives 870 mg 4- [2-oxo-2- (4-pyridin-4-yl-piperazin-l-yl) ethyl] cyclohexanone * H NMR (CD1 ₃ ) ό = 8 35 ppm (d. 2H), 6 65 (d. 2H), 3 85 (broad t. 2H). 3 62 (broad t. 2H). 3 38 (broad q. 4 H). 2 40 (m. 7H). 2.25 (m, 2H), 1 45 (. 2H)

d) 1 5 ml of n-butyllithium (1 6 M in hexane) are added dropwise to a solution of 0 34 ml of diisopropylamine in 5 ml of tetrahydrofuran stirred under nitrogen at −15 ° C., the solution is stirred for a further 30 minutes at −15 ° C., it then cools to -78 ° C. and adds the solution of 0 27 ml of tert-butyl acetate in 2 ml of tetrahydrofuran drop by drop. The reaction mixture is then stirred for a further hour at -78 ° C. and then with a solution of 600 mg of the Cvclohexanone derivative prepared under 2 c) in 2 ml of tetrahydrofuran and 2 ml of l, 3-dimethyl-3,4,5,6-tetrahydro-2 (lH) pyrimidione (DMPU) added dropwise. The reaction mixture is then stirred for a further 30 min at -78 ° C., then warmed to room temperature within one hour and finally stirred for another three hours at room temperature. After the addition of 5 ml of saturated ammonium chloride solution, the reaction mixture is extracted three times with 5 ml each Methylenchioπd. dries the combined organic phases over sodium sulfate, removes the solvent on a rotary evaporator and cleans the crude product by means of preparative HPLC (Select B. 12 μ, MethanoL / buffer

(pH 7 5) = 65/35) The two isomers {l-hydroxy-4- [2-oxo-2- (4-pyridin-4-yl-piperazin-l-yl) ethyl] cyclohexyl are thus obtained } -Acetic acid tert-butyl ester (cis / trans isomer) FAB 417. cis isomer 340 mg, iH-NMR (CDCI3) δ = 8 25 ppm (d. 2H). 6 60 (i.e. 2H). 3 92

(broad see 1H, OH), 3 75 (m, 2H), 3 58 (m, 2H). 3 30 (m, 4H), 2 41 (see 2H). 2.25 (d. 2H), 1 88 (, 1H), 1 75 (broad t. 4H), 1 50 (t with fem splitting, 2 H). 1 40 (see 9H), 1 08 (broad q. 2H trans isomer 100 mg, ^ -N vIR (CDC1) δ = 8 25 ppm (d. 2H). 6 60 (d. 2H), 3 72 (m. 2H). 3 60 (m. 2H). 3 3 1 (m. 4H), 2 28 (see 2H). 2 21 (d. 2H), 1 80 (m. 1H), 1 70 (broad d. 2H), 1 55 (m. 2H). 1 40 (s, 9H). 1 34 (m.4H)

2 e) The solution of 300 mg of cis isomer in 1 ml of trifluoroacetic acid is stirred for 1 h at room temperature, then evaporated and dried under high vacuum. This gives 300 mg of cιs- {l -Hydroxv-4- [2-oxo-2 - (4-pyπdιn-4-yl-pιperazιn-l -vl) -ethyl] - cyclohexyU-acetic acid tπfluoroacetate as white powder nve 361

^Ϊ H-NMR-MSO-d ⁶ ) δ = 8 29 ppm (d. 2H), 7 20 (d. 2H). 3 65 (broad t. 8H), 2 40 (s, 2H), 2 31 (d, 2H). 1 88-1 60 (m, 5H). 1 35 (broad t. 2H), 1 10 (m, 2H),

¹⁹ F-NM (DMSO-d ⁶ ) δ = -73 30 ppm (s)

2 f) .Analogous to 2 e), 50 mg trans- { oxo-2- (4-pyπdιn-4-yl-pιperazιn- 1 -yl) -ethyl] -cyclohexyl} -acetic acid-trifluoroacetate m / e 361 'H-NMR (DMSO-d ⁶ ) δ = 8 25 ppm (d , 2H), 7 15 (d, 2H), 3 65 (m, 8H),

