NZ264883A

NZ264883A - 5-phenylpyrazolyl-3-oxy derivatives and pharmaceutical compositions

Info

Publication number: NZ264883A
Application number: NZ264883A
Authority: NZ
Inventors: Wolfgang Kehrbach; Michael Mlinaric; Dieter Ziegler; Reinhard Bruckner; Willi Bielenberg
Original assignee: Kali Chemie Pharma Gmbh
Priority date: 1993-12-08
Filing date: 1994-11-08
Publication date: 1995-12-21
Also published as: FI945750A; HU9403458D0; AU7769494A; CA2137446A1; JPH07196622A; EP0663395B1; SK150694A3; DE59409756D1; ATE201200T1; PL306155A1; CN1109051A; IL111539A0; KR950017965A; RU94045839A; DE4341749A1; EP0663395A1; JP3492433B2; NO944722L; FI945750A0; CZ303194A3

Abstract

Pyrazole derivs. of formula (I) and their acid-addn. salts are new: n = 1-5; A = a gp. of formula (a) or (b): R1 = H or lower alkyl; Q =(CH2)m opt. mono- or disubstd. by lower alkyl α to the O atom; or 2-hydroxypropylene; m = 2-8; p = 4-6; B = linear 1-3C alkylene opt. mono- or disubstd. by lower alkyl α to the O atom; R2 = H, halo,etc.;R3 = H, halo, lower alkyl, lower alkoxy, OH or lower alkanoyloxy; or adjacent R2+R3 = 1-2 alkylenedioxy; R4 = H or lower alkyl; R5 = H, lower alkyl or phenylalkyl; R6 = H, lower alkyl,etc.;R7 = H, lower alkyl,etc.;or adjacent R6+R7 = 1-2C alkylenedioxy; provided that none of R2, R3, R6 and R7 is alkanoyloxy if any of the others is OH and/or A contains OH.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £64883 a ) 264883 Patents Form 5 | Priority DalG(s): Complete Specification Filed: Class: i§)....fisdik%t:. I Publication Date: | P.O. Journal No: p.0 fl ; *^(4 N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION THERAPEUTICALLY USEFUL PYRAZOLE DERIVATIVES We, KALI-CHEMIE PHARMA GMBH, a body corporate organised under the laws of the Federal Republic of Germany, of Hans-Bockler-Allee 20, 30173 Hannover, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: *r \ \' -1 A- 264883 5 THERAPEUTICALLY USEFUL PYRAZOLE DERIVATIVES Description The present invention relates to novel phenyl-alkylaminoalkyl compounds which carry on the alkyl radical a 5-phenylpyrazolyl-3-oxy substituent, and to 10 their salts and also to pharmaceutical preparations containing these compounds and to processes and intermediates for the preparation of these compounds. European Patent Application No. 70 19 discloses 3-hydroxycarbonylmethoxy-5-phenylpyrazole compounds and 15 esters and amides thereof having properties of lowering blood lipids. European Patent Application No. 170 861 discloses 3- (aminoalkylaminocarbonylmethoxy) -5-phenylpyr-azole compounds having antiarrhythmic effects, in particular properties of raising the stimulus threshold for 2 0 the initiation of cardiac arrhythmias. The object of the present invention is to develop novel 5-phenylpyrazole compounds having valuable pharmacological properties. A further object of the invention is to develop novel active pharmaceutical substances 25 which can be employed to lower the heart rate. It has now been found that the novel 5-phenylpyrazole compounds according to the invention, carrying a phenylalkylaminoalkyloxy radical in the 3 position, possess valuable cardioactive pharmacological properties 3 0 and exhibit pronounced effects of lowering the heart rate together with a favourable activity profile. Because of their activity profile the substances according to the invention are suitable as active substances which are effective in lowering heart rate for the treatment of 3 5 ischaemic conditions. The invention therefore relates to novel compounds of the - 2 - general formula I 26A883 10 25 30 in which n denotes an integer from 1 to 5, A represents a group of the general formula a — N — Q ~ in w'aich R1 denotes hydrogen or a lower alkyl group and Q denotes a (CH2)m group in which m denotes 2 to 8 and which may optionally be sub-^ stituted in the ct position to the oxygen atom by 1 to 2 lower alkyl groups, or represents the 2-hydroxypropylene chain, or A represents a group of the general formula b 20 in which p denotes 4 to 6 and B represents a (CH2)r group in which r denotes 1 to 3 and which may optionally be substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups, R2 denotes hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl or nitro or, if A contains no OH group and R3, R6 and R7 are not hydroxyl, alternatively denotes lower alkanoyl-oxy, and R3 denotes hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or, if A contains no OH group and R2, R6 and R7 are not hydroxyl, alternatively denotes lower alkanoyloxy, or R2 and R3 are attached to two adjacent carbon atoms and together represent an alkylenedioxy group having 1 to 2 carbon atoms, R4 denotes hydrogen or lower alkyli ^T v R5 is disposed in the 1 or 2 position and dgitates hydrogen, lower alkyl or a fphenyl-lower "ag.kyl I v ** - 3 - 26 4 88 3 group, R6 denotes hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, trifluoromethyl or nitro or, if A contains no OH group and R2, R3 and R7 are not hydroxyl, alternatively denotes lower alkano-yloxy, and R7 denotes hydrogen, lower alkyl, lower alkoxy, hydroxyl or halogen or, if A contains no OH group and R2, R3 and R6 are not hydroxyl, alternatively denotes lower alkyanoloxy, or R6 and R7 are attached to two adjacent carbon atoms and together form an alkylenedioxy group having 1 to 2 carbon atoms, and their acid addition salts. Where in the compounds of the formula I the substituents R2, R3, R6 and R7 of the phenyl rings represent or contain lower alkyl groups, these groups may be straight or branched and may contain in particular 1 to 4, preferably 1 to 2, carbon atoms and represent in particular methyl, methoxy or acetoxy. Where the substituents represent halogen they are suitably, in particular, fluorine, chlorine or bromine, preferably fluorine or chlorine. Where the group A represents a group of the formula a) R1 preferably denotes lower alkyl, especially methyl, or hydrogen, and Q represents a preferably unsubstituted alkylene chain (CH2)m in which m denotes 2 to 8, preferably 2 to 6, in particular 2, 3 or 4. If A represents a group of the formula b) this group preferably contains a 6-membered ring, i.e. p is preferably 5 and B preferably represents an unsubstituted alkylene chain having 1 to 3 carbon atoms, in particular the me thy1ene group. The substituents R2 and R3 preferably represent lower alkoxy groups, especially methyoxy, hydroxyl or hydrogen. The substituents R6 and R7 preferably represent lower alkoxy, especially methoxy, hydroxyl or hydrogen, or alternatively R6, if desired, nitro. R4 preferably denotes hydrogen. If R4 represents m 26 4 R « ^ m 10 lower alkyl it is preferably methyl. A lower alkyl group or phenyl-lower alkyl group Rs is preferably disposed on that nitrogen atom of the pyrazole ring which is adjacent to the oxygen atom. R5 preferably represents hydrogen or alternatively a phenyl-lower alkyl group. If R5 represents lower alkyl, it preferably denotes methyl or ethyl. If Rs represents a phenyl-lower alkyl group, the alkylene chain thereof may contain 1 to 3 carbons, and the group preferably represents benzyl. In accordance with the invention the novel compounds of the formula I and their acid addition salts are obtained in that, in a manner known per se a) for the preparation of compounds of the general formula la 15 R2' (CH2)„- A - O la 20 m f in which R*, R5, A and n possess the above meaning and R2', R3', R6' and R7' possess the meaning given for Ra, R3, Rs and R7 with the exception of lower alkanoyloxy, compounds of the general formula II R4 U in which R4, R5, and R possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, are reacted with compounds of the general formula III R2' (ch2)„-a-x III in which R2', R3', n and A possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and X represents a leaving group which can be eliminated, and subsequently any hydroxyl -prote^iTn^o^^oiipa are eliminated again, or 10 15 20 - 5 264883 b) for tiie preparation of compounds of the general formula lb R3 R3 in which R10 and RAX each denotes lower alkyl, and the reaction product is reacted with compounds of the general formula IV »ll (CH2)n-A'-0H IV R3 in which R2', R3', n and A' possess the above meaning, but in which any free NH group in the radical A' is provided with an amino-protecting group and any free hydroxyl groups are provided with hydroxyl-protecting groups, and subsequently any amino- or hydroxyl-protecting groups are eliminated again, or lb in which R , R , R- , R , R , R and n possess the above meaning and A' possesses the meaning given for A with the exception of a radical containing an OH group, compounds of the formula II are reacted with triphenylphosphine in the presence of azodicarbox-ylic eBters of the general formula XVIII R,0OOC-N=N-COORn XVIII 25 c) for the preparation of compounds of the general formula Ic 30 , R , Q and n possess possesses the meaning of RJ in which R1, R2', R3', R4, the above meaning and Rs given for Rs, but in which, if the chain lem_ the radical Q is 3, R5' represents a fWyl- // « alkyl group or lower alkyl group which is arrangd^* on that nitrogen atom of the pyrazolejl ring which i6"' adjacent to the oxygen atom, compounds lc general formla V - 6 - (CH2)„-N-H 264883 ft 10 15 in which R , R2', R and n possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, are reacted with compounds of the general formula VI • r" Y-Q-O-f Vf d) in which R4, R5', Rs', R7' and Q possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and Y denotes a leaving group which can be eliminated by aminolysis, and subsequently any hydroxyl-protecting groups are eliminated again, or <1 20 25 for the preparation of compounds of the formula la, compounds of the general formula VII i (chj)n -y VII in which R2 ', R3', n and Y possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, are reacted with compounds of the general formula VIII /R4 h-a-0 VIII in which R4, R®, R® , R7 and A possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and subsequently any hydroxyl-protecting groups are eliminated again, or e) for the preparation of compound^, formula Xd i w i-z Faneral - SEP 10 15 20 25 30 RJ f) R2 « - .7 -r1 OH V. | / XV- (CHJ^N-CHj-CH-CHrO 26 A 883 in which R1, R2', R3', R4, Rs, R6', R7' and n possess the above meaning, compounds of the general formula IX IX in which R*, R6' and R7' possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, Z denotes hydrogen or the 2,3-epoxypropy1 radical and Rs'' denotes a phenyl-lower alkyl group or lower alkyl group which is arranged on that nitrogen atom of the pyrazole ring which is adjacent to the oxygen atom, or, i£ Z is hydrogen, possesses the meaning given for R5, are reacted with compounds of the general formula X / R2 R1 I (CH^-N-Z X R3 in which R1, R2' , R3' and n possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and Z' represents the 2,3-epoxypropy1 radical if Z denotes hydrogen, or Z' is hydrogen if Z denotes the 2,3-epoxypropyl radical, and subsequently any hydroxyl-protecting groups are eliminated again, or for the preparation of compounds formula Ie Rl of the general (cm.-N-ovtf-o in which R meaning, R2 ,2 j „S R , R , R , R and n possess the above and Rs possess the meaning given for r-4 and R" with the exception of nitro and lavrgi# alkanoyloxy, and Q' represents a (CHj) which m' denotes I __ substituted in the a position to the oxygen?,atom by group; Vic? /' r to 7 and which is optionally Id Ie %. st? f c V>i 8 2648 1 to 2 lower alkyl group a, compounds of tile general formula XI r1' I \S_ (CH,)„-N-C0-Q-'0 in which R2", R3', R4, Rs, Rs", R7', n and Q' possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and R1' denotes lower alkyl or an amino-protecting group, ar« reduced and subsequently any amino- and/or hydroi.yl-pro tec ting groups are eliminated again, or for the preparation of compounds of the general formula I f (CH2)n-A'-0 in which R4, possess the above meaning, R5 possesses the meaning given for does not denote benzyl if the radical A' contains an possess the 7 with the NH group, and R2'", R3", R6" and R7 meaning given for R2, R3, Rs and exception of hydroxyl, but where at least one of the denotes lower substituents R2'", R3", Rs" and R7 alkanoyloxy, in compounds of the general formula XXI R4 (CH2)n-£0 in which n and R4 possess the above meaning. ,2IV b6IV and R7'" possess the meaning given for and R7 with the exception of lower the alkanoyloxy, but in which at least one of substituents ,2 iv ,siv and R denotes hydroxyl, RSIV denotes lower alkyl or a pheny.l~lro«ei~ alkyl group and A' ' possesses the meanings-given for^ A' , but in which any NH group present in^the radical A'' is protected by a benzyl protective''group, the free hydroxyl groups R2IV, .