SK150694A3 - 1-(phenylalkylaminoalkoxy)-5-phenylpyrazole compounds, as their method and intermediates for their production - Google Patents

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

Technical field

The present invention relates to novel phenylalkylaminoalkyl compounds having 5-phenyl-pyrazolyl-3-oxisubstitutents on the alkyl moiety, and salts thereof, as well as pharmaceutical compositions containing them and a process and intermediates for the preparation of such compounds.

The state of the art

European patent application no. 7019 discloses 3-hydroxycarbonylmethoxy-5-phenylpyrazole compounds and esters and amides thereof which have the ability to reduce blood lipids. European patent application no. No. 170861 discloses 3- (aminoalkylaminocarbonylmethoxy) -5-phenylpyrazole compounds having antiarrhythmic effects, in particular an increased effect on cardiac arrhythmia.

The present invention solves the object of discovering novel 5-phenylpyrazole compounds with valuable pharmacological properties. The present invention further solves the task of discovering new pharmaceutical active substances suitable for lowering heart rate.

Recently, it has been found that the novel 5-phenylpyrazole compounds having the 3-position phenylalkylaminoalkyloxil moiety of the present invention possess valuable heart-acting pharmacological properties and cause a decrease in heart rate with a good efficacy profile. Because of their efficacy profile, these substances are useful in the present invention as heart rate reducing agents for the treatment of ischemic conditions.

SUMMARY OF THE INVENTION

The invention relates to novel compounds having the general formula I

(I) wherein n is an integer from 1 to 5,

A is a group of formula a

-NQ (a) wherein R ¹ is hydrogen or lower alkyl and

Q represents a (CH ₂ ) _n - group wherein n represents 2 to 8 and which optionally in the position of the oxygen atom may be substituted by 1 to 2 lower alkyl groups, or represents a 2-hydroxipropylene chain, or A represents a group of formula b '

P

B (b) wherein p is 4 to 6 and B is (CH ₂ ) -group, wherein r is 1 to 3, and which may optionally be in the position ar is 1 to 3, and which may optionally be in the position a to the oxygen an atom substituted with 1 to 2 lower alkyl groups,

R is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro, or when A contains no OH-group and R, R and R are not hydroxyl, it is also a lower alkanoyloxy group and

R ³ is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, or when A does not contain an OH-group and R, R and R are not hydroxy, also means lower alkanoyloxy;

3 «. .

R @ 1 and R @ 2 are bonded to two adjacent carbon atoms and together represent an alkylene dioxide group having 1 to 2 carbon atoms,.

R is hydrogen or lower alkyl,

R ⁵ is located in the 1 or 2 position and represents hydrogen, lower alkyl or phenyl lower alkyl,

R ⁶ is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl or nitro, or when A does not contain an OH group and R, R and R are not hydroxi, it is also alkanoyloxy;

R ⁷ is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, or when A does not contain an OH-group and R, R and R are not hydroxy, it also means lower alkanoyloxy;

R ⁶ and R ⁷ are bonded to two adjacent carbon atoms and together form an alkylene dioxy group having 1 to 2 carbon atoms, as well as their acid addition salts.

When in the compounds of formula I the substituents R ² , R ³ , R ⁶ and R ⁷ represent or contain a lower alkyl group of the phenyl ring, such groups are suitable as linear or branched groups and in particular with 1 to 4, preferably 1 to 4, preferably 1 to 2 carbon atoms and are preferably methyl, methoxy or acetoxi. When the substituents are halogen, in particular fluorine, chlorine or bromine, preferably fluorine or chlorine, are suitable.

When A is a group of formula a, R ^{@ 1 is} preferably lower alkyl. especially methyl, or hydrogen, and Q is preferably an unsubstituted alkylene chain _{(CH2) n,} wherein m is 2 to 6, especially 2, 3 or 4. Where A is R b, comprises preferably the 6-membered ring, that is, p is preferably 5 and B is preferably an unsubstituted C 1 -C 3 alkylene chain, in particular a methylene group.

The substituents R and R preferably represent lower alkoxy groups, in particular methoxy, hydroxy, or hydrogen. The substituents R ⁶ and R ⁷ preferably represent lower alkoxy, in particular methoxy, hydroxy or hydrogen, or R ⁶ optionally also represents nitro.

R ^{4 is} preferably hydrogen. When R ⁴ represents lower alkyl, it is preferably methyl. The lower alkyl or phenyl-lower alkyl group R ⁵ is preferably located on the nitrogen atom of the pyrazole ring adjacent to the oxygen atom. R ⁵ is preferably hydrogen or also a phenyl-lower alkyl. When R ⁵ represents lower alkyl, this is preferably methyl or ethyl. Where R ⁵ is phenyl-lower alkyl group, its alkylene chain contains 1 to 3 carbon atoms and R is preferably benzyl.