2 29 (see 2H), 2 22 (see 2H), 1 60 (see 3H), 1 40 (.6H) ¹⁹ F-NMR (DMSO-d ⁶ ) δ = - 73 30 ppm (s)

Example 3

! 1 -Hvdroxy-4-f2- (4-pyπdιn-4-yl-pιperazιn- 1 -vD-ethyl-cvclohexy!} -Acetic acid

3 a) The solution of 12 gl, 4-dioxaspιro [4,5] decan-4-one and 26 g (ethoxycarbonyl-methylene-phenylphosphorane in 100 ml of toluene is heated at 100 ° C. for 24 h. Then the toluene is removed in vacuo , the residue is mixed with 10 ml of a mixture of ethyl acetate / isohexane = 1/5, the precipitated triphenylphosphine oxide is filtered off, the filtrate is concentrated in vacuo and the product is purified by column chromatography. 1 1 4g (1.4-dioxa-spιro [4.5] -dec -8- vlιden) -essιgsaureethvlester as colorless oil me 226th b) The product (1 1 g) prepared under 3 a) is dissolved in 100 ml of tetrahydrofuran and the solution is mixed with 15 g of 10% palladium / carbon. Hydrogenation is now carried out at room temperature and normal pressure until the hydrogen uptake has ended. filtered off. evaporates to dryness and takes up the residue in 50 ml of tetrahydrofuran. The solution thus obtained becomes a mixture of 1 2 g of lithium aluminum hydride in 50 m

Tetrahydrofuran added dropwise so that the reaction temperature does not rise above 50 ° C. Then the reaction mixture is stirred for a further 2 hours at room temperature and then the excess lithium aluminum hydride is carefully decomposed with water. After the reaction mixture has been worked up in the usual way, 7 3 g of 2- (l, 4-Dioxa-spιro [4.5] dec-8-yl) ethanol as colorless oil m / e 186 ^Ϊ H-NTvflUCDC ^ CD3COOD) δ = 3 88 ppm (see 4H). 3 60 (t. 2H). (1 65 m. 4H). 1 55-1 48 (t superimposed with m. 5H). 1 20 (m. 2H)

c) l g of the alcohol prepared under 3 b) is dissolved in 20 ml of diethyl ether and mixed with 1 4 ml of tπethylamine. A solution of 0 47 ml is added dropwise to this solution

Methanesulfonic acid chloride in 5 ml of diethyl ether at room temperature. The reaction solution is then left to stir for a further 30 min, then washed successively with 10 ml of saturated sodium bicarbonate solution and 10 ml of water and the organic phase is dried over sodium sulfate. After the solvent has been stripped off, the residue is added 5 ml of dimethylformamide dissolved. 1 g of l- (4-pyridyl) piperazine and 0.8 g of potassium carbonate are added to this solution, the reaction mixture is heated for 3 hours at 50 ° C. and the dimethylformamide is then removed in vacuo ml of saturated ammonium chloride solution and extracted three times with 5 ml each of methylene chloride. After drying the combined extracts over sodium sulfate and removing the solvent, the crude product is subjected to column chromatography (prap HPLC, Select B, 12 μ, methanol / buffer (pH 75)) = 7 / 3) cleaned This gives 0 6 g of l- [2- (1,4-D.oxa-spιro [4,5] dec-8-yl) ethyl] -4-pyridin-4-yl-l-piperazine as light gray powder m e 331 l NMR (CDCl3) δ = 8 20 ppm (i.e. 2H). 6 58 (d, 2H), 3 90 (s, 4H), 3 28 (dd. 4H), 2 48 (t, 4H). 2 35 (t. 2H). 1 67 (broad d, 4H), 1 45 (q, 4H), 1 25 (m, 3H)

d) Analogously to 2 c), 1 1 g of the product produced under 3 c) gives 0 8 g - JJ -