«5> 6 4 8 8 - 9 - are acylated, and subsequently any benzyl protective group is eliminated again, and if desired, in resulting compounds of the formula I in which R2, R3, R6 and/or R7 denote methoxy a hydroxyl group 5 is liberated from these groups, and/or if desired the benzyl group is eliminated from resulting compounds of the formula I in which R5 denotes benzyl, and if desired free compounds of the formula X are converted to their acid addition salts or the acid addition salts are 10 converted to the free compounds of the formula X. The reaction of compounds of the formula IX with compounds of the formula XXI in accordance with process variant a) can take place in a manner known per se under conditions which ate usual for the formation of pyrazole 15 ether compounds by alkylation of pyrazolols. Suitable leaving groups X in the compounds of the formula III are preferably halogens such as chlorine, bromine or iodine or else organic sulphonic acid radicals, for example radicals of lower alkanesulphonic acids such as methane-20 sulphonic acid or of aromatic sulphonic acids such as benzenesulphonic acid or benzenesulphonic acids substituted by lower alkyl or halogen, for example toluenesul-phonic acids or bromosulphonic acids. In general approximately equivalent quantities of compounds of the formulae 25 II and III are employed. If R5 denotes a lower alkyl or phenyl-lower alkyl group an excess of compounds of the formula III may also be employed, but if R5 denotes hydrogen it is expedient to employ an excess of compounds of the formula II or to protect the free NH function of 30 the pyrazole ring by an amino-protecting group which can subsequently be eliminated again, in order to avoid secondary reactions. The reaction is expediently carried out under basic conditions in an organic solvent which is inert under the reaction conditions. Suitable inert 35 organic solvents are dimethylformamide, tetramethylurea, acetone or alternatively, depending on the nature of the base added as acid-binding agent, ethers, especially cyclic ethers such as tetrahydrofuran, lower alcohols, or 26 4 8 10 - aromatic hydrocarbons such as benzene or toluene, or mixtures of the abovementioned solvents. The reaction is expediently carried out in the presence of an at least equivalent quantity of an acid-binding base. Examples of 5 suitable bases are inorganic or organic alkali metal compounds. Examples of suitable bases are alkali metal carbonates or else alkali metal hydroxides, alkali metal hydrides such as sodium hydride or lower alkali metal alcoholates such as, for example, potassium tert-butylate 10 or sodium methylate or alkali metal amides such as, for example, lithium amide or lithium diisopropylamide. If desired, catalytic quantities of an iodide salt, for example an alkali metal iodide or ammonium iodide, such as potassium iodide or tert-butylammonium iodide, can be 15 added in order to accelerate the reaction. The reaction can be carried out at temperatures of between room temperature and the boiling temperature of the reaction mixture. The reaction is expediently carried out using, for example, an inorganic base such as potassium 20 carbonate or sodium hydride in an inert solvent such as dimethylformami de, preferably at temperatures of between 80 and 120°C. If desired the reaction can also be carried out in a two-phase system in the presence of a phase transfer catalyst, for example benzyltri-lower alkyl-25 ammonium chloride. Any hydroxyl group in the group A can be protected during the reaction by a hydroxyl-protecting group which can easily be eliminated again subsequently. The preparation of compounds of the formula I b in accordance with process variant b) can take place 30 under the conditions which are usual for Mitsunobu reactions. For example, the reaction can be carried out in an inert, anhydrous, aprotic organic solvent, in particular a cyclic ether such as tetrahyrofuran or dioxane and/or an aromatic hydrocarbon such as benzene or 35 toluene. The reactions of compounds of the formula V with compounds of the formula VI and of compounds of the formula VII with compounds of the formula VIII in accordance with the process variants c) and d) can be 26 4 8 - 11 - performed by methods which are usual for the alkylation of amines. Suitable radicals Y which can be eliminated by aminolysis in the compounds of the formulae VI and VII are halogens such as chlorine, bromine or iodine, prefer-5 ably bromine or chlorine, or alternatively an organic sulphonic acid radical, for example the radical of a lower alkanesulphonic acid such as, for example, methanesulphonic acid or of aromatic sulphonic acids such as benzenesulphonic acid or benzenesulphonic acids which 10 are substituted by lower alkyl or by halogen, for example toluenesulphonic acids or bromobenzenesulphonic acids. The reaction can be carried out under basic conditions in an organic solvent which is inert under the reaction conditions. The solvents, bases and reaction conditions 15 given above for the process variant a) can be employed. Any hydroxyl group in the chain Q or in the group A is expediently protected during the reaction, as given for the process variant a) , by a hydroxyl-protecting group which can easily be eliminated again. Expediently the 20 reaction is performed at temperatures of between room temperature and the boiling temperature of the reaction mixture and, depending on the reaction conditions, may require from 1/4 to 6 hours. The reaction is expediently carried out, for example, in an inert solvent such as 25 dime thy lformamide in the presence of an inorganic base such as potassium carbonate at temperatures of between 80 and 120 °C. The process variants c) and d) are particularly suitable for the preparation of those compounds of the formula I in which R5 denotes a phenyl-3 0 lower alkyl or lower alkyl group which is attached to the nitrogen atom adjacent to the oxygen atom. The reaction of compounds of the formula IX with compounds of the formula X in accordance with process variant c) can take place in a manner known per se by 35 methods which are usual for the reaction of alcohols or ami nee with epoxides. Thus compounds of the formula IX are reacted with compounds of the formula X under basic conditions in an organic solvent which is inert under the reaction conditions. The solvents and '16 4 8 - 12 - bases given for the process variants a) , c) and d) can be employed. The reaction temperature may lie within the range from 60 to 120°C. The duration of reaction, depending on the nature of the reaction conditions, may be between 4 and 12 hours. The reaction is expediently carried out, for example, in an inert solvent such as dimethylformamide in the presence of an inorganic base such as potassium carbonate at temperatures of around 100°C. The reduction of compounds of the formula XI in accordance with process variant f) can take place by methods which are conventional per se for the reduction of amides. Suitable reducing agents are complex metal hydrides capable of amide reduction, especially aluminium hydrides such as lithium aluminium hydride. The reaction takes place in a sufficiently anhydrous solvent which is inert under the reaction conditions. Examples of suitable solvents are cyclic ethers such as tetrahydrofuran or dioxane or open-chain ethers such as ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, if desired in a mixture with aromatic hydrocarbons such as benzene or toluene. The reaction can be carried out, depending on the nature of the reducing agent used, at elevated temperature, for example the boiling point of the reaction mixture. The reaction with lithium aluminium hydride at the boiling temperature of the reaction mixture, for example, proves to be favourable. The reaction time may be between 1 and 10 hours. The acylation of compounds of the formula XII in accordance with process variant g) may take place by methods which are conventional per se for the formation of phenol esters, by reaction of compounds of the formula XII with a reactive derivative of a corresponding lower carboxylic acid, for example a lower carboxylic acid halide or anhydride. If the group A'' in the compounds of the formula XII contains a benzyl-protected NH function, this benzyl protective group can subsequently be eliminated again by methods which are known per se for benzylamine cleavages. 264883 13 - In this context any benzyl group R5 is likewise eliminated at the same time. A reductive elimination, for example, is advantageous. This can be carried out using formic acid as reducing agent in the presence of a 5 palladium catalyst or by hydrogenolysis, using hydrogen as reducing agent in the presence of a palladium catalyst. If the radicals R2', R3', R6' and R7' represent free hydroxyl substituents, they must be protected in a 10 manner known per se, during the above-described reactions in accordance with process variants a) - f) and during the preparation of the starting materials, by protecting groups which can easily be eliminated again. Examples of protective groups which are suitable for hydroxyl groups 15 and can easily be -eliminated again after the reaction are known from E. McOmie "Protective Groups in Organic Chemistry" Plenum Press 1971. For example, a hydroxyl group can suitably be protected by esters, for example acetates, readily ellminable carbonates such as benzyl 20 carbonates and readily eliminable ethers such as tetra-hydropyranyl ethers or benzyl ethers. In each case protective groups must be chosen which are not attacked during the reactions carried out and which can subsequently be eldLminated under conditions under which 25 the products formed are not attacked. Preferably it is possible to use ether protective groups such as benzyl ethers. Hence in the reaction of starting compounds of the formula II with starting compounds of the formula III in which at least one of the radicals R2 ', R3', R6' and R7 3 0 represents a hydroxyl group which is protected by benzyl ether formation, the compounds initially obtained are of the general formula XXVIII y yK=J XXVIII R5 in which R4, R5, A and n possess the above meaning and the radicals R2V, R3IV, R6V and R7IV possess the meaning given for R2', R3', R6' and R7' or denote benzyloxy, but where at least one of the radicals R2V, R3IV, R6V and R7IV 26 4 3 - 14 - is benzyloxy. The compounds of the formula XXVIII are novel and represent valuable intermediates for the preparation of pharmacologically active compounds, for example compounds of the formula I, and also themselves 5 possess cardioactive pharmacological properties similar to the properties of the compounds of the formula I. If the radical R5 represents hydrogen and/or the radical A contains a free NH group, the free NH groups may if desired be protected in a manner known per se by 10 protective groups which can easily be eliminated again. This may be expedient, for example, during the reaction of the compounds of the formula V with the compounds of the formula VI, if the chain length m of the radical Q is 3. Suitable protective groups for NH groups, which can 15 easily be eliminated again after the reaction, are known for example from E. McOmie "Protective Groups in Organic Chemistry" Plenum Press 1971. For example, to protect an NH function in the pyrazole ring, the benzyl and the trityl group or the tetrahydropyranyl group are suitable. 20 In each case protective groups must be chosen which are not attacked during the reactions carried out and which can subsequently be eliminated under conditions under which the products formed are not attacked. Preferably the benzyl group can be used as protective group. * 25 In compounds of the formula I in which the substituents R2, R3, R6 and/or R7 denote methoxy, it is possible, if desired, subsequently to liberate the hydroxyl group from these groups. Methoxy groups can be cleaved to form hydroxyl groups in a manner known per se, 30 using methods suitcible for cleaving methoxyaryl ethers. For example, ether cleavage can take place by treatment with hydrogen iodide or hydrogen bromide in a solvent which is inert under the reaction conditions, for example acetic anhydride or acetic acid, or with iodotri-35 methylsilane or boron tribromide in a halogenated hydrocarbon such as dichlorome thane. Any lower alkanoyloxy groups are likewise cleaved under the conditions of the ether cleavage. From compounds of the formula I, in which R5 26 4$ - 15 - represents a benzyl group, it is possible subsequently to eliminate this benzyl group by methods which are known per se for benzylamine cleavages, in order to obtain corresponding compounds of the formula I in which R5 5 denotes hydrogen. The elimination of the benzyl group can take place by reductive or hydrogenolytic cleavage, for example under conditions given in process variant g) for the elimination of a benzyl protective group. The compounds of the formula I can be isolated 10 from the reaction mixture and purified in a manner known per se. Acid addition salts can be converted in a conventional manner to the free bases which if desired can be converted, in a known manner, into pharmacologically tolerable acid addition salts. 