According to the process of the invention, the compounds of the formula I and their acid addition salts are obtained in a manner known per se a) for the preparation of the compounds of the formula Ia

(la) where R

R ⁵ ,

A and n are as defined above and R ² , R ³ are

The meaning given for R and R with the exception of lower alkanoylox, leaving the compounds of formula II

(II) wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, but wherein all free hydroxy groups are protected with a hydroxy protecting group, react with compounds of formula III

- ⁽ CH ₂ ) _n -N - & - X (III) wherein R ² , R ³ , on A are as defined above, wherein all free hydroxy groups are protected with a hydroxy protecting group and X is a leaving group and then all protecting groups for hydroxy groups, cleavage again, or b) for the preparation of compounds of formula Ib

wherein R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ and n are as defined above and

A is as defined for A except that the radical containing the OH group is reacted with compounds of formula II with triphenylphosphine in the presence of azodicarboxilic acid esters of formula XVIII

R ¹⁰ OOC - N = N - COOR ¹¹ (XVIII) wherein R ¹⁰ and R ¹¹ are each lower alkyl and the reaction product is left with compounds of formula IV

(IV)

Wherein R, R, n and A have the meanings given above, wherein all free NH-groups in the residue A are protected by an amino-protecting group and the free hydroxyl groups are protected by hydroxyl groups and then the amino- or hydroxyl-protecting groups present or

c) for the preparation of compounds of formula Ic

(.Ic) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , Q and n are as defined above and R ⁵ is as defined for R ⁵ , however, when the chain length is m of Q 3 , R ⁵ is a lower alkyl group or a phenyl lower alkyl group located on a nitrogen atom adjacent to an oxygen atom with compounds of formula V

(V) wherein R ¹ , R ² , R ³ and n are as defined above but wherein the hydroxy groups present are provided with a hydroxy protecting group, they are reacted with compounds of formula VI

(VI) wherein R, R, R, R and Q are as defined above, but all free hydroxy groups are protected with a hydroxy protecting group and Z is an aminolytically cleavable group, and then the hydroxy protecting groups present are cleaved again, or

d) for the preparation of compounds of the formula Ia, a compound of the formula VII is combined

(VII) wherein R ² , R ³ , and Y are as defined above, wherein all free hydroxy groups present are protected with a hydroxy protecting group, reacted with compounds of formula VIII

(VIII) where R ⁴ , R ⁵ , R ⁶ , R ⁷ and A are as defined above, wherein the free hydroxyl groups are protected with a hydroxy protecting group and then the hydroxy protecting groups present are cleaved again, or

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined above, is fused with the general formula IX

(ix) wherein R ⁴ , R ⁶ and R ⁷ are as defined above, but the optional free hydroxyl groups are protected with a hydroxy protecting group, Z is hydrogen or a 2,3-epoxipropyl radical and R ⁵ is lower alkyl or phenyl lower alkyl located on a nitrogen atom adjacent to an oxygen atom of the pyrazole ring, or when Z is hydrogen> is as defined for R ⁵ , reacted with compounds of formula X

wherein R ¹ , R ² , R ³ and n are as defined above, but all free hydroxy groups are protected with a hydroxy protecting group and Z is a 2,3-epoxy-propyl radical when Z is hydrogen or Z is hydrogen when Z is 2 A 3-epoxy-propyl radical, and then optionally protecting groups for the hydroxy group are cleaved, or

f) for the preparation of compounds of the formula Ie

(Ie)

13 * 4 5 7 '2' 6 * where R, R, R, R, R and R are as defined above, R and R are as defined for R ² and R ⁶ except nitro and lower alkanoyloxy, and Q is ( CH ₂ ) _m - a group wherein m is 1 to 7, and which is optionally substituted with 1 to 2 lower alkyl groups at the position of the oxygen atom, compounds of formula XI

wherein Ŕ, R ³ , R ⁴ , R ⁶ , R ⁷ , and Q are as defined above, but all free hydroxy groups are protected with a hydroxy protecting group and R ¹ is lower alkyl or an amino protecting group.

are reduced and then the optionally present amino and / or hydroxyl protecting groups are removed again, or

g) for the preparation of the compounds of the general formula 1f

(If)

wherein R, n and A are as defined above, R is as defined for R ⁵ , but R ^{5 is} not benzyl when the residue A contains an NH group and R, R are as defined for R ² , R ³ , and R ⁷ with the exception of hydroxi, but wherein at least one of R ² , R ³ , R ⁶ and R ⁷ is lower alkanoyloxy, in the compounds of formula XII

,, _4. . Where R and R are as defined above, R, R, R and R are as defined for R, R, R and R, except for lower alkanoyloxy, but at least one of R being ^2IV, R, R ^6IV and R ⁷ is hydroxyl, R ^5IV is lower alkyl or phenyl-lower alkyl group and a is as defined for a, but with a protected NH group present in the radical a, the protecting group. The free hydroxyl groups R ^2IV , R ³ , R ⁶ and / or R ⁷ are acylated and then the optional benzyl protecting group is cleaved again and optionally in the compounds of formula I obtained, where R, R, R and / or R ⁷ is methoxy, from these groups the hydroxyl group is released and / or optionally the obtained compound having the formula I, wherein R ⁵ is benzyl, is cleaved off the benzyl group and optionally the free compounds of the formula I are converted into the free compounds of the formula I.