4. [2- (4-pyridin-4-yl-piperazin-1-yl) ethyl] cyclohexanone. m / e. 287 Η NMR (CDCI3) δ 8 20 ppm (d, 2H); 6 59 (i.e. 2H). 3 28 (t, 4H); 2.50 (t, 4H), 2 40 (t, 2H), 2 30 (m. 4H); 2 0 (m. 2H); 1 75 (m. 1H); 1 51-1 26 (m.4H)

3 e) .Analogue to 2 d) is obtained from 580 mg of the product 3 d), 0 27 ml of tert-butyl acetate. 1 5 ml of n-butyllithium (1 6 M in hexane) and 0.34 ml of diisopropylamine, two stereoisomeric {1-hydroxy-4- [2- (4-pyridin-4-yl-piperazin-yl) ethyl] cyclohexyl} acetic acid -tert -butyl ester (cis / trans isomers). FAB 403 cis isomer 190 mg, Η-NMR (CDCI3) δ = 8 18 ppm (d. 2H), 6 60 (d, 2H), 3 30 (d. 4H), 2 75 (broad see 1 H. OH); 2 50 (t, 4H), 2 35 (dd. 2H). 2 25 (see 2H), 1 70 (d, 2H). 1 55- 1 35 (s overlaid with m. 9H + 4H). 1 22 (m. 5H) trans isomer 130 mg. ^Ϊ H-NMR (CDCI3) δ = 8 15 ppm (d. 2H), 6 59 (d. 2H). 3 30 (t. 4H). 2 50 (t. 4H). 2 40 (s. 2H), 2.35 (dd. 2H) 2.25 (broad see 1H. OH), 1 68 (m. 4H). 1 55-1 30 (s overlaid with m.9H + 6H). 1 0 (m, 1H)

3 0 .Analogous to 2 e), 170 mg of cis {l-hydroxy-4- [2- (4-pyridin-4-yl-piperazin-l-yl) ethyl] cyclohexyl is obtained from 170 mg cis isomer } acetic acid trifluoroacetate FAB 347. mp 130 ° C.

20 from 1 10 mg trans-isomer corresponding to 100 mg trans- {1 -hydroxy-4- [2- (4-pyridin-4-yl-piperazin-1-yl) ethyl-cyclohexyl} acetic acid trifluoroacetate FAB

347. mp 207 ° C

-> 5

Example 4

.4- [2- (4-Pyridin-4-yl-piperazin-1-yl.-Ethyl ^" j-cvclohexyH-acetic acid

30 4 a) From 9 8 g of product 3 b), analogously to process 2 c), 5 2 g of 4- (2-hydroxyethyl) cyclohexanone are obtained Η-NMR (DMSO-d ⁶ ) δ = 4 41 ppm (t 1H. OH), 3 48 (q, 2H), 2.36 (3 xd. 2H). 2 18 (d with fine splitting, 2H), 1 95 (German 2H), 1 85 (m, 1H), 1 40 q, 2H), 1 30 (m. 2H) b) The solution of 5.2 g of 4- (2-hydroxyethyl) cyclohexanone, 6 8 g of imidazole and 6 g of tert-buti-dimethylsilyl chloride in 50 ml of dimethylformamide is stirred for 2 hours at room temperature. The solution is then concentrated in vacuo, the residue is taken up in 10 ml of water and the aqueous solution is extracted three times with 10 ml of diethyl ether after drying the combined organic phases over