15 Examples of pharmacologically acceptable acid addition salts of the compounds of the formula I which are suitable are their salts with inorganic acids, for example hydrohalic acids, especially hydrochloric acid, sulphuric acid or phosphoric acids, or with organic 20 acids, for example lower aliphatic mono- or dicarboxylic acids such as maleic acid, fumaric acid, lactic acid, tartaric acid or acetic acid, or sulphonic acids, for example lower alkanesulphonic acids, such as methanesulphonic acid, or benzenesulphonic acids which are 25 optionally substituted in the benzene ring by halogen or by lower alkyl, such as p-toluenesulphonic acid, or cyclohexylaminesulphonic acid. If, in the compounds of the formula I, A represents the group b) or a group a) in which Q denotes 3 0 a hydroxypropylene chain, the compounds contain a centre of chirality and may be present in two optically active forms or as a racemate. The present invention comprises both the racemic mixtures and the optical isomers of these compounds of the formula I. The optically active 35 compounds can be obtained from the racemic mixtures by conventional separation methods in a manner known per se, for example by chromatographic separation on chiral separating materials or fractional crystallization of suitable salts with optically active acids. - 16 - 264883 Enantiomerically pure compounds can also be prepared by synthesis from corresponding enantiomerically pure starting compounds. For example, sterically pure isomers of the starting compounds of the formulae XXI, IV and 5 VIII can be converted into sterically pure compounds of the formula I by the above-described process variants a) , b) and d). The starting compounds of the formula II are known or can be prepared by methods known per se. It is 10 known that the compounds of the formula II exist in more than one tautomeric form and that, in addition to the enol form of the 5-phenylpyrazol-3-ols, represented by the formula II, the corresponding keto form of the 5-phenylpyrazol-3-ones also exists. In general, mixtures of 15 the different tautomeric forms are present whose composition may vary depending on the nature of the substituents . Both forms and their mixtures can be used for the preparation according to the invention of compounds of the formula I. By compounds of the formula II, therefore, 20 in the present application all of the tautomeric forms of these compounds are meant. Compounds of the formula II can be obtained by methods which are known per se for the preparation of 5-phenylpyrazolin-3-ones, for example by cyclizing conden-2 5 sation of optionally substituted hydrazines of the general formula XXX nh,-nhr5 xix 30 in which R possesses the above meaning, with benzoyl-acetic esters of the general formula XX r2 r4 co-ch-cooc2h5 R in which R2', R3' and R4 possess the above meaning, or with phenylpropionic esters of the general formula XXX oc-COOCjhj xx XXI -* 17 - 2641 in which R2' and R3' possess the above meaning. The reaction is carried out in an organic solvent which is inert under the reaction conditions. If R5 denotes lower alkyl or a phenyl-lower alkyl group, the reaction produces 5 mixtures of isomeric compounds in which R5 is in the 1 or 2 position. The ratio of 1- to 2-substituted compounds may vary depending on the nature of the starting substances and of the solvent used. Isomer mixtures of 1-and 2-substituted compounds may be separated in a manner 10 known per se by fractional crystallization or by chromatography . In compounds of the formula II in which Rs denotes hydrogen, it is possible if desired subsequently to introduce in a manner known per se a benzyl group R5, 15 by reacting the compounds with a benzyl halide, preferably benzyl bromide, in an organic solvent which is inert under the reaction conditions, for example an aromatic hydrocarbon such as toluene, in the presence of a base, for example pyridine or preferably collidine. In the 20 course of the benzylation, isomer mixtures of compounds benzylated in the 1 position and in the 2 position of the pyrazole ring may occur. These can be separated in a manner known per se, for example by fractional crystallization or by chromatography. 25 Compounds of the formula III are known or can be prepared by methods known per se or in analogy to methods known per se. For example, compounds of the general formula Ilia R1 R ' IUa ^ y- (ch2)n-n-q-x in which R1, R2', R3', n, Q and X possess the above meaning, can be obtained by reacting amines of the formula V with compounds of the general formula XXX y-q-t xxx in which Q possesses the above meaning, Y possess the above meaning and preferably denotes halogen, especially 264883 18 chlorine or bromine, and T represents a leaving group X or represents hydroxyl, and subsequently converting the group T, if desired, by a manner known per se into a different leaving group X. The reaction can take place by 5 methods which are conventional per se for amino -alkylation, for example under the conditions given above for the reaction of compounds of the formula V with compounds of the formula VT - In order to avoid secondary reactions it is expedient to employ an excess of 10 compounds of the formula XXX. Where in the compounds of the formula XXX the radical T represents a leaving group X, it is advantageous if the two leaving groups present in the compound of the formula XXX are of different reactivity, in order to avoid simultaneous reaction of 15 both leaving groups with compounds of the formula V. Where the amines of the formula V have been reacted with haloalcohols of the formula XXX, in the reaction product the hydroxyl group can subsequently be exchanged in a manner known per se for a radical X. Hence the hydroxyl 2 0 compounds can be reacted, for example, with thionyl choride in order to introduce a halogen radical X or with phosphorus halides in a manner known per se. Sulphonic acid radicals X can be introduced in a manner known per se by acylating the hydroxyl compounds with a corres-2 5 ponding sulphonyl halide. Compounds of the general formula Illb can be obtained, for example, by reacting compounds of the general formula VII with compounds of the general formula XXII in which p and B possess the above meaning, and by / Illb m which R , R , n, p, B and X possess the above meaning XXII exchanging, in the resulting 20 264883 - 19 - formula XXIII b-oh xxi" in which R2', R3', n, p and B possess the above meaning, the hydroxyl group for a radical X in a manner known per se. The reaction of the compounds of the formula VII with the amines of the formula XXII can take place by methods which are conventional per se for aminoalkylation, for example under the conditions given for the process variants c) and d). Compounds of the formula IV can be obtained by reacting compounds of the formula VII with aminoalcohols of the general formula XXIV h-a'-oh xxiv in which A' possesses the above meaning under conditions which are usual for aminoalkylation. Compounds of the formula V are known or can be prepared by methods known per se or in analogy to methods known per se. For example, compounds of the formula V can be obtained starting from corresponding acids of the general formula XIV (// ch2(n.i)-c00h xu xiv r2 r5' in which R2', R3' and n possess the above meaning. For instance, reactive acid derivatives of the acids of the formula XIV can be reacted with amines of the general formula XIII r'-nh2 xiii in which R1 possesses the aibove meaning to give corresponding amides which can subsequently be reduced to give compounds of the formula V. The reduction can take place, for example, under the conditions given for the reduction of the compounds of the formula XI in ac^oc^ance with 20 26A 883 process variant f) . Acids of the formula XXV are known or can be obtained in a manner known per se. Compounds of the formula VI can be obtained in a 5 manner known per se by reacting corresponding compounds of the formula II with compounds of the general formula XXIX x-q-t' xxix in which X and Q possess the above meaning and T' repre-10 sents a group Y which can be eliminated by aminolysis or represents hydroxyl, and then converting the group T' if desired into a group Y which can be eliminated by aminolysis. The reaction can take place under the conditions given for the reaction of compounds of the formula II 15 with compounds of the formula III in accordance with process variant a) . In order to avoid secondary reactions it is expedient to employ an excess of compounds of the formula XXIX. Where in the compounds of the formula XXIX the radical T' represents a leaving group Y, it is 20 advantageous if the two leaving groups present in the compound of the formula XXIX are of different reactivity. Where compounds of the formula XXIX are employed in which T' denotes hydroxyl, the hydroxyl group in the resulting compounds can subsequently be converted in a manner known 25 per se into a group Y. This can take place., for example, in the manner described above for the preparation of the compounds of the formula III. Compounds of the formula VIII can be obtained by reacting compounds of the formula II with compounds of 3 0 the general formula XXV d-a-x xxv in which A and X possess the above meaning and D is a protective group which can be eliminated by solvolysis or hydrogenolysis, and eliminating again the protective 3 5 group from the resulting reaction products of the general I T. 21 - formula (XXVI) 264883 d.a.O —i 1 XXVI in. which R4, Rs, R6', R7', A and D possess the above meaning. The reaction of compounds of the formula II with the compounds of the formula XXV can take place in a manner known per se, for example under the conditions given for the reaction of the compounds of the formula II with compounds of the formula III in accordance with process variant a) . Suitable examples of protective group D are radicals which can be eliminated by hydrogenolysis, 15 such as benzyl, which can be eliminated by catalytic hydrogenation in the presence of a palladium catalyst. Compounds of the formula XXV are known or can be obtained in a manner known per se, for example in analogy to the preparation of the compounds of the formula III. Thus compounds of the general formula XXVa R' XX Va D-N-Q-X ■in which R1, Q, D and X possess the above meaning can be obtained by introducing an amino-protecting group D into amines of the formula XIII and then reacting the protected amines with compounds of the formula XII, and compounds of the general formula XXVb 25 XXVb D-N * B"X in which D, p, B and X possess the above meaning can be 3 0 obtained by introducing an amino-protecting group D into amino alcohols of the formula XXII and then converting the hydroxyl group into a radical X. Compounds of the formula IX in which Z denotes hydrogen correspond to the compounds of the formula II. Compounds of the formula IX in which Z denotes the 2,3-epoxypropyl radical can be obtained in a manner known per se by reacting corresponding compounds of the f'ormulst?II<> with epichlorohydrin. The reaction cam take/place under'. 264883 22 - the conditions given for the reaction of compounds of the formula II with compounds of the formula III. In this context it is expedient to employ an excess of epichlorohydrin. 5 Compounds of the formula X, in which Z' repre sents hydrogen, represent compounds of the formula V. Compounds of the formula X in which Z' represents the 2, 3 - epoxypropy 1 radical cam be obtained in a manner known per se from corresponding compounds of the formula V by 10 reaction with epichlorohydrin. The reaction can take place, for example, under the reaction conditions described for the reaction of compounds of the formula V with compounds of the formula VI. It is expedient to employ an excess of epichlorohydrin. 