The reaction of the compounds of formula II with the compounds of formula III according to process variant a) can be carried out in a manner known per se under the conditions customary for the formation of a pyrazolether bond by alkylation of pyrazolols. Suitable leaving group X in the compounds of the formula III is preferably a halogen such as chlorine, bromine or iodine, or else organic sulfonic acid residues such as lower alkanesulfonic acid residues such as methanesulfonic acid or aromatic sulfonic acids such as benzenesulfonic acid, or lower alkyl or halogen substituted benzenesulfonic acids, e.g. toluenesulfonic acids or bromosulfonic acids. Generally, approximately equivalent amounts of compounds of formulas II and III are reacted. Where R ⁵ is a lower alkyl or phenyl-lower alkyl, it can also be used an excess of the compounds of formula III, when R is not hydrogen, it is advantageous to use an excess of the compounds of formula I, a free or protected NH function of the pyrazole ring followed by re-cleavable with an amino protecting group to avoid side reactions. The reaction is preferably carried out in a solvent which is inert under the reaction conditions (under basic conditions). Suitable inert organic solvents are dimethylformamide, tetramethylurea, acetone or, depending on the nature of the base used as the acid-binding agent, also an ether, in particular a cyclic ether such as tetrahydrofuran, a lower alcohol or aromatic hydrocarbons such as benzene or toluene or mixtures of said solvents. Preferably, the reaction is carried out in the presence of at least an equivalent amount of an acid-binding base. Suitable bases are e.g. inorganic or organic alkali metal compounds. For example, suitable bases are alkali metal carbonates or hydroxides thereof, alkali metal hydrides such as sodium hydride or lower alkali metal alcoholates such as e.g. potassium tertiary butylate or sodium ethylate or alkali metal amides such as e.g. lithium amide or lithium diisopropylamide. If desired, catalytic amounts of iodide salts, e.g. an alkali metal iodide or ammonium iodide such as potassium iodide or tertiary butylammonium iodide. The reaction proceeds at temperatures between room temperature and the boiling point of the reaction mixture. Preferably, the reaction takes place e.g. using an inorganic base such as potassium carbonate or sodium hydride in an inert solvent such as dimethylformamide, preferably at temperatures between 80 and 120 ° C.

The reaction may optionally be carried out in a biphasic system in the presence of a phase transfer catalyst, for example benzyl-trisubstituted alkylammonium chloride. Any hydroxy groups present in Group A may be protected during the reaction by hydroxy protecting groups which are then readily cleaved off.

The preparation of compounds of formula Ib according to process variant b) can be carried out under conditions customary for the Mitsunobu reaction. For example, the reaction may be carried out in an inert anhydrous aprotic organic solvent, in particular a cyclic ether such as tetrahydrofuran or dioxane and / or an aromatic hydrocarbon such as benzene or toluene.

in organic conditions, for

The reaction of compounds of formula V with compounds of formula VI and of compounds of formula VII with compounds of formula VIII according to variant c) and d) can be carried out by known methods for the alkylation of amines. Suitable aminolytically cleavable Y radicals in the compounds of formulas VI and VII are halogens such as chlorine, bromine or iodine, preferably bromine or chlorine, or else an organic sulfonic acid residue, for example a lower alkanesulfonic acid residue such as e.g. methanesulfonic acids or aromatic sulfonic acids such as benzenesulfonic acid or benzylsulfonic acid substituted with lower alkyl or halogen substituted e.g. toluenesulfonic acid or bromobenzenesulfonic acid. The reaction may be carried out with a solvent which is inert under the reaction basic conditions. The solvents, bases and reaction conditions set forth above in process variant a) may be used. The optionally present hydroxy group in the chain Q or group A is preferably protected as in process variant a) during the reaction by a readily cleavable hydroxy protecting group. Preferably, the reaction is carried out at temperatures between room temperature and the boiling point of the reaction mixture and may last from 1/4 to 6 hours depending on the reaction conditions. Preferably, the reaction takes place e.g. in an inert solvent such as dimethylformamide in the presence of an inorganic base such as potassium carbonate at temperatures between 80 and 120 ° C. Variants c) and d) are particularly suitable for the preparation of compounds of formula I, wherein R ⁵ represents a lower alkyl- or phenyl-lower alkyl group attached to the oxygen atom adjacent to the nitrogen atom.