Sodium sulfate and removal of the solvent, the crude product is purified by column chromatography (silica gel. Ethyl acetate / isohexane = 1/8). 7 g of 4- [2- (tert-butyldimethylsilanyloxy) ethyl] cyclohexanone are obtained as colorless Ol ^ H NMR (CDCI3) δ = 3 65 ppm (t. 2H), 2.35 (m. 4H). 2 05 (m. 2H), 1 85 (m. 1H), 1 50 (q. 2H), 1 38 (m. 2H), 0 85 (s, 9H), 0 00 (s, 6H)

c) Analogously to 3 a), 7 g of product 4 b) and 9 give 2 g (ethoxycarbonyl-methylene-tπphenylphosphorane 8 1 g of {4- [2- (tert-butyl-dimethyl-silane-vinyloxy-ethyl] cyclohexylidene acetic acid -ethyl ester. ^ -NMR (CDCI3) δ = 5 52 ppm (see 1H), 4 10 (q, 2H). 3 70 (broad d. 1H), 3 60 (t. 2H), 2 30-2 05 (m. 2H). 1 85 (m. 3H),

1 60 (m. 1H), 1 40 (q, 2H), 1 20 (t, 3H), 1 06 (m. 2H). 0 85 (see 9H). 0 00 (s, 6H)

d) The product 4 c) (8 g) is dissolved in 70 ml of a tetrahydrofuran / methanol = 1/1 -

The mixture was dissolved and the solution was mixed with 0 9 g of 10% palladium / carbon. The mixture was then hydrogenated at normal pressure and room temperature for 4 h, and then the

The catalyst is evaporated, the filtrate is evaporated to dryness, the residue is taken up in 70 ml of a 1 M hydrofluoric acid / acetonitrile mixture and the reaction solution is stirred for 12 hours at room temperature. The solvent is then evaporated off in vacuo, the residue with 10 ml of saturated sodium Solution added and the aqueous solution thus obtained extracted three times with 10 ml of methylene chloride

After drying the combined organic phases over sodium sulfate and chromatographing the residue on silica gel (methylene chloride / methanol = 9/1), 2 4 g of ethyl 4- (2-hydroxyethyl) -cyclohexyl] -acetic acid are obtained as light yellow Ol ^Ϊ H- NMR (DMSO-d ⁶ ) δ = 4 35 ppm (broad see 1H. OH), 4 05 (q, 2H). 3 40 (broad see 2H), 2.15 (sextet. 2H), 1 90 (m. 1H), 1 78-1 25 (m. 8H). 1 16 (t. 3 H).

0 90 (m, 3H) e) Analogously to process 3 c), 2 4 g of product 4 d) give 93 ml of methanesulfonic acid chloride and 2.2 ml of triethylamine 2 4 g of mesylate. that in the reaction with 1 4 gl - (4-pyridyl) -pιperazιn in the presence of 1 2 g of potassium carbonate 420 mg of 4- [2- pyridin-4-yl-pιperazιn-1 -yl) -ethyl] -cyclohexyl [-acetic acid ethyl ester gives FAB 359. iH-NMR (CDC1 ₃ ) δ = 8 20 (d, 2H). 6 55 (i.e. 2H). 4 08 (q, 2H), 3 25 (t, 4H),

2 50 (t. 4H), 2 35 (m. 2H), 2 0 (d. 2H). 1 68 (m. 5H). 1 46 (, 2H), 1 35 (m, 2H), 1 19 (t. 3H). 1 13 (m. LH), 0 90 (d. 2H)

f) The solution of 170 mg of product 4 e) in 4 ml of tetrahydrofuran and 0 5 ml of water is mixed with 0 57 ml of 1N sodium hydroxide solution. The reaction mixture obtained in this way is heated at 50 ° C. for 4 hours and then the tetrahydrofuran is removed in vacuo The residue is then taken up in 5 ml of water and the product is purified by ion chromatography (Dowex 50 H form. Eluent conc. Ammonia). This gives 70 mg of the title compound as a light gray powder m / e = 331

Pharmacological test

Assay

Microtiter plates are coated overnight with 2 μg / ml isolated activated GpIIb / IIIa receptor. After removing the unbound receptor by washing several times, the surface of the plates is blocked with 1% casein and washed again. The test substance is added in the required concentrations, and the plates are incubated for 10 minutes under rubble. The natural ligand of the gpIIb / IIIa receptor , Fibrinogen is added. After an hour of incubation, the unbound fibrinogen is removed by washing several times, and the bound fibrinogen is determined by a peroxidase-conjugated, antifibrinogenic monoclonal antibody by measuring the optical density at 405 n in an ELISA device Inhibition of fibrinogen-GpIIb / IIIa interaction results in low optical density. An IC ₅ is calculated based on a concentration-response curve

literature

The GpIIb / IIIa finbrinogen Elisa is a modification of assays that is described in the following literature

Nachman, RL & Leung, LLK (1982) Complex formation of platelet membrane glycoproteins Iib and lila with fibrinogen J Clin Invest 69 263-269 Wright, PS et al (1993) An echistatin C-terminal peptide activated Gpllbllla binding to fibrinogen, fibronectin, vitronectin and collagen type 1 and type IV Biochem J 293 263-267

Pharmacological data

Example IC _f . «(ΜMol / 1)

2 cis isomer 0.30

3 trans isomer 0.006

3 cis isomer 0.30

4 0.10

Comparative tests

The compound cis-l-hydroxy-4- [4- (4-pyridyl) piperazin-1-yl] acetic acid, which is contained in patent WO 94/22835 as example No. 102, was prepared as a comparative substance above assay an IC 50 value of 2.50 μmol / | i

Claims

Compounds of formula I.

in the

R1 hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, an optionally substituted mono- or bicyclic aryl, an optionally substituted hetaryl, an optionally substituted arylalkyl or one of the groups

-OR ² , -NR R ⁴

means

W means nitrogen or -CR ⁵ .

X, Z independently of one another denote nitrogen or the group -CH, and in the event that W denotes a nitrogen atom. X must be the group -CH.

A represents a valence line or the carbonyl group,

B is a valence line or one, if necessary, by lower alkylene

OR group means mono- or polysubstituted C1-C alkylene chain D denotes a valence dash, and in the event that X is a nitrogen atom, can also be the carbonyl group, where A, B and D must not simultaneously denote the valence dash,

R ^{2 represents} hydrogen, lower alkyl or arylalkyl,

R ³ , R4 independently of one another are hydrogen or lower alkyl, or together with the nitrogen atom to which they are attached form a five- to six-membered heterocyclic ring,

R ^{5 represents} hydrogen or a group OR ² ,

and their optically active isomers, and their pharmacologically acceptable salts

Process for the preparation of compounds of formula I.

in the

Hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, an optionally substituted mono- or bicyclic aryl, an optionally substituted hetaryl. an optionally substituted arylalkyl or one of the groups

-OR ² . -NR ³ R ⁴

means W means nitrogen or -CR ⁵ .

X, Z independently of one another denote nitrogen or the group -CH, and in the event that W denotes a nitrogen atom, X must be the group -CH,

A represents a valence line or the carbonyl group,

B a valence line or one optionally by lower alkyl or a

OR group denotes mono- or polysubstituted C j -C6 alkylene chain,

D denotes a valence dash, and in the event that X is a nitrogen atom, can also be the carbonyl group, where A, B and D must not simultaneously denote the valence dash,

R ^{2 represents} hydrogen, lower alkyl or arylalkyl,

R ³ , R ^{4 are} independently hydrogen, or lower alkyl, or together with the nitrogen atom to which they are attached form a five- to six-membered heterocyclic ring.

R ^{5 represents} hydrogen or a group OR ² ,

and their optically active isomers, and their pharmacologically acceptable salts.

characterized in that a compound of formula II

in which R ¹ , A, B, D, W, X and Z have the meaning given above and R6 is a methyl, ethyl, tert. Butyl or benzyl radical, hydrolyzed and the compounds obtained converted into their optical isomers and, if desired, compounds of the formula I obtained converted into pharmacologically acceptable salts

Medicaments containing at least one compound of the general formula I according to claim 1 in addition to conventional carriers and auxiliaries

Use of compounds of formula I according to claim 1 for the manufacture of medicaments for the treatment of diseases which are attributable to thromboembolic events