15 The starting compounds of the formula XI are novel compounds which represent valuable intermediates for the preparation of pharmacologically active compounds, for example the compounds of the formula Ie. Compounds of the formula XI can be obtained by 20 methods which are conventional per se for forming amides, by reacting amines of the formula V with acids of the .general formula XV HOOC-Q-O N 25 R above meaning, or reactive acid derivatives thereof, under conditions which are usual for aminoacylation. Hence the amines of the formula V can be reacted with reactive derivatives of the acids of the formula XV, expediently in a solvent which is inert under the reaction conditions, and in the presence of an acid-binding reagent. Suitable reactive derivatives of the acids of 35 the formula XV are, in particular, acid halides, optionally mixed acid anhydrides and esters. Suitable solvents are halogenated hydrocarbons such as dichloro-methane, chloroform, dichloroe thane, or carbon tetrachloride, aromatic hydrocarbons such as benzene^toljoene or T O y. chlorobenzene, cyclic ethers such as tetrahy^drof uran ox-^ // ^ < il «" XV \S8& 264883 r- - 23 - dioxane, dimethylformamide or mixtures of these solvents. Suitable acid-binding reagents are organic or inorganic bases. Examples of suitable organic bases are tertiary organic amines, especially tertiary lower alkyl amines 5 such as triethylamine, tripropylamines or N-lower alkyl-piperidines. Suitable inorganic bases are, in particular, alkali metal carbonates or alkali metal bicarbonates. If the acylating agent employed is the acid itself or else an ester, the reaction of the compounds of the formula V 10 with the acids of the formula XV can expediently be carried out in the presence of a dehydrating reagent, for example a coupling reagent which is known from peptide chemistry to be suitable for forming amides. Examples which may be mentioned of such reagents, which also 15 promote the acylation by reacting with the acid in situ to form a reactive acid derivative, are in particular alkyl-, preferably cycloalkylcarbodiimides such as dicyclohexylcarbodiimide, carbonylimidazole or N-lower alkyl-2-halopyridinium salts, in particular halides or 20 tosylatea, preferably N-m.ethyl-2-chloropyridinium iodide (= Mukaiyama's reagent). The reaction in the presence of such a coupling reagent can expediently be carried out at temperatures of from -30°C to +50°C under neutral reaction conditions in solvents such as halogenated 25 hydrocarbons and/or aromatic hydrocarbons. If the starting compounds employed are derivatives of acids of the formula XV in which R5 is hydrogen, then under the abovementioned reaction conditions for the amidation these can initially be converted in part, 3 0 especially if Q' represents a methylene group, into corresponding cyclic compounds of the general formula XVa in which R*, R6 ' , R7' and Q' possess the above meaning, which compounds then react further with the amines of the formula V. The acids of the formula XV can be obtained by 10 20 25 ■i. -il - 24 - 264882 of the formula XI with halocarboxylic esters or halo-carbonitriles of the general formulae XVTa and XVIb Hal-Q-COOR12 XVla Hal-Q-CN XVIb in which Q' possesses the above meaning/ Hal represents halogen, especially chlorine or bromine, and R12 denotes lower alkyl, and then hydrolyBing the resulting esters or nitriles to the acids of the formula XV. The reaction of compounds of the formula II with the compounds of the formulae XVla or XVIb can be carried out under basic conditions by methods which are known per se for the alkylation on the oxygen atom in the 3 position of 5-phenylpyrazolin-3-ones, for example under the conditions indicated for the process variant a). The reaction ^2 is expediently carried out in dimethylformamide in the presence of potassuim carbonate. The subsequent hydrolysis to give the acids of the formula XV takes place preferably under alkaline conditions. The acids of the formula XV can be converted into their reactive acid derivatives by a method known per se. In this context they can in some cases be condensed to give corresponding cyclic compounds of the formula XVa. Since cyclic compounds of the formula XVa can be reacted further with the amines of the formula V, in the same way as the reactive derivatives of the acids of the formula XV, the separation of any mixtures of derivatives of the acids of the formula XV and compounds of the formula XVa is unnecessary . Compounds of the formula XI can also be obtained by reacting compounds of the general formula XXVII 30 R v (ch2)n-n-c0-cf-x xxvii 35 r2 r3 in which R1, R2" , R3', n, Q' and X possess the above meaning with corresponding compounds of the formula II. The reaction can take place in a manner known per se, for example under the conditions indicated in gEoCfs'ssojariant sf % H T O a) for the reaction of compounds of the^|'ormula EI\with I - 25 - 264883 compounds of the formula III. Compounds of the formula XXVII can be obtained by reacting amines of the general formula Va R1 (ch2)„-n-h va R2 r3' in which R1', R2' , R3' and n possess the above meaning with reactive derivatives of the acids of the general formula XVII X-Q'-COOH XVII in which Q' and x possess the above meaning, by methods which are usual for aminoacylation. The reaction can take place, for example, under the conditions given for the reaction of amine compounds of the formula V with 15 reactive derivatives of the acids of the formula XV. As reactive derivatives of the acids of the formula XVII it is preferred to employ their halides. Compounds of the formula XII represent, with the exception of those compounds in which A'' contains an NH 20 group protected by a benzyl group, corresponding compounds of the formula I. The remaining compounds of the general formula Xlla Xlla 30 in which R2IV, R3'", R4, RSIV, RSIV. R7'" and n possess the above meaning, R12 denotes benzyl and Q' ' represents a (CHjij, group in which m denotes 2 to 8 and which may optionally be substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups can be obtained by reacting corresponding compounds of the general formula IIIc Riz (ch2)n-n-q*-x / o ( in which R3'". *12. 0" X P°"°|*the ^685 2 6 4 8 8 - 26 - meaning under the conditions given above for the process variant a) . Compounds of the formula IIIc can be obtained by the methods described for the preparation of compounds of the formula Xlla. For example, corresponding acids of 5 the formula XXV can be reacted with benzylamine to give benzylamides which can subsequently be reduced to give amines which can then be reacted with corresponding compounds of the formula XXX to give compounds of the formula XXXc. 10 The compounds of the formula X and their pharma cologically acceptable acid addition salts are notable for their advantageous pharmacological properties. Xn particular the compounds exhibit properties of acting on the cardiac circulation and are distinguished by pro-15 nounced effects of lowering the heart rate. Xn this context they possess an activity profile which is favourable for the treatment of ischaemic conditions such as, for example, in the case of coronary heart disease, since cytoprotective effects are also present in the group of 20 substances. The cardioactive properties of the compounds can be demonstrated in vitro and in vivo in standard pharmacological test methods. Description of the pharmacological investigation 25 methods: 1. Determination of the minimum toxic dose Maximum doses of 300 mg of test substance per kg are administered perorally to male mice weighing 20 to 25 g. The animals are carefully observed for 3 hours for 30 symptoms of toxicity. Xn addition, over a period of 72 hours following administration all symptoms and fatalities are recorded. Concomitant symptoms are likewise observed and recorded. If death or severely toxic symptoms are observed, increasingly smaller doses are admini-35 stered to further mice until no further toxic symptoms appear. The lowest dose which induces death or severely toxic symptoms is reported in Table A below as the 26 4 8®$ - 27 - minimum toxic dose. The example numbers given in Table A relate to the Preparation Examples below. Table A 5 10 15 2. In vitro demonstration of the heart rate-lowering effect. 20 The direct influence of the active substances on the heart rate (FRQ) was tested on spontaneously beating, isolated right atria of male Pirbright-white guinea-pigs of weight class 250-300 g. In Table B below FRQ 75 denotes that concentration, in ^unol/1, at which 20 25 minutes after the adminstration of the substance there is a reduction in the rate to 75 % of the initial value. The example numbers given for the test substances in Table B relate to the Preparation Examples below. Test substance Example No. Minimum toxic dose mg/kg mouse p.o. 1 >300 7 >300 8 >300 9 >300 15 >300 17 >300 18 >300 21 >300 26 >300 44 300 46 >300 47 >300 26 4 88 - 28 -Table B Test substance Example No. Heart rate-lowering effect Effective concentration in /xmol/1 to attain FRQ 75 % 1 1.6 3 1.7 6 6.1 7 2.6 8 2.5 9 5.7 12 3.5 13 0.9 15 4.3 17 4.0 18 1.3 21 3.4 26 5.6 27 1.9 32 9.1 44 1.6 46 7.0 47 6.4 51 3.0 52 3.5 53 4.9 25 3. In vitro demonstration of the cytoprotective effect The cytoprotective effect was tested on isolated left atria of male Pirbright-white guinea-pigs of weight class 250 to 300 g, which atria were maintained in a nutrient solution and electrically stimulated. By gassing 30 the nutrient solution with nitrogen for 60 minutes a temporary hypoxia was induced. As a result of the hypoxia, contraction of the atria took place. The measurement parameter used was the integral of the 26 4 88 contraction over the period of hypoxia. Xn Table C below the effective concentration is given in fm.ol/l at which the integral of the contraction was reduced to 50 % of the control value. 5 Table C Test substance Example No. Cytoprotective effect on atrial contraction induced by hypoxia. Effective concentration in fimol/1 21 3.0 26 2.8 44 0.27 In in vitro experiments on isolated heart muscle cells the compounds exhibited cytoprotective effects with regard to cytotoxic substances such as veratridine or a combination of oligomycin and deoxyglucose. 15 Because of their above-described effects the compounds of the formula X are suitable as cardioactive medicaments for larger mammals, especially humans, for the treatment of ischaemic conditions such as, for example, in coronary heart disease and its consequences 20 such as, for example, cardiac insufficiency. The doses to be employed may be different individually and may of course vary depending on the condition to be treated, on the substance used and on the administration form. For example, parenteral formulations generally contain less 25 active substances than oral preparations. In general, however, medicament forms having an active substance content of from 1 to 200 mg per single dose are suitable for administration to larger mammals, especially humans. As medicaments, the compounds of the formula X 30 may be present with usual pharmaceutical adjuvants in pharmaceutical formulations such as, for example, tablets, capsules, suppositories or solutions. These pharmaceutical preparations may be prepared by methods - 30 - 26 4 88 known per se using usual solid or liquid excipients such as, for example, lactose, starch or talc or liquid paraffins and/or using conventional pharmaceutical adjuvants, for example tablet disintegrants, solubilizers 5 or preservatives. The examples which follow are intended to illustrate the invention in more detail without in any way restricting its scope. The structures of the novel compounds were 10 ascertained by spectroscopic analyses, in particular by analysis of the NMR, mass, IR and/or UV spectra. Tg-g-airrpl g> 1« 3-{3- [N- (2- (3,4-Dimethoxyphenyl) -ethyl) -N-methylamino] -propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole 32 ml of ethyl acetoacetate were added dropwise with ice cooling to 100 ml of 21 % strength sodium ethylate solution in ethanol (= solution I). After 20 minutes 75 ml of a solution of 50 g of 3,4-di-methoxybenzoyl chloride in 150 ml of tetrahydrofuran (= solution II) were added dropwise to the reaction solution. Subsequently further quanities of solutions I and II were added dropwise to the reaction mixture alternately, each at intervals of 20 minutes, until the reaction mixture contained a total of 190 ml of solution I and 176 ml of solution II. After 16 hours the precipitated salts were filtered off, washed with tetrahydrofuran and then suspended in water. The aqueous mixture was acidified to pH 1 with ice cooling and was extracted with methyl tert-butyl ether. The extract was evaporated to dryness, and 45 g of ethyl 2-acetyl-2-(3,4-dimethoxybenzoyl)-acetoacetate were obtained as a yellow oil.2 B) 45 g of the product obtained in A) were boiled at reflux in 197 ml of aqueous ethanol with the addi-35 tion of 0.72 g of sodium acetate. The reaction mixture was subsequently evaporated to dryness three 15 A) 20 25 26 4 88 - 31 - times with the addition of ethanol. The residue was dissolved in dichloromethane and dried with sodium sulphate. The solution was subsequently evaporated to dryness, and 33 g of ethyl 3,4-dimethoxybenzoyl-acetate were obtained as a yellow oil. C) 33 g of the product obtained above were" placed in 250 ml of ethanol, and 10 ml of hydrazine hydrate were added dropwise to the reaction mixture with ice cooling. The mixture was left to stand for 16 hours at room temperature and then the crystallized reaction product was filtered off, washed with isopro-panol and dried. 24 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one were obtained. D) 29 ml of l-bromo-3-chloropropane were dissolved in 300 ml of dimethylformamide, and 24 g of potassium carbonate were added to the solution. A solution of 18 g of 2-(3,4-dimethoxyphenyl)-ethyl-N-methylamine in 50 ml of dimethylformamide was added dropwise with stirring to the reaction mixture over the course of 2 hours. Subsequently the reaction mixture was stirred for a further hour. The salts formed were then filtered off. The filtrate was concentrated at a bath temperature of max. 50°C and the residue was dissolved in 200 ml of 0.5 H citric acid solution, and the solution was extracted with tert-butyl methyl ether in order to remove unreacted bromochloropropane. The aqueous phase was then rendered slightly alkaline by addition of sodium hydrogen carbonate and was extracted several times with ethyl acetate. The combined ethyl acetate extracts were subsequently dried with magnesium sulphate and concentrated. The residue obtained was 21 g of 3-[N- (2-(3,4-dimethoxyphenyl) -ethyl) -lime thy 1 amino]-propyl chloride. E) 17 g of 5-(3,4-dimethoxyphenyl) -pyrazolin-3-one were dissolved in 200 ml of dimethylformamide. 11 g of £6 4 8 8 3 - 32 - potassium carbonate were added to the solution and the reaction mixture was heated at 100°C under a nitrogen atmosphere for 0.5 hours. A solution of 21 gof 3- [N- (2- (3,4-di-methoxyphenyl) -ethyl) -N-methyl-amino] -propyl chloride in 150 ml of dimethylformamide was then added dropwise. After 2 hours the salts formed were filtered off, the filtrate was evaporated to dryness, and the residue was dissolved in ethyl acetate. The solution was subsequently washed with 7 % strength aqueous sodium hydroxide solution in order to remove unreacted 5-(3,4-dimethoxyphenyl) -pyrazolin-3-one, dried with sodium sulphate and evaporated to dryness. The residue which remained was 35 g of oily crude product. This product was purified by chromatography over finely particulate silica gel Tinder slightly elevated pressure (flash chromatography) using tert-butyl methyl ether/methanol 10:1 as eluent. 22.3 g of the title compound were obtained as an oil. IR spectrum of the base (as film) : 1513 cm"1, 1260 cm"1, 1236 cm"1. To form a salt, 2.6 g of the oily title compound obtained above were dissolved in isopropanol, 3.7 ml of a 2N solution of hydrochloric acid in isopropanol were added 25 to this solution, and the reaction mixture was evaporated to dryness under reduced pressure. The salt which remained as residue was recrystallized from isopropanol and dried at 80°C under a high vacuum. 2.1 g of 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyl-30 oxy}-5-(3,4-dimethoxyphenyl)-pyrazole hydrochloride were obtained, having a melting point of from 189 to 192°C. KyaTtirtle 2: 3-{3- [N- (2- (3,4-Dimethoxyphenyl) -ethyl) -N-methylamino] -propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole 10 15 35 1.31 g of triphenylphosphine were dissolved in 15 ml of tetrahydrofuran. 1.6 ml of a solution of 0.8 ml of ethyl 264 8 33 azodicarboxylate in 0.8 ml of toluene were added dropwise to the solution at a temperature of 5°C. After 5 minutes a solution of 1.1 g of 5-(3,4-dimethoxyphenyl) -pyrazolin-3-one in 10 ml of dimethylformamide was added dropwise. 5 After 20 minutes a solution of 1.26 g of 3- [N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propanol in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was subsequently stirred at 2 0°C for 48 hours. The reaction mixture was then evaporated to dryness. The 10 crude product obttained was purified by flash chromatography in accordance with -he method described in Example IE). 1.14 g of the title compound were obtained as an oily base. This base was converted to the hydrochloride, as described in Example 1 E) , having a 15 melting point of from 189 to 192°C. Example 3: 3-{[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-piperid-3-yl]-methoxy}-5-(3,4-dimethoxyphenyl)-pyrazole A) A mixture of 5.75 g of 3- (hydroxymethyl)-piperidine, 20 13.8 ml of triethylamine and 10 g of 2-(3,4-dimeth- 25 30 oxyphenyl)-ethyl chloride was heated under reflux for 4 hours. After it had cooled the reaction mixture was acidified with about 30 ml of aqueous 2N hydrochloric acid solution, and unreacted 2-(3,4-dimethoxyphenyl) - ethyl chloride was separated off by extraction with tert-butyl methyl ether. The aqueous phase was then rendered alkaline by addition of sodium hydroxide solution and was extracted by dichloromethane. The organic phase was separated off, dried and concentrated. 5.3 g of N-[2-(3,4-dimethoxyphenyl) -ethyl] -3- (hydroxymethyl) -piperidine were obtained. 35 B) 5.3 g of the product obtained above were dissolved in 70 ml of dichloromethane to which 0.1 ml of dimethylformamide had been added, and 5 ml of thionyl chloride were added to the solution. The 2 64 8<B3 - 34 - reaction mixture was stirred at room temperature for 12 hours, concentrated and evaporated to dryness twice with toluene. The residue which remained was dissolved in a mixture of saturated sodium carbonate solution and ethyl acetate. The organic phase was separated off, dried with sodium sulphate and evaporated. The residue obtained was 6.6 g of N- [2-(3 , 4 -dimethoxyjShenyl) -ethyl] -3 - (chloromethyl) -piperidine. C) 6.6 g of the product obtained above were reacted with 4.4 g of 5-(3,4-dimethoxyphenyl) -pyrazolin-3-one in accordance with the method described in Example 1 E). The crude title compound obtained was purified as described in Example IE). 4.1 g of the title compound were obtained as an oily base. To form a salt 4.1 g of the title compound were dissolved in ethanol, and 1.07 g of oxalic acid in ethanol were added to the solution. 3.4 g of 3-{[N-(2-(3,4-dimethoxyphenyl)-ethyl)-piperidin-3-yl]-methoxy}-.3,4-dimethoxyphenyl)-pyrazole monohydrogen oxalate were obtained, having a melting point of from 147 to 150°C. Example 4: 3-{3- [N- (2- (3-Methylphenyl) -ethyl) -N-methylamino] -propyl-oxy}-2-methyl- 5-(2-fluorophenyl)-pyrazole. A) 32 g of methylhydrazine were added dropwise with ice cooling to a solution of 100 g of ethyl 2-fluoroben-zoylacetate in 400 ml of ethanol. In order to complete the reaction the reaction mixture was left to stand at room temperature for 2 days. The crystalline precipitate of 2-methyl-5-(2-fluorophenyl)-pyrazolin-3-one was then filtered off. B) 5 g of the product obtained above were dissolved in 60 ml of dimethylformamide. 0.86 [lacuna] of sodium hydride (as an 80 % strength solution in paraffin) 26 4 8 - 35 - was added to the solution and the reaction mixture was stirred at 80°C for 1 hour. It was then cooled to room temperature, 4.1 g of l-broxno-3-chloropro-pane were added and the reaction mixture was stirred 5 at room temperature for 12 hours. The reaction mixture was subsequently concentrated, and the residue was taken up in water and extracted with diethyl ether. The ethereal solution was separated off and purified by flash chromatography over silica 10 gel. 4.8 g of 3-(3-chloropropyloxy) -2-methyl-5-(2- fluorophenyl)-pyrazole were obtained. C) 2.4 g of the product obtained above and 1.5 g of N-methyl-2-(3-methylphenyl)-ethylamine were dissolved in 75 ml of dimethylformamide. 2.5 g of finely 15 ground anhydrous potassium carbonate were added to the solution. The reaction mixture was stirred at a bath temperature of 100°C for 11 hours. The mixture was subsequently concentrated, the residue was taken up in water, and the reaction product was extracted 20 with ethyl acetate. The organic phase was separated off and extracted twice with aqueous 2M citric acid solution. Subsequently the aqueous solution of the product, containing citric acid, was rendered alkaline by addition of sodium carbonate and the reac-25 tion product was extracted with ethyl acetate. The ethyl acetate phase was dried with magnesium sulphate and concentrated. 1.0 g of the title compound was obtained as an oily base. IR spectrum of the base (as film) : 1555 cm"1, 30 1508 cm"1, 1464 cm"1. To form a salt 0.9 g of the title compound was dissolved in ethanol, a molar quantity of L-(+)-tartaric acid was added to the solution, and the mixture was concentrated. 1.25 g of 3-{3-[N-(2-(3-Methylphenyl)-ethyl)-N-methyl-35 amino]-propyloxy}-2-methyl-5-(2-fluorophenyl)-pyrazole x 1.1 hydrogen tartrate were obtained as an amorphous solid. 2 6 4 8 8 - 36 - gr-ampt.e 5 * 3 -{3-[N-(2-(4-Nitrophenyl)-ethyl)-N-methylamino]-propyl-oxy}-5-(2-fluorophenyl)-2-methyl-pyrazole A) 260 ml of l-bromo-3-chloropropane were dissolved in 5 400 ml of acetone. 230 g of potassium carbonate were added to the solution. A solution of 115 ml of N-methyl -N-benzylamine in 115 ml of acetone was added dropwise to the reaction mixture with stirring at a bath temperature of 40°C, the addition being j.0 distributed over a period of 30 minutes. The reaction mixture was subsequently stirred at a temperature of 40°C for 4 hours. The precipitated salts were then filtered off. The filtrate was concentrated under reduced pressure at a temperature 15 of 40°C. The residue was acidified to a pH of 1 using 16 % strength aqueous hydrochloric acid solution and was washed 3 times with tert-butyl methyl ether in order to remove unreacted l-bromo-3-chloropropane. The aqueous phase was subsequently 20 brought to a pH of 8 by addition of 16 % strength sodium hydroxide solution and was extracted repeatedly with ethyl acetate. The combined ethyl acetate phases were dried with magnesium sulphate and concentrated. 71 g of 3-(N-benzyl-N-methyl-25 amino)-propyl chloride were obtained. B) 3.3 g of 2-methyl-5-(2-fluorophenyl)-pyrazolin-3-one were dissolved in 50 ml of 1,3-dimethyl-3,4,5, 6-tetrahydro-2(1H)-pyrimidone. 0.55 g of sodium hydride (as an 80 % strength solution in paraffin) 30 was added to this solution and the reaction mixture was stirred at 80°C for 30 minutes. 3.3 g of 3-(N-benzyl-N-methylamino)-propyl chloride were added to the reaction mixture which was stirred at 80°C for a further 2 hours. After the reaction mixture had 35 cooled 10 ml of a 2N solution of hydrochloric acid in isopropanol were added to it and the mixture was then added dropwise to 2 litres of a 1:3 mixture of 16 4 8 - 37 - acetone and tert-butyl methyl ether. The precipitate formed was filtered off and dissolved in a mixture of saturated aqueous sodium carbonate solution and ethyl acetate. The organic phase was separated off 5 and the aqueous phase was subsequently extracted repeatedly with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulphate and evaporated. The crude base obtained was purified by chromatography on silica gel. 4.4 g of 3-[3-(N-10 benzyl-N-methylamino) -propyloxy] -2-methyl-5- (2- fluorophenyl)-pyrazole were obtained. C) 4.4 g of the product obtained above were dissolved in aqueous methanol. The solution was acidified with hydrochloric acid. Then a catalytic quantity of 15 palladium on charcoal was added and the reaction mixture was hydrogenated at room temperature with hydrogen at a pressure of 6 bar for 24 hours. Subsequently the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The 20 residue which remained was dissolved in a mixture of saturated aqueous sodium carbonate solution and ethyl acetate. The organic phase was separated off and the aqueous phase was subsequently extracted repeatedly with ethyl acetate. The combined ethyl 25 acetate phases were dried and evaporated. 3.2 g of 3-[3-(N-methylamino)-propyloxy]-2-methyl- 5 -(2-fluorophenyl)-pyrazole were obtained. D) 3.1 g of the product obtained above were dissolved in 30 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)- 30 pyrimidone. 3 g of potassium carbonate were added to the solution, and the reaction mixture was stirred at a temperature of 80°C for 30 minutes. Then 2.5 g of 2-(4-nitrophenyl)-ethyl bromide were added, the reaction mixture was stirred at 50°C for 5 hours, 35 then a further 0.25 g of 2-(4-nitrophenyl)-ethyl bromide was added and the mixture was stirred at 80°C for 13 hours more. Subsequently the reaction 38 26 4 88 mixture was worked up in the manner described in Example 5 B) . 2.6 g of the title compound were obtained as an oily base. IR spectrum (as film) : 1555 cm"1, 1515 cm"1, 5 1345 cm"1. The title compound was subsequently converted into its hydrogen tartrate as described in Example 4 C). 3.54 g of the monohydrogen tartrate of the title compound were obtained as an amorphous solid. 10 Example 6: 3 -{3 -[N-(3,4-Dimethylbenzyl)-N-methylamino]-2-hydroxy-propyloxy}-5- (2-fluorophenyl) -2-methylpyrazole . A) 78 g of thionyl chloride were added to 50 g of 3,4-dimethylbenzoic acid and the reaction mixture is 15 heated at reflux for 3 hours. The reaction mixture was subsequently concentrated and the residue was taken up twice in toluene and concentrated again. 53 g of 3,4-dimethylbenzoyl chloride were obtained. B) 108 ml of a 40 % strength aqueous solution of 20 methylamine were dissolved in 300 ml of tetrahydro furan. 53 g of 3,4-dimethylbenzoyl chloride were added dropwise to this solution with ice cooling. The reaction mixture was subsequently stirred at room temperature for 1 hour. Then the reaction 25 mixture was concentrated to half its volume under reduced pressure, saturated sodium chloride solution was added, and the mixture was acidified with concentrated hydrochloric acid. The product which then precipitated was filtered off with suction and dried 3 0 at 40 °C over potassium hydroxide in a drying cabinet. 47 g of N-methyl-3,4-dimethylbenzamide were obtained. C) 6.4 g of lithium aluminium hydride were placed in 200 ml of tetrahydrofuran and heated to boiling. 2648 Over the course of one hour a solution of 25 g of the amide prepared in B) in tetrahydrofuran was added dropwise and the reaction mixture was heated at reflux for a further 3 hours. The reaction mixture was subsequently decomposed with aqueous sodium hydroxide solution in order to remove excess lithium aluminium hydride and was diluted with" water and ethyl acetate. The precipitated salts were filtered off, and the organic phase was separated off, dried over magnesium sulphate and concentrated. 22.55 g of N-methyl-(3,4-dimethylbenzyl) -amine were obtained. 10 g of the product obtained above and 0.2 ml of water were added dropwise at a temperature of 28 to 30°C to 5.25 ml of epichlorohydrin. The reaction mixture was stirred at about 30°C for 5 hours. After the reaction mixture had cooled to room temperature, 60 % strength aqueous sodium hydroxide solution was added dropwise to it and it was stirred subsequently for a further 40 minutes. For working up, the reaction mixture was poured into 26 ml of water. The oil which separates out was separated off and dried with potassium hydroxide. The aqueous phase was extracted with ethyl acetate, the ethyl acetate extract was dried and concentrated, and the oil which remained as residue was combined with the major proportion of the product, which had separated out as an oil. A total of 11.3 g of 2-[N-(3,4-dimethylbenzyl)-N-methyl-aminomethyl]-oxirane were obtained. 500 mg of 5-(2-fluorophenyl)-2-methylpyrazol-3-one were stirred with 360 mg of anhydrous potassium carbonate in 10 ml of dimethylformamide at a temperature of 100°C for 15 minutes. After the reaction mixture had cooled to 60°C, 535 mg of the oxirane obtained in D) were added. The reaction mixture was subsequently stirred at 100°C for 8 hours. For working up, the reaction mixture was concentrated and the residue was taken up in water and extracted 26 4 883 - 40 - with ethyl acetate. The organic phase was separated off and concentrated. The crude product which remained as residue was purified by flash chromatography. 0.11 g of the title compound was obtained as 5 an oily base. IR spectrum (as film): 1556 cm"1, 1462 cm"1, 754 cm". To form a salt, 320 mg of the title base obtained above were dissolved in a 1:1 mixture of ethanol/ethyl acetate, and a molar quantity of fumaric acid was added 10 to the solution. The reaction mixture was concentrated to dryness and the salt obtained was dried at 50°C. 540 mg of 3-{3- [N- (3,4-dimethylbenzyl) -N-methylamino] -2-hydroxy-propyloxy}-5- (2-fluorophenyl) -2-methylpyrazole monohydrogen fumarate were obtained as an amorphous solid. 15 Example 7: 3 -{2- [N- (2- (3, 4-Dimethoxyphenyl) -ethyl) -N-methylamino] -1,1-dimethylethoxy}-5-(3,4-dimethoxyphenyl)-pyrazole A) 8.8 g of 5-(3,4-dimethoxyphenyl) -pyrazolin-3-one were dissolved in 50 ml of dimethylformamide, and 20 5.5 g of potassium carbonate were added. The reac tion mixture was heated under nitrogen at 100°C for 0.5 hours. Subsequently 8.9 g of ethyl 2-bromo-2-methylpropionate were added dropwise at 80°C. The mixture was stirred at 80°C for 1 hour and cooled 25 and the precipitated salts were filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in tert-butyl methyl ether. After filtration to remove insoluble fractions the product was washed with saturated sodium chloride solution 30 and concentrated. 10 g of 3- (2-ethoxycarbonylpropyl- 2-oxy)-5-(3,4-dimethoxyphenyl)-pyrazole were obtained as an oil. 35 B) 10 g of the product obtained above were dissolved in a mixture of 20 ml of 20 % strength sodium hydroxide solution and 40 ml of ethanol and the reaction 26 4 8 - 41 - mixture was heated under reflux for 2 hours. After the reaction mixture had been cooled it was acidifed to a pH of 1 using concentrated hydrochloric acid and extracted repeatedly with tert-butyl methyl ether. The combined extracts were dried with magnesium sulphate and concentrated. 9 g of 3-(2-hydroxycarbonylpropyl-2-oxy)- 5 -(3,4-dimethoxy-phenyl)-pyrazole were obtained. 5 g of the product obtained above were suspended in dichloromethane, 4.5 ml of triethylamine were added at room temperature, the mixture was cooled to -30°C, and 1.28 ml of me thane sulfonyl chloride were added. The reaction mixture was stirred at -30°C for 1 h, and then a spatula-tipful of pyrrolidinopyri-dine was added and the mixture was heated to room temperature. After 12 h it was diluted with dichloromethane. After removing the basic constituents by extraction with a solution of sodium chloride containing citric acid, the organic phase was washed free of acid with concentrated sodium carbonate solution, dried with sodium sulphate and concentrated. 3.7 g of 2,2-dimethyl-6-(3, 4-dimethoxy-phenyl )-pyrazolo(5,1)oxazole were obtained. Melting point 120 to 130°C. 3.5 g of the product obtained above and 4.2 g of N-methyl-2-(3,4-dimethoxyphenyl)-ethylamine were dissolved in diglyme and heated under nitrogen at 150°C for 2 h. After the mixture had been cooled it was diluted with methyl tert-butyl ether, washed free from base with sodium chloride solution containing citric acid and then washed free from acid with saturated sodium carbonate solution. The organic phase was dried with magnesium sulphate and concentrated by evaporation. 6 g of 3-{2-[N-(2-(3,4-dimethoxyphenyl) -ethyl) -N-methylaminocarbonyl] -propyl-2-oxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained. 25 4 88 - 42 - E) A solution of 6 g of the product obtained above in dry tetrahydrofuran was added dropwise to 2 0 ml of a boiling 1 molar solution of lithium aluminium hydride in tetrahydrofuran. The reaction mixture was 5 heated at reflux for 2 hours. In order to work it up, 0.57 ml of water, 0.75 ml of 15 % strength sodium hydroxide solution and a further 2.5 ml of water were added in succession with ice cooling. The precipitated aluminium hydroxide was filtered off 10 and the filtrate was concentrated. The residue was dissolved in aqueous 1M citric acid solution. The solution was washed with ethyl acetate. Subsequently the solution, which contained citric acid, was separated off and rendered alkaline by addition of 15 aqueous sodium carbonate solution and the reaction product was extracted with ethyl acetate. The ethyl acetate phase was dried and concentrated by evaporation. 4.1 g of crude product were obtained which was purified by chromatography on silica gel. 2.7 g 20 of the title compound were obtained as an oily base. IR spectrum (as film) : 1512 cm"1, 1464 cm"1, 1261 cm"1. Subsequently the title compound was, to form a salt, reacted with a molar quantity of L- (+) - tartaric acid 25 in accordance with the method described in Example 4 C). 3.56 g of 3-{2-[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-N-methylamino]-1,1-dimethylethoxy}-5 - (3,4-dimethoxyphenyl)-pyrazole x 1.2 hydrogen tartrate were obtained as an amorphous solid. 30 Example 8: 3-{6- [N- (2- (3,4-Dimethoxyphenyl) -ethyl) -N-methylamino] -hexyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole A) 10 ml of 6-bromohexanoyl chloride were dissolved in a mixture of 100 ml of absolute dichloromethane and 35 100 ml of absolute toluene. A solution of 13.6 g of N-methyl-N- [2- (3,4-dimethoxyphenyl) -ethyl] -amine and 26 4 8 8 3 9.5 ml of triethylamine in 25 ml of absolute toluene was added dropwise to the solution with ice cooling. The reaction mixture was subsequently stirred at room temperature for 12 hours. For working up, the precipitated salts are filtered off and washed with toluene. The filtrate was washed first with 1 molar citric acid solution and then with sodium bicarbonate solution, dried with magnesium sulphate and concentrated. 19.3 g of 5-{N-[2-(3,4-dimethoxyphenyl) -ethyl] -N-methylami nocarbonyl} -pentyl bromide were obtained as an oil. 3.85 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one were dissolved in 50 ml of anhydrous dimethylformamide. 3.15 g of finely ground potassium carbonate were added to the solution and the reaction mixture was heated under a nitrogen atmosphere to 100°C with stirring. A solution of 5.6 g of 5-{N- [2-(3,4-dimethoxyphenyl) -ethyl]-N-methylaminocarbonyl}-pentyl bromide in 10 ml of anhydrous dimethyl formamide was slowly added dropwise to the solution, and the reaction mixture was stirred at 100°C for a further 2 hours. For working up, the reaction mixture was cooled and then the precipitated salts were filtered off and the filtrate was concentrated by evaporation. The oily residue which remained was dissolved in ethyl acetate and washed with 7 % strength sodium hydroxide solution in order to remove unreacted 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one. The organic phase was separated off, dried with sodium sulphate and concentrated by evaporation. 6.5 g of 3-{5-[N-(2-(3,4-dimethyloxyphenyl)-ethyl)-N-methylaminocarbonyl] -pentyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained as an oil. 6.5 g of the product obtained above were reduced using lithium aluminium hydride in accordance with the method described in Example 7 B). Subsequently the reaction mixture was worked up in accordance 26488 ? - 44 - with the method described in Example 7 E). 2.5 g of the title compound were obtained as an oily base. IR spectrum (as film) : 1509 cm"1, 1465 cm"1, 1261 cm"1. 5 Subsequently the title compound was reacted, to form a salt, with a molar quantity of L-( + )-tartaric acid in accordance with the method described in Example 4 C) . 3.25 g of 3-{6-[N- (2-(3,4-dimethoxyphenyl)-10 ethyl)-N-methylamino]-hexyloxy}-5-(3, 4-dimethoxy phenyl)-pyrazole x 1,1-hydrogen tartrate were obtained as an amorphous solid. Example 9; 3-{2- [N-(2-(4-Chlorophenyl)-ethyl)-N-methylamino]-ethyl-15 oxy}-5-(4-hydroxyphenyl)-2-methylpyrazole 1.8 g of 3-{2-[N-(2-(4-Chlorophenyl)-ethyl)-N-methyl amino] - ethyl oxy} - 5 - (-4-methoxyphenyl) -2-methylpyrazole (see Example 24) were dissolved in 100 ml of dichloromethane. 10 ml of a 1 molar solution of boron 20 tribromide in dichloromethane were added to the solution. The reaction mixture was left to stand for 12 hours and then placed in water and extracted with dichloromethane. The aqueous phase was separated off, rendered alkaline and extracted three times with a mixture of dichloro-25 methane and methanol and the combined organic phases were dried and concentrated. The crude title compound obtained as an oil was purified by chromatography on silica gel using dichloromethane/methanol. The purified title compound was reacted, to form a salt, with a molar 30 quantity of L- ( + ) -tartaric acid in accordance with the method described in Example 4 C) and the resulting Bait was crystallized from a mixture of diethyl ether and isopropanol. 1.15 g of 3-{2-[N-(2-(4-chlorophenyl)-ethyl) -N-methylamino] -ethyloxy}-5- (4-hydroxyphenyl) -2-35 methylpyrazole x 1.3 hydrogen tartrate were obtained having a melting point of from 90 to 91°C. - 45 - 26 4 8 Example 10: 3-{2- [N- (2-(4-Chlorophenyl)-ethyl)-N-methylamino]-ethyl-oxy}-5-(4-acetoxyphenyl)-2-methylpyrazole 100 mg of 3-{2-[N-(2-(4-chlorophenyl)-ethyl)-N-5 me thy 1 amino ] - e thy loxy} - 5 - (4-hydroxyphenyl) -2-methylpyrazole (preparation see Example 9) were dissolved in 2 ml of dichloromethane. 0.15 ml of pyridine and 1 ml of acetic anhydride were added to the solution and the reaction mixture was stirred at room temperature for 10 24 hours. The reaction mixture was subsequently evaporated under reduced pressure, and the residue was taken up in aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated off, dried and concentrated. The crude title compound which 15 remained as residue was taken up in tert-butyl methyl ether. To form a salt, a 2N solution of hydrochloric acid in isopropanol was added. The precipitated salt was separated off. 80 mg of the hydrochloride of the title compound were obtained having a melting point of from 20 160 to 175°C. Example 11: 3-{3 -[N-(2 -(3,4-Dimethoxyphenyl)-ethyl)-amino]-propyl-oxy}-2-benzyl-5-(3,4-dimethoxyphenyl)-pyrazole A) 6.6 g of ethyl 3,4-dimethoxybenzoylacetate were 25 suspended in ethanol, and 3.5 g of benzylhydrazine were added dropwise with ice cooling over the course of 1.5 hours. The reaction mixture was stirred at room temperature for 12 hours. Then the precipitated product was filtered off and washed first with 3 0 ethanol and then with tert-butyl methyl ether. 4.36 g of 5-(3,4-dimethoxyphenyl)-2-benzyl-pyrazolin-3-one were obtained. Melting point: 164-166°C. 35 B) 5.5 g of the above product were dissolved in 50 ml of dimethylformamide. 0.5 g of sodium hydride was 26 4 8 - 46 - added to the solution and the mixture was stirred under a nitrogen atmosphere at 80°C for 0.5 h. Then 1.97 ml of l-bromo-3-chloropropane were added drop-wise at room temperature and the reaction mixture was stirred for 14 hours. The reaction mixture was then concentrated by evaporation under reduced pressure and taken up in tert-butyl methyl ether and the insoluble residue was filtered off. The filtrate was concentrated and purified by chromatography over finely particulate silica gel under slightly elevated pressure ( = flash chromatography). 7 g of 3- (3-chloropropyloxy) -5- (3,4-dimethoxyphenyl) -2-ben-zylpyrazole were obtained. C) 6 g of the product obtained above and 7 g of homo-15 veratrylamine were dissolved in 20 ml of dimethyl formamide, 10 ml of triethylamine were added, and the mixture was heated at 120°C for 4 hours. The reaction mixture was concentrated by evaporation, and the residue was taken up in ethyl acetate and 20 extracted with 2M citric acid. Subsequently the aqueous solution, containing citric acid, of the product was rendered alkaline by addition of sodium hydrogen carbonate and the reaction product was extracted with ethyl acetate. The extract was 25 purified by chromatography over finely particulate silica gel under slightly elevated pressure (= flash chromatography) . 4.9 g of 3-{3- [N- (2- (3 ,4-dimethoxy-phenyl)-ethyl) -amino]-propyloxy}-2-benzyl-5-(3,4-dimethoxyphenyl)-pyrazole were obtained. IR spectrum 30 of the base (as film) : 1524 cm"1, 1260 cm"1, 1236 cm"1. K-rg-mpI P 12: 3 -{3 -[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-amino]-propyl-oxy}-5-(3,4-dimethoxyphenyl)-pyrazole 35 4.9 gof 3-{3-[N-(2-(3,4-dimethoxyphenyl) -ethyl) - amino]-propyloxy}-2-benzyl-5-(3,4-dimethoxyphenyl)- 5 10 2 6 4 8 8 3 - 47 - pyrazole were dissolved in glacial acetic acid, 0.5 g of palladium on charcoal was added, and the reaction mixture was hydrogenated at 80 bar hydrogen pressure and at 80°C for 24 hours. After removal of the catalyst by filtration the reaction mixture was concentrated by evaporation and rendered alkaline (pH = 10) with sodium hydroxide solution and the product was extracted with ethyl acetate. The organic phase was separated off, concentrated and purified by flash chromatography over silica gel. 1.1 g of 3-{3-[N-(2-<3,4-dimethoxyphenyl)-ethyl)-amino]-propyloxy} -5- (3, 4-dimethoxyphenyl) -pyrazole were obtained. IR spectrum of the base (as film) : 1511 cm"1, 1465 cm"1, 1262 cm"1. To form a salt, 1.1 g of the title compound were dissolved in ethanol, a molar quantity of L-(+)-tartaric acid was added to the solution, and the mixture was concentrated. 1.46 g of 3-{3- [N-(2-(3,4-Dimethoxyphenyl)-ethyl) -amino] -propyloxy}-5- (3,4-dimethoxyphenyl) -pyrazole monohydrogen tartrate were obtained as an amorphous solid. gTrampI.e 13 Z 3-{3- [N- (2- (3,4-Dimethoxyphenyl) -ethyl) -N-methylamino] -propyloxy}-5-(3,4-dimethoxyphenyl)-2-benzyl-pyrazole A) 5 g of 5-(3,4-dimethoxyphenyl) -pyrazolin-3-one (preparation see Example 1C) were suspended in 100 ml of toluene. First 3 ml of collidine and subsequently 3.6 ml of benzyl bromide were added dropwise to the suspension. After heating for 6 hours under reflux the reaction mixture was cooled, and the precipitated crystals were filtered off and washed with isopropanol. The crystals obtained were dissolved in dichloromethane and washed with 2M citric acid. The organic phase was dried with magnesium sulphate and concentrated. For purification the residue was recrystallized from isopropanol. 4 g of 5-(3,4-dimethoxyphenyl)-2-benzyl-pyrazolin-3-one were obtained with a melting - 48 - 26 4 88 point of 165°C. B) 62 g of the product obtained above were dissolved in 500 ml of dimethylformamide. 31 g of potassium carbonate were added to the solution and the reac-5 tion mixture was heated under nitrogen at 100°C for 0.5 hours. Following the dropwise addition of a solution of 56 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl) -N-methylamino] -propyl chloride in 70 ml of dimethylformamide, the reaction mixture was heated 10 at 100°C for a further 4 hours. The precipitated salts were filtered off and the filtrate was concentrated to dryness. The residue was taken up in 350 ml of 0.75 N hydrochloric acid and extracted with ethyl acetate. The aqueous acidic phase was 15 rendered alkaline by addition of aqueous sodium hydroxide solution and was extracted with ethyl acetate. The crude product obtained after drying and concentration by evaporation of the organic phase was concentrated [sic] by flash chromatography. 68 g 20 of 3-{3-[N- (2-(3,4-Dimethoxyphenyl)-ethyl) -N-methyl amino] -propyloxy}-5-(3,4-dimethoxyphenyl)-2-benzyl-pyrazole were obtained. IR spectrum of the base (as film) : 1524 cm"1, 1260 cm"1, 1236 cm"1. 25 1.63 g of oxalic acid dihydrate dissolved in 20 ml of acetone were added dropwise to 7.1 g of the base, dissolved in 100 ml of acetone. The precipitated crystals were filtered off and dried. 7.7 g of the hydrogen oxalate of 3-{3- [N-(2-(3,4-Dimethoxy-30 phenyl)-ethyl) -N-methylamino] -propyloxy} - 5 - (3,4- dimethoxyphenyl)-2-benzyl-pyrazole were obtained with a melting point of 135 to 137°C. 26 4 8 8 3 - 49 - T^-ramp 1 c. 14 ; 3-{3- [N- (2- (3,4-Dimethoxyphenyl) -ethyl) -N-methylamino) -propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole A) 2 g of 3-{3-[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-N-5 methyl amino] -propyloxy}-5- (3,4-dimethoxyphenyl) - 2 - benzyl-pyrazole (preparation see Example 13) were dissolved in 10 ml of methanol and added to 2 g of palladium black under nitrogen. 5.5 ml of 98 % strength formic acid were added to the solution, 10 which was stirred under nitrogen. After the mixture had been stirred for 3 hours under nitrogen the catalyst was filtered off and the filtrate was concentrated by evaporation. The oily residue was taken up in saturated sodium carbonate solution and 15 extracted repeatedly with ethyl acetate. The com bined organic phases were dried with sodium sulphate and concentrated by evaporation. 1.6 g of 3-{3-[N-(2- (3,4-Dimethoxyphenyl) - ethyl) -N-methylamino] -propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were 20 obtained as an oily base. This base was converted analogously to Example 1 E) into the hydrochloride having a melting point of from 189 to 192°C. In accordance with the methods described in the above examples it is also possible to prepare the com-25 pounds of the formula I listed in the table which follows. The IR bands given in the table in cm"1 are the characteristic bands of the IR spectra of the respective free bases (as a film unless otherwise stated). EX. NO. R2 R3 R4 R5 R6 R7 n A Notas H.p. in °C; IR bands in cm'1 15 3-CH30 4-CH30 H 2-CH3 3-CH30 4-CH30 1 -NH-(CH2)3- 1,1 TA: am, B: oil IR:1513, 1262,1235 16 3-CI 4-CI H 2-CH3 3-CH3O 4-CH3O 1 -NH-(CH2)3- 1,1 TA: am, B: oil IR:1553,1523, 1257 17 3-CHaO H H 2-CH3 3-CI 4-CI 2 -NH-(CH2)3- 1.3 TA: am, B: oil IR:1564, 1550, 1498 18 3-CH30 4-CH30 H H 4-N02 H 2 -N(CH3)-(CH2)3- 0,5 FU: am, B: oil IR:1512,1342, 1261 19 3-CHa0 4-CH3O H H 3-CI 4-CI 2 -N(CH3)-(CHz)2- 1 FU: am, B: oil IR:1511,1462, 1142 20 4-CH3 H H 2-CH3 3-CH30 4-CH30 1 -NH-(CH2)3- 1 TA: am, B: oil IR:1553,1524, 1258 B a base; Oil = oily; am= amorphous solid; TA ■ hydrogen tartrate; FO s hydrogen fumarate; OX o oxygen oxalate; HC1 = hydrochloride; o> OO GO CM EX. No. R2 R3 R* R5 R6 R7 n A Notes 21 H H H 2-CH3 2-F H 2 -N(CH3)-(CH2)3- 0,9 TA: am, B: oil IR: 1553, 1463, 752 22 3-CHaO 4-CH3O H 2-CH3 3-CH3 4-CH3 1 *N(CH3)-(CH2)3- 1.1 TA: am, B: oil IR:1554, 1513, 1262 23 3-CI 4-CI H 2-CH3 CO 0 0 X r°- 1 -N(CH3)-(CH2)2- 1 TA: am, B: oil IR:1560, 1460, 1240 24 4-CI H H 2-CH3 4-CHgO H 2 -N(CH3)-(CH2)2- 1,1 TA: M.p. 94 25 H H H 1-CH3 2-F H 2 -N(CH3)-(CH2)3- 0,9 TA: am, B: oil IR:1508, 1458, 759 26 H H H 2-CH3 2-F H 5 -N(CH3)-(CH2)3- 10X: 142, B: on IR:1555, 1509, 1464 27 3-CH3O 4-CH30 H H 3-CH3O 4-CH3O 2 -N(CH3)-(CH2)4- 2.4 HCl: M.p. 158-ieo 28 3,4-0-CH2 -0- H 2-CH3 2-F H 1 -N(CH3)-(CH2)2- 1.1 TA: am, B: oil IR:1554, 1488, 1039 29 2-F H H 2-CH3 2-F H 2 -N(CH3)-(CH2)2- 10X: 152 - 153, B: oil IR:1555,1492,1463 30 4-NO-, H H 2-CH3 3-CH3O 4-CH3O 2 -N(CH3)-(CH2)2- 1FU: am, B: oil IR:1517, 1346. 1258 B = base; Oil = oily; am= amorphous solid; TA = hydrogen tartrate; FO = hydrogen fumarate; OX = oxygen oxalate; HCl =» hydrochloride; Ex. No. R2 R3 R4 Rs R8 . R7 n A Notes 31 3-CH30 4-CH3O CH3(CH2)2 H H H 2 -N(CH3)-(CH2)3. 1 OX: M.p. 169 32 3-CH30 4-CHjO H H 3-CHjO 4-CH30 2 -N(CH3)-(CH2)a- 0,9 OX: M.p. 92, Bi oil IR: 1513, 1260, 1028 33 4-N02 H H H 3-CH30 4-CH3O 2 "N(CH3)-(CH2)2- 1 OX: M.p. 140-141 34 3-CH3O 4-CH3O H H 4-CF3 H 2 *N(CH3)-(CH2)3- 1 FU: am, B: oil IR:1512, 1465, 1326 35 3-CH3O h h 2-CH3 4-CH3 H 2 -N(CH3)-(CH2)3- 1,1 TA: am, B: on IR:1584, 1554, 1529 36 3-CH3O H ch3 I-CH3 4-CI H 2 ■N(CH3)-(CH2)3- 1 TA: am, B: IR: 1508, 1466, 1260 37 3-CH3O 4-CH3O H 1-CH3 H H 2 -N(CH3)-(CH2)3- 1 FU: am, B: on IR: 1512, 1463, 1263 38 3-CH3O 4-CH3O h 2-CH3 h H 2 -N(CH3)-(CH2)3- 1,1 FU: am, B: oil IR:1554, 1513, 1263 39 3-CH3COO H h 2-CH3 4-CH3 H 2 *N(CH3)-(CHj)3- B: oil IR:1765,1554,1208 40 3-HO H h 2-CH3 4-CH3 H 2 -N(CH3)-(CH2)3- 2,1 HCl: M.p. 165-170 B = base; Oil = oily; am= amorphous solid; TA = hydrogen tartrate) FU = hydrogen fumarate; OX = oxygen oxalate; HCl = hydrochloride; Ex. Ko. R2 R3 R4 R5 R6 R7 n A Notos M.p. in "C; IR bandB in cm'1 41 4-CF3 H H H 4-N02 H 2 -N(CH3)-(CH2)3- 1 OX:M.p.89, B: oil IR: 1670, 1514, 1327 42 H H H H H H 2 -N(CH3)-(CH2)3- 1 OX: M.p.157 IR: 1507, 1465, 1374 43 H H H H 4-N02 H 2 -N(CH3)-(CH2)a- 0,9 OX:"-P-160 - 161 IR; 1604, 1517, 1343 44 3-CH30 4-CH3O H H H l. H 2 -N(CH3)-(CH2)3- 1 TA: am, B: Fp. 95 IR: 1513, 1463, 1265 45 4-CI H H H 4-F H 2 -N(CH3)-(CH,)3- 1 OX: M.p.103 46 3-CH30 4-CH3O ch3 H 4-CI H 2 -N(CH3)-(CH2)3- 1,2 TA: am, B: oil IR:1501,1463, 1262 47 3-CHJO 4-CH30 H H 3-CH3O 4-CH30 2 -N(CH3)-(CH2)2- 1,1 TA: am, B: oil IR:1512, 1260, 1027 48 H H H H 4-F H 2 -N(CH3)-(CHj,)3- 1 OX: M.p.149 49 H H H H 3-CH30 4-CH3O 2 -N(CH3)-(CH2)3- 1,2 FU: am, B: oil IR: 1518, 1464, 1262 50 4-CF3 H H H 4-F H 2 -N(CH3)-(CH?)3- 1 OX: M.p.90 51 3-CHgO 4-CH3O H H 3-CH3O 4-HO 2 -N(CH3)-(CH2)3- 1,1 TA: am IR:1517, 1466, 1265 52 3-CH30 4-CH30 H H 3-CH3O 4-CHaO 2 -NH-(CH2)3- 1 TA: am IR: 1511, 1465, 1262 53 3-CH30 4-HO H H 3-CH3O 4-CH30 2 -N(CH3)-(CH2)3- 1 TA: am IR: 1259, 1374, 1517, 1595 B « basei Oil = oily; am= amorphous solid; TA = hydrogen tartrate; FU = hydrogen fumarate; OX = oxygen oxalate; HCl = hydrochloride; - 54 - 26 4 88 Ex«nir»le I: Tablets containing 3-{3 - [N-(2 -(3,4-dimethoxy-phenyl) -ethyl)-N-methylamino]-propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole hydrochloride 5 Tablets were produced having the following compo sition per tablet: 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl) -N-methylamino]-propyloxy}-5-(3,4-dimethoxyphenyl) -pyrazole hydrochloride 2 0 mg 10 Corn starch 60 mg Lactose 13 5 mg Gelatine (as 10 % solution) 6 mg The active substance, the com starch and the lactose were thickened with the 10 % gelatine 15 solution. The paste was comminuted and the resulting granules were applied to a suitable metal sheet and dried at 45°C. The dried granules were passed through a comminution machine and mixed in a mixer with the following further adjuvants: 2 0 Talc 5 mg Magnesium stearate 5 mg Com starch 9 mg and then pressed to give tablets of 240 mg. The chemical formulae referred to hereinabove are set forth below for convenience. V ,{\ - 55 264883 (CH^- A - O -J R1 N ~Q — -N B- (CH2)n- A - O la / lb 264883 R2 R3 - 56 - R1 (CHJ)o-N-CH2-Cf-0-T Ie R2 R3 V (CH2)„-A'-0 If II (CH2)n-A-X III I (CH^-N-Q-X (CH2)„-N (CH2)p R'2 I (CH2)n-N-Q-X -B-X (CH^-A'-OH Ilia Illb xi iiia iia ia BA £88^92 h-n-Thd) —^ .H - LS - <• h 58 - 264883 (CH2)n-N-C0-Cf-0 —j N R2 R3 \ (CH2)n-A-0 XI XII R 12 I . (CH2)n-N-(f-0 Xlla R'-NH, XIII ^y-CH^-COOH R2 XIV ,6* 59- 264883 9 i Hal-Q'-COOR12 Hal-Q-CN x-q-cooh R10OOC-N=N-COORn nh2-nhr5 XVla XVIb XVII XVIII XIX r3' r4 I CO-CH-COOCTH 2n5 r2 oc-cooc,h 2"5 r3 ■(CH2) h-n d-n (CH^p b-oh \ /" ">(CH2)P XV- (CH^-N b-oh b-x XX XXI XXII xxiii XXIV XXV XXVa XXVb </div>

Claims

<div class="application article clearfix printTableText" id="claims"> -60 - 264883 D-A-0 XXVI R2 R3 R1 I (CH2)n-N.-CO-Q'-X XXVII R2 R3 rv (CH2)n-A-0 XXVIII X-Q-T XXIX Y-Q-T XXX -61- 264 WHAT WE CLAIM IS:

1. Compounds of the general formula I r2 ^ ,r4 (CH,).- A - O rs r3 in which 5 n denotes an integer from 1 to 5, A represents a group of the general formula a r' — n —q— a in which R1 denotes hydrogen or a lower alkyl group and Q denotes a (CH2)m group in which m 10 denotes 2 to 8 and which may optionally be substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups, or represents the 2-hydroxypropylene chain, or A represents a group of the general 15 formula b in which p denotes 4 to 6 and B represents a (CH2)r group in which r denotes 1 to 3 and which may optionally be substituted in the 20 a position to the oxygen atom by 1 to 2 lower alkyl groups, R2 denotes hydrogen, halogen, lower alkyl, lower 264 8 -62 - alkoxy, hydroxyl, trifluoromethyl or nitro or, if A contains no OH group and R3, R6 and R7 are not hydroxyl, alternatively denotes lower alkanoyloxy, and 5 R3 denotes hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or, if A contains no OH group and R2, R6 and R7 are not hydroxyl, alternatively denotes lower alkanoyloxy, or R2 and R3 are attached to two adjacent carbon 10 atoms and together represent an alkylenedioxy group having 1 to 2 carbon atoms, R4 denotes hydrogen or lower alkyl, R5 is disposed in the 1 or 2 position and denotes hydrogen, lower alkyl or a phenyl-lower alkyl 15 group, R6 denotes hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, trifluoromethyl or nitro or, if A contains no OH group and R2, R3 and R7 are not hydroxyl, alternatively denotes 20 lower alkanoyloxy, and R7 denotes hydrogen, lower alkyl, lower alkoxy, hydroxyl or halogen or, if A contains no OH group and R2, R3 and R6 are not hydroxyl, alternatively denotes lower alkanoyloxy, or 25 R6 and R7 are attached to two adjacent carbon atoms and together form an alkylenedioxy group having 1 to 2 carbon atoms, and their physiologically tolerable acid addition salts. 3 0 2. Compounds according to Claim 1, in which A repre sents a group of the formula a) in which R1 denotes lower alkyl or hydrogen and Q represents a (CH2)m group in which m denotes 2 to 6, or A represents a group of the formula b) in which p is 5. 35 3. Compounds according to either of the preceding claims, in which R4 denotes hydrogen and R5 denotes hydrogen, alkyl having 1 to 2 carbon atoms or benzyl. 26488 -63 - 4. Compounds according to any preceding claim, in which n denotes 2 or 3• 5. Compounds according' to any preceding claim, characterized in that n denotes 2 or 3, A represents 5 a group of the formula a) in which R1 denotes hydro gen or lower alkyl and Q denotes a (CH2)m group in which m denotes 2 to 4, or A represents a group of the formula b) in which p denotes 5, and R2 denotes hydrogen, lower alkoxy or hydroxyl, R3 denotes 10 hydrogen or lower alkoxy, R4 denotes hydrogen, R5 denotes hydrogen or benzyl, R6 denotes hydrogen, lower alkoxy, hydroxyl or nitro and R7 denotes hydrogen or lower alkoxy. 6. Compounds according to Claim 5, characterized in 15 that n dentotes 2, A represents a group of the formula a) in which R1 denotes methyl or hydrogen and Q represents a (CH2)m group in which m denotes 3 or 4, R2 denotes methoxy or hydroxyl, R3 denotes methoxy, R4 denotes hydrogen, Rs denotes hydrogen or 20 benzyl, R6 denotes methoxy, hydrogen or hydroxyl and R7 denotes methoxy or hydrogen. 7. 3 -{3-[N-(2 -(3,4-Dimethoxyphenyl)-ethyl)-N-methylamino] -propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole, or 3 -{3 -[N-(2 -(3,4-dimethoxyphenyl)-ethyl) -N-methyl- 2 5 amino] -propyloxy} - 5 - (4-hydroxy-3 -methoxyphenyl) - pyrazole and their physiologically tolerable acid addition salts. 8 . 3 - { [N- (2 - (3, 4-Dimethoxyphenyl) -ethyl) -piperid-3 -yl] -methoxy}-5-(3,4-dimethoxyphenyl)-pyrazole and its 3 0 physiologically tolerable acid addition salts. 9. Medicaments containing a pharmacologically effective quantity of a compound according to any preceding claim and at least one conventional pharmaceutical adjuvant and/or -64 - excipient 10 • Process for the preparation of a compound of the general formula I (CHJ,,- A - O in which n denotes as integer from 1 to 5, A represents a group of the general formula a R1 I N —Q 10 15 in which R1 denotes hydrogen or a lower alkyl group and Q denotes a (GH2)ni 9r°up in which m denotes 2 to 8 and which may optionally be substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups, or represents the

2-hydroxypropylene chain, or A represents a group of the general formula b (ou, B- in which p denotes 4 to 6 and B represents a -65 - 264883 (CH2)r group In which r denotes 1 to 3 and which may optionally be substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups, 5 R2 denotes hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl or nitro or, if A contains no OH group and R3, R6 and R7 are not hydroxyl, alternatively denotes lower alkanoyloxy, and 10 R3 denotes hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or, if A contains no OH group and R2, R6 and R7 are not hydroxyl, alternatively denotes lower alkanoyloxy, or R2 and R3 are attached to two adjacent carbon 15 atoms °and together represent an alkylenedioxy group having 1 to 2 carbon atoms, R4 denotes hydrogen or lower alkyl, R5 is disposed in the 1 or 2 position and denotes hydrogen, lower alkyl or a phenyl-lower alkyl 20 group, R6 denotes hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, trif luoromethyl or nitro or, if A contains no OH group and R2, R3 and R7 are not hydroxyl, alternatively denotes 25 lower alkanoyloxy, and R7 denotes hydrogen, lower alkyl, lower alkoxy, hydroxyl or halogen or, if A contains no OH group and R2, R3 and R6 are not hydroxyl, alternatively denotes lower alkanoyloxy, or 3 0 R6 and R7 are attached to two adjacent carbon atoms and together form an alkylenedioxy group having 1 to 2 carbon atoms, and its physiologically tolerable acid addition salt , 35 characterized in that a) for the preparation of a compound of the general formula la -6S . 264883 r2 r3' (ch2)n- a - o la in which R4, R5, A and n possess the above meaning and R2', R3', R6' and R7' possess the meaning given for R2, R3, Rs and R7 with the exception of lower alkanoyloxy, a compound of the general formula IX ii 10 in which R4, R5 and R possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, is reacted with a compound of the general formula III (ch2)n-a-x iii 15 in which R2', R3', n and A possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and X represents a leaving group which can be 264883 eliminated, and subsequently any hydroxyl-protecting groups are eliminated again, or b) for the preparation of a compound of the general formula lb in which R2', R3', R4, R5, Rs*, R7' and n possess the above meaning and A' possesses the meaning given for A with the exception of a radical containing an OH group, a compound of the formula 10 II is reacted with triphenylphosphine in the presence of at least one azodicarboxylic ester of the general formula XVTII riqooc-n=n-coor11 xwm in which R10 and R11 each denotes lower alkyl, 15 and the reaction product is reacted with a compound of the general formula IV (ch^-a'-oh iv in which R2', R3', n and A' possess the above meaning, but in which any free NH group in the 20 radical A' is provided with an amino-protecting group and any free hydroxyl groups in the radical a' are provided with hydroxyl-protecting groups, and subsequently -68 - 2648 any amino- asd/or hydroxyl-protecting groups are eliminated again, or c) for the preparation of a compound of the general formula Ic Ic in which R1, R2', R3', R4, R6', R7', Q and n possess the above meaning and R5' possesses the meaning given for R5, but in which, if the chain length m of the radical Q is 3, R5' represents a 10 phenyl-lower alkyl group or lower alkyl group which is arranged on that nitrogen atom of the pyrazole ring which is adjacent to the oxygen atom, a compound of the general formla V 15 in which R1, R2', R3' and n possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, is reacted with a compound of the general formula VI in which R4, R5', R6', R7' and Q possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, 5 and Y denotes a leaving group which can be eliminated by aminolysis, and subsequently any hydroxyl-protecting groups are eliminated again, or d) for the preparation of a compound of the formula 10 la, a compound of the general formula VII in which R2', R3', n and Y possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, 15 is reacted with a compound of the general formula VIII 2648 in which R4, Rs, R6 , R7 and A possess the above meaning, but in which amy free hydroxyl groups are provided with a hydroxyl-protecting group, and subsequently any hydroxyl-protecting groups are eliminated again, or e) for the preparation of a compound of the general formula Id r3 r1 oh \\ I | xv~ (ch2)n-n-ch2-ch-ch2-0 r5 in which R1, R2', R3', R4, R5, R6', R7' and n 10 possess the above meaning, a compound of the general formula IX in which R4, Rs' and R7' possess the above meaning, but in which any free hydroxyl groups 15 are provided with a hydroxyl-protecting group, Z denotes hydrogen or the 2,

3-epoxypropy1 radical and R5'' denotes a phenyl-lower alkyl group or lower alkyl group which is arranged on that nitrogen atom of the pyrazole ring which is 20 adjacent to the oxygen atom, or, if Z is hydro gen, possesses the meaning given for R5, is reacted with a compound of the general formula X 71 26488 R2 R3 R1 V- (CH2)n-N-Z' in which R1, R2', R3' and n possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and Z' represents the 2,3-epoxypropyl radical if Z denotes hydrogen, or Z' is hydrogen if Z denotes the 2,3 -epoxypropyl radical, and subsequently any hydroxyl-protecting groups are eliminated again, or f) for the preparation of a compound of the general formula Ie in which R1, R3', R4, R5, R7' and n possess the above meaning, R2" and R6" possess the meaning given for R2 and Rs with the exception of nitro and lower alkanoyloxy, and Q' represents a (CH2)m, group in which m' denotes 1 to 7 and which is optionally substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups, a compound of the general formula XI 26A 883 in which R2", R3', R*, R5, R6", R7', n and Q' possess the above meaning, but in which any free hydroxyl groups are provided with a hydroxyl-protecting group, and R1' denotes lower alkyl or an amino-protecting group, is reduced and subsequently any amino- and/or hydroxyl-protecting groups are eliminated again, or 10 g) for the preparation of a compound of the general formula X f v)— (CH2)n-A'-0 If in which R4, n and A' possess the above meaning, R5'" possesses the meaning given for R5 but R5" does not denote benzyl if the radical A' contains 15 an NH group, and R2'", R3", R6 " and R7" « ^ g 7 possess the meaning given for R , R , R and R with the exception of hydroxyl, but where at least one of the substituents R2'", R3", R6'" and R7'' denotes lower alkanoyloxy, in a compound « . , 73 of the general formula XII 264 8 < In which n and R4 possess the above meaning, R2rv, R3'", R6IV and R7'" possess the meaning 5 given for R2, R3, R6 and R7 with the exception of lower alkanoyloxy, but in which at least one of the substituents R2iv, R3"', Rsrv and R7'" denotes hydroxyl, RSIV denotes lower alkyl or a phenyl-lower alkyl group and A' ' possesses the 10 meaning given for A', but in which any NH group present in the radical A' ' is protected by a benzyl protective group, the free hydroxyl groups R2iv, R3 ", R6 " and/or R7"' is acylated, and subsequently any benzyl protective group is 15 eliminated again, and XII if desired, in a resulting compound of the formula I in which R2, R3, Rs and/or R7 denote methoxy or a hydroxyl group is liberated from these groups, and/or if desired the benzyl group is eliminated from a resulting compound of 20 the formula I in which R5 denotes benzyl, and if desired a free compound of the formula I is converted to its acid addition salt or the acid addition salt is converted to the free compound of the formula I. * " ' « 74 264 11. Compounds of the general formula XX * r1 (CH^-N-CO-Q-O in which R1' denotes a lower alkyl group or an amino-pro-5 tecting group, R2" denotes hydrogen, halogen, lower alkyl, tri- fluoromethyl or lower alkoxy, and R3' denotes hydrogen, halogen, lower alkyl or lower alkoxy, or 10 R2" and R3' are attached to two adjacent carbon atoms and together represent an alkylenedioxy group having 1 to 2 carbon atoms, n denotes an integer from 1 to 5, Q' represents a (CH2)m, group in which m' denotes 15 1 to 7 and which is optionally substituted in the a position to the oxygen atom by 1 to 2 lower alkyl groups, R4 denotes hydrogen or lower alkyl, R5 is disposed in the 1 or 2 position and denotes 20 hydrogen, lower alkyl or a phenyl-lower alkyl group, R6" denotes hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, and R7' denotes hydrogen, lower alkyl, lower alkoxy or 25 halogen, or R6" and R7' are attached to two adjacent carbon atoms and together form an alkylenedioxy group having 1 to 2 carbon atoms. 9 I *75 t. s> -rf- 264883 12. A compound according to claim 1 substantially as herein described or exemplified. 13. A medicament according to claim 9 substantially as herein described or exemplified. 14. A process according to claim 10 substantially as herein described or exemplified. 15. A compound according to claim 11 substantially as herein described or exemplified. KALI-CHEMIE PHARMA GMBH By Their Attorneys HENRY HU£HES Per; </div>