The reactions of compounds of formula IX with compounds of formula X according to process variant a) can be carried out in a manner known per se by methods customary for the reaction of alcohols or amines with epoxides. Compounds of formula IX can be reacted with compounds of formula X in an organic solvent inert under the reaction conditions, under basic conditions. The solvents mentioned for process variants a), c) and d) as well as bases can be used. The reaction temperature may range from 60 to 120 ° C. The duration of the reaction is between 4 and 12 hours, depending on the reaction conditions. Preferably, e.g. the reaction takes place in an inert solvent such as dimethylformamide in the presence of an inorganic base such as potassium carbonate at 100 ° C.

The reduction of the compounds of the formula XI according to process variant f) can be carried out by methods customary for the reduction of amides. Suitable reducing agents are complex metal hydrides capable of reducing amides, in particular aluminum hydrides such as lithium aluminum hydride. Suitable solvents are, for example, cyclic ethers such as tetrahydrofuran or dioxane or an open-chain ether such as ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, optionally in admixture with aromatic hydrocarbons such as benzene or toluene. The reaction may be carried out at an elevated temperature, for example at the boiling point of the reaction mixture, depending on the type of reducing agent used. For example, reaction with lithium aluminum hydride at the boiling point of the reaction mixture seems advantageous. The reaction time may be between 1 and 10 hours.

The acylation of compounds of formula XII according to process variant g) can be carried out by known methods for forming a phenol ester linkage by reacting compounds of formula XII with a reactive derivative of the corresponding lower cyrboxilic acid, for example a lower carboxylic acid halide or anhydride thereof.

If the group A in the compounds of formula XII contains a benzyl-protected NH-group, then this benzyl-protecting group can then be cleaved again by known methods for the cleavage of benzylamine. It may thereby also be split off an optionally present benzyl R ^5th For example, reductive cleavage is preferred. This can be done, for example, using formic acid as a reducing agent in the presence of a palladium catalyst, or using hydrogen as a reducing agent in the presence of a palladium catalyst.

If the radicals R @ ² , R @ ³ , R @ ⁶ and R @ ⁷ represent a free hydroxy group, they must be protected by readily cleavable protecting groups during the reactions described above according to process variant a) to g) as well as in the formation of starting materials. . Suitable hydroxyl-cleavable groups which can be cleaved after the reaction are those which are known from the E. McOmie Protective Groups in Organic Chemistry, Plenum Press. For example, esters, e.g. acetate, readily cleavable carbonates such as benzyl carbonate, and readily cleavable ethers such as tetrahydropyranyl ether or benzyl ether. Protecting groups must always be selected which are stable during the reactions and then cleaved under conditions where the products are still formed. Preferably, ether protecting groups such as benzyl ether may be used. Thus, in the reaction of the starting compounds of formula II with the starting compounds of formula III, wherein at least one of the radicals R, R, R and R is a benzyl ether bonded hydroxy group, the compounds of formula XXVIII may first be obtained.

R ¹⁰ OOC - N = N - COOR ¹¹

XVIII wherein R ^4, R ⁵ and n are as defined above and the radicals R ^{2 V,} R ^3IV, R ^{6 V} and ^{R IV} are as defined for the radicals R ^2, R ^3, R ⁶ and R ⁷ or are benzyloxiskupinu, but at least a one of R ^2V , R ^3iv , R ^6v and R ^7iv is benzyloxy. Compounds of formula XXVIII are novel and are valuable intermediates for the preparation of pharmacologically active compounds, for example compounds of formula I, and also have heart-acting properties as compounds of formula I themselves.

If the radical R ⁵ is hydrogen and / or the radical A contains a free NH-group, the free NH-groups can optionally be protected in a known manner by means of easily cleavable protecting groups. This may be particularly useful during the reaction of compounds of formula V with compounds of formula VI when the chain length m in the residue Q is 3. As suitable, readily cleavable protective groups for NH groups are e.g. known from E. McOmie's Protective Groups in Organic Chemistry, Plenum Press 1971. For example, benzyl trityl or tetrahydropyranyl are suitable for protecting the NH-group of the pyrazole ring. It is always necessary to select those groups which are not damaged during the reaction and which are then cleavable under such conditions that the prepared product is not damaged. A benzyl group may be used as a protecting group.

In compounds of Formula I, wherein R, R, R ⁶ and / or R ⁷ presdtavujú methoxiskupinu, may of which optionally follows liberated hydroxy groups, if desired. Methoxy groups can be cleaved by known methods suitable for cleavage of methoxy methoxy ethers to hydroxy groups. For example, the ether cleavage can be carried out by reaction with hydrogen iodide or hydrogen bromide in a solvent which is inert under the reaction conditions, e.g. acetic anhydride or acetic acid, or iodotrimethylsilane or boron tribromide in a halogenated hydrocarbon such as dichloromethane. Optionally present lower alkanoyloxy groups can also be cleaved under ether cleavage conditions.

Preferred compounds of formula I, wherein R ⁵ is benzyl, may be cleaved subsequently the benzyl group by known methods for the cleavage of the corresponding benzaldehyde, the corresponding compounds of formula I, wherein R ⁵ is hydrogen. The cleavage of the benzyl group may be carried out by reductive or hydrogenolytic cleavage, for example under the conditions outlined in process variant g) for cleavage of the benzyl protecting group.

The compounds of formula I can be isolated from the reaction mixture and purified in a known manner. The acid addition salts may be converted into the free bases in a customary manner and, if appropriate, in the known manner into pharmacologically acceptable acid addition salts.

Suitable pharmacologically acceptable acid addition salts of the compounds of the formula I are, for example, salts with inorganic acids, e.g. hydrohalic acids, in particular hydrochloric acid, sulfuric or phosphoric acids, or with organic acids, for example lower aliphatic mono- or dicarboxilic acids such as maleic, fumaric, lactic, tartaric or acetic acids, or sulphonic acids, for example lower alkanesulfonic acids such as methanesulfonic acid or optionally benzenesulfonic acids, such as p-toluenesulfonic acid or cyclohexylaminosulfonic acid, substituted on the benzene ring by halogen or lower alkyl.

In the compounds of formula I, when A represents group b) or group a), wherein Q represents a hydroxipropylene chain, the compounds contain a chiral center and may exist in two optically active forms or as a racemate. The present invention encompasses both racemic mixtures and optical isomers of these compounds of Formula I. Optically active compounds can be obtained from the racemic mixture by conventional resolution methods, e.g. by chromatographic separation on chiral carrier materials, or by fractional crystallization of a suitable salt with optically active acids. Enantiomerically pure compounds may also be prepared by synthesis from the corresponding enantiomerically pure starting compounds. For example, the spherically pure isomers of the starting compounds of formulas III, IV or VIII according to the methods of variants a), b) and d) described above may be converted to sterically pure compounds having the formula I.

The starting compounds of the formula II are known or can be prepared by known methods. It is known that compounds of formula II exist in several tautomeric forms, and that in addition to the enol form of the 5-phenylpyrazol-3-ol of formula II, there is also the corresponding ketoform. In general, there are mixtures of different tautomers, the composition of which may vary according to the type of substituents.Therefore, both forms or mixtures thereof can be used for the production of the compounds of the formula I. All tautomeric forms of these compounds together with the compounds of the formula II are . T

The compounds of formula II can be obtained for the preparation of 5-phenylpyrazolin-3-ones by known methods, e.g. cyclic condensation of optionally substituted hydrazines of formula XIX nh ₂ -nhr ⁵ (XIX) wherein R ⁵ is as defined above, with benzoylacetic acid esters of formula XX

R '

R

W-CO-C 1 H -COOC 9 H 2 (XX) wherein R ² , R ³ and R ⁴ are as defined above, or phenylpropiolic acid esters of formula XXI

O-COOCoIL · 2?

(XXI) wherein R ² and R ³ are as defined above. The reaction is carried out in an organic solvent which is inert under the reaction conditions. When R ⁵ is lower alkyl or phenyl-lower alkyl group, resulting from the reaction of a mixture of isomeric compounds wherein R ⁵ is located at position 1 or 2. The ratio of the 1- and 2-substituted compounds can vary according to the type of starting material and solvent used t _e . An isomeric mixture of 1- and 2-substituted compounds may be separated by fractional crystallization or chromatography.

In compounds of formula II wherein R ⁵ is hydrogen, the benzyl group R ⁵ may optionally be subsequently introduced in a known manner, preferably reacting the benzyl bromide in an organic solvent under inert conditions, for example in an aromatic hydrocarbon such as toluene. Benzyl bromide is a preferred representative of benzyl halogen. The reaction is carried out in the presence of a base, for example pyridine. Benzylation can produce isomeric mixtures of benzylated compounds at the 1-position and 2-position of the pyrazole ring. These may be separated in a known manner, e.g. fractional crystallization or chromatography.

The compounds of formula III are known or can be prepared by known methods or analogous to known methods. For example, compounds of formula IIIa

1 (CH ₂ ⁾ n -N- ^Q- X (IIIa) wherein R ¹ , R ² , R ³ , n, Q and X are as defined above, may be obtained by a process wherein the amine of formula V is reacted with compounds of formula XXX (XXX) wherein Q is as defined above, Y is as defined above, and preferably represents halogen, especially chlorine or bromine, and T represents a leaving group X or hydroxyl, and then optionally T is converted in a known manner to another leaving group X. may be carried out by known methods for aminoacylation, for example under the conditions previously mentioned for the reaction of compounds of formula V with compounds of formula VI. To suppress side reactions, it is preferred to use an excess of compounds of formula XXX. When in the compounds of formula XXX the radical T represents a leaving group X, it is preferable that the two leaving groups present in the compound of formula XXX have different reactivity, thus preventing the simultaneous reaction of both leaving groups with the compounds of formula V. in the reaction product, the hydrocompounds of the formula VII can be exchanged for amines of the formula XXII in a known manner. This may be accomplished by known methods conventional for aminoalkylation, for example under the conditions outlined for process variants c) and d).

Compounds of formula IV may be obtained by reacting compounds of formula VII with aminoalcohols of formula XXIV under conventional amino acid conditions.

H-A-OH (XXIV) wherein A is as defined above.

The compounds of formula V are known or can be prepared by known methods, or analogously to known methods. For example, compounds of formula V may be obtained starting from the corresponding acids of formula XIV

- CH _{2 (nl)} - COOH (XIV) wherein R ^2, R ^{3 and} n are as defined above. Thus, acid derivatives of acids of formula XIV may be reactive with amines of formula XIII

R ¹ - NH ₂ (XIII) wherein R ¹ is as defined above, converted to the corresponding amide, and then to the compound of formula V by reduction. For example, the reduction may be carried out under conditions for reducing compounds of formula XI according to process variant f).

The acids of formula XIV are known as they can be obtained in a known manner.

Compounds of formula VI can be obtained by a known method by reacting the corresponding compounds of formula II with compounds of formula XXIX

X - Q - τ '(XXIX) wherein X and Q are as defined above and T represents an aminolytically cleavable group Y or hydroxi, and then the T group is optionally converted to an aminolytically cleavable group Y. The reaction may be carried out under the conditions indicated for the reaction of compounds of formula II with compounds of formula III according to process variant a). To suppress side reactions, it is preferred to use an excess of compounds of formula XXIX. When in the compounds of formula XXIX the radical T represents a leaving group Y, it is preferable that the two leaving groups present in the compound of formula XXIX show different reactivity. When compounds of formula XXIX, where T is hydroxy, are used, then the hydroxy group in the compounds obtained can then be converted in a known manner to the group Y. This can be converted, for example, in the manner described for the preparation of compounds of formula III.

Compounds of formula VIII can be obtained by reacting compounds of formula II with compounds of formula XXV

Η - A - OH (XXV) wherein A and X are as defined above and D represents a solvolytically or hydrolytically cleavable protecting group, and from the obtained reaction products of formula XXVI

wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , A and D are as defined above, the protecting groups are cleaved again. The reaction of compounds of formula II with compounds of formula XXV may be carried out in a known manner, for example under the conditions set forth for the reaction of compounds of formula II with compounds of formula III according to process variant s). Suitable protecting group D are, for example, hydrogenolytically cleavable radicals such as benzyl, which can be cleaved by catalytic hydrogenation in the presence of a palladium catalyst.

The compounds of formula XXV are known or can be obtained in a known manner, for example analogously to the preparation of compounds of formula III. Compounds of formula XXVa '

R ¹

I

D - N - Q - X (XXVa) wherein R ¹ , Q, D and X are as defined above, can be obtained by introducing the amino protecting group D into an amine of formula XVIII and following reacting the protected amine with compounds of formula XII and a compound of formula XXVb

D

B - X (XXVb) wherein D, p, B and X are as defined above may be obtained by introducing the amino protecting group D into the aminoalcohol of formula XXII and then converting the hydroxy group to the residue X.

T

Compounds of formula IX wherein Z is hydrogen correspond to compounds of formula II. Compounds of formula IX wherein Z is a 2,3-epipropyl radical can be obtained in a known manner by reaction of the corresponding compounds of formula II with epichlorohydrin. The reaction may be carried out under the conditions set forth for the reaction of compounds of formula II with compounds of formula III. Preferably an excess of epichlorohydrin is used.

Compounds of formula X wherein Z is hydrogen are compounds of formula V. Compounds of formula X wherein Z is 2,3-epipropyl may be obtained in a known manner from the corresponding compounds of formula V by reaction with epichlorohydrin. For example, the reaction may be carried out under the conditions set forth for the reaction of compounds of Formula V with compounds of Formula VI. Preferably an excess of epichlorohydrin is used.

The starting compounds of formula XI are novel compounds which are valuable intermediates for the preparation of pharmacologically active compounds, for example compounds of formula Ie.

Compounds of formula XI can be obtained by methods common to amide formation, wherein the amine of formula V is reacted with acids of formula XV

wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and Q are as defined above, or with their reactive acid derivatives under conventional aminoacylation conditions. Thus, the amines of formula V can be reacted with the reactable acid derivatives of formula XV, preferably in a solvent inert under the reaction conditions and in the presence of an acid binding agent. Suitable reactive acid derivatives of the formula XV are, in particular, acid halides or mixed acid anhydrides and esters. Suitable solvents are halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane or carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene or chlorobenzene, cyclic ethers such as tetrahydrofuran or dioxane, dimethylformamide or mixtures of these solvents. Suitable acid-binding agents are organic or inorganic bases. For example, suitable organic bases are tertiary organic amines, especially tertiary lower alkyl amines such as triethylamine, tripropylamine or N-lower alkylpiperidine. Suitable inorganic bases are, in particular, alkali metal carbonates or bicarbonates. When the acid or ester itself is used as the acylating agent, the reaction of compounds of formula V with acids of formula XV can advantageously be carried out in the presence of a dehydrating agent, for example a coupling agent known in peptide chemistry for amide production. Examples of such agents that allow acylation by reacting with an acid in situ to form a reactive acid derivative include, in particular, alkyl-, preferably cycloalkylcarbodiimides such as dicyclohexylcarbodiimide, carbonylimidazole or lower alkyl-2-halopyridinium salts, especially halides or tosylates, -methyl-2-chloropyridinium iodide (= Mukayama reagent). The reaction in the presence of such a coupling agent can preferably be carried out at temperatures from -30 to +50 ° C under neutral conditions in a solvent such as halogenated hydrocarbons and / or aromatic hydrocarbons.

When acid derivatives of the formula XV, wherein R ⁵ is hydrogen, are used as starting compounds, these can first be partially converted to the corresponding cyclic compounds of formula XVa under the above reaction conditions to form an amide bond, especially when Q is a methylene group.

(XVa) wherein R ⁴ , R ⁶ , R ⁷ and Q are as defined above, which are then further reacted with amines of formula V.

The acids of formula XV may be obtained by known methods in which the corresponding compounds of formula II are reacted with esters of halocarboxylic acids or their nitriles of formula XVIa and XVIb

Hal-Q-COOR ¹² (XVIa)

Hal - Q '- CN (XVIb) wherein Q is as defined above, hal is halogen, especially chlorine or bromine, and R is lower alkyl, and the ester or nitrile obtained is then hydrolyzed to the acids of formula XV. The reaction of the compounds of formula II with the compounds of formulas XVIa and / or XVIb may be carried out according to a known procedure for alkylation at an oxygen atom in the 3,5-phenylpyrazolin-3-one position under basic conditions, for example those described in process variant a). Preferably, the reaction is carried out in dimethylformamide in the presence of potassium carbonate. The subsequent hydrolysis to the acids of formula XV is preferably carried out under alkaline conditions. The acids of the formula XV can be converted into their reactive derivatives with acids in a known manner. They can be partially condensed to the corresponding cyclic compounds of the formula XVa. Since cyclic compounds of formula XVa in the same manner as reactive acid derivatives of formula XV further react with amides of formula V, the separation of a random mixture of acid derivatives of formula XV from compounds of formula XVa is saved.

Compounds of formula XI can also be obtained by the formula XXVII by compounds

R ²

I

N-CO-Q (XXVII) wherein R ¹ , R ² , R ³ , n, Q and X are as defined above, are reacted with the corresponding compounds of formula II. The reaction may be carried out in a manner known per se, for example under the conditions outlined in process variant a) for the reaction of compounds of formula II with compounds of formula III.

Compounds of formula XXVII can be obtained by reacting an amine of formula Va

N- - H (Va) wherein R ¹ , R ² , R ³ and n are as defined above, is reacted with reactive acid derivatives of formula XVII

X - Q * - COOH XVII

Where Q and X are as defined above, by methods conventional for acylation. The reaction may be carried out under the conditions set forth, for example, for the reaction of amine compounds of formula V with reactive acid derivatives of formula XV. The reaction-reactive acid derivatives of the formula XVII are preferably their halides.

Compounds of formula XII, with the exception of those in which A contains a benzyl-protected NH-group, represent the corresponding compounds of formula I.

Other compounds of formula XIIa

2IV \\ (θ ^Η 2) _n - ^N - Q '' - ⁰ '

R

6IV (ΧΙΙά) wherein R ^2IV , R ³ , R ⁴ , R ^5IV , R ^6IV , R ⁷ and n are as defined above and Q represents (CH ₂ ) _m - wherein m is 2 to 8, R ¹² represents benzyl, and which optionally at the position of the oxygen atom may be substituted by 1 to 2 lower alkyl groups may be obtained by the corresponding compounds of formula IIIc

R

F

N - Q (IIIc) wherein R ^2IV , R ³ , R ¹² , n, Q and X are as defined above, under the conditions set forth in process variant a). Compounds of formula IIIc may be obtained by the methods described for the preparation of compounds of formula IIIa. For example, the corresponding acids of formula XIV can be reacted with benzylamine to give benzylamides, which are then reduced to amines, which can then react with the corresponding compounds of formula XXX to compounds of formula IIIc.

The compounds of formula I and their pharmacologically acceptable acid addition salts exhibit interesting pharmacological properties. In particular, the compounds possess properties which affect heart rate and exhibit excellent heart rate-reducing properties. They exhibit a suitable efficacy profile in the treatment of ischemic conditions such as e.g. in coronary heart disease because they also have cytoprotective effects.

The heart action properties of these compounds can be demonstrated by standard pharmacological test methods.

Description of pharmacological test methods:

1. Determination of minimum toxic doses

Male mice weighing 20-25 g were p.o. maximum doses of 300mg / kg test substance. The animals were monitored for signs of toxicity for 3 hours. In addition, all symptoms and cases of death are registered at 72 hours after administration. The accompanying symptoms are monitored and registered. When death or severe toxic symptoms are observed, further mice will receive a lower dose until toxic symptoms no longer occur. The lowest doses that do not cause death or toxic symptoms are listed in Table A below as minimum toxic doses. The example numbers given in the table refer to the following production examples.

Table A

Test substance Example no. minimal toxic 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

2. In vitro demonstration of the effectiveness of heart rate reduction

The direct effect of active substances on heart rate (FRQ) was tested in spontaneously quenching, isolated, right atriums of male Pirbright-white guinea pigs weighing 250-300 g. In the following Table B, the concentration in / mole / l is reported as FRQ 75 at which the frequency is reduced to 75% of the initial value after administration of the substance for 20 minutes. The example numbers for the test substances in Table B refer to the following production examples.

Table B

Test Substance Efficiency Reducing Heart Rate Example no. effective concentration in μιηοΐ / l to achieve 75% FRQ

9

21 | 26 | 27 | 32 |

1.6

1.7

6.1

2.6

2.5

5.7

3.5

0.9

4.3 4.0

1.3

3.4

5.6

1.9 9.1

1.6 7.0

6.4 3.0

3.5

4.9

3. Demonstration of cytoprotective efficacy in vitro

Cytoprotective efficacy was tested on electrically irritated left atria of male Pirbright-white guinea pigs in nutrient solution. The animals weighed 250-300 g. Removing gases from the nutrient solution with nitrogen for 60 minutes induces temporary hypoxia. Hypoxia results in atrial contraction.

The integral of the contraction during hypoxia serves as a measure. The following Table C shows the effective concentration in / mole / l at which the contraction integral is reduced to 50% of the control value.

Table C

Test substance cytoprotective activity against Example no. hypoxia-induced contraction effective concentration in / mole / l

3.0

2.8

00:27

In in vitro experiments on isolated cardiac muscle cells, the compounds showed a cytoprotective effect against cytotoxic substances such as Veratridine or a combination of oligomycin and deoxiglucose.

In view of the efficacy described, the compounds of formula I are useful as heart medicaments for higher mammals, especially humans, for the treatment of ischemic conditions such as e.g. coronary heart disease and their consequences such as e.g. cardiac insufficiency. The dosages used may vary individually and will vary with the type of condition being treated, the substance employed and the form of administration. For example, parenteral formulations will generally contain less active ingredient than oral formulations. In general, however, forms of medicaments with an active ingredient content of 1 to 200 mg per single dose are suitable for administration to higher mammals, in particular humans.

As a medicament, the compounds of formula I may be formulated with conventional pharmaceutical excipients into galenic formulations such as e.g. tablets, capsules, lace or solutions. These galenic formulations can be made by known methods using conventional solid or liquid carriers such as e.g. milk sugar, starch or talc or liquid paraffins and / or using conventional pharmaceutical auxiliaries, for example tablet disintegrating agents, solubilizers or preservatives.

The following examples illustrate the invention without limiting it in any way.

The structures of the novel compounds were confirmed by spectroscopic analyzes, in particular by NMR, mass, IR- or UV spectra.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- {3- [N- (2- (3,4-Dimethoxyphenyl) ethyl) -N-methylamino] propyl] -5 (3,4-dimethoxyphenyl) pyrazole

(A) To 100 ml of a 21% solution of sodium methylate in ethanol (=

I) 32 ml of ethyl acetate were added dropwise under ice-cooling. After 20 minutes, 75 ml of a solution of 50 g of 3,4-dimethoxibenzoyl chloride in 150 ml of tetrahydrofuran (= solution II) is added dropwise to the reaction solution. Thereafter, solutions I and II in successive amounts were added dropwise alternately after 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 are filtered off,. They were washed with tetrahydrofuran and then transferred to water. Acidification of the aqueous mixture to pH 1 takes place during ice-cooling, followed by extraction with methyl tertiary butyl ether. The extract was dried to dryness to give 45 g of 2-acetyl-2- (3,4-dimethoxibenzoyl) -acetic acid ethyl ester as a yellow oil.

B) 45 g of the product obtained in A) are boiled in 197 ml of aqueous ethanol and 0.72 g of sodium acetate is added at reflux temperature. The reaction mixture was then evaporated three times after addition of ethanol to dryness. The residue was dissolved in dichloromethane and dried over sodium sulfate. The solution was then evaporated to dryness to give 33 g of 3,4-dimethoxibenzoylacetic acid ethyl ester as a yellow oil.

C) 33 g of the product obtained above are taken up in 250 ml of ethanol and 10 ml of hydrazine hydrate are added dropwise to the reaction mixture under ice-cooling. After standing for 16 hours at room temperature, the crystalline reaction product is filtered off, washed with isopropanol and allowed to dry. 24 g of 5- (3,4-dimethoxy-phenyl) -pyrazolin-3-one are obtained.

D) 29 ml of 1-bromo-3-chloropropane are dissolved in 300 ml of dimethylformamide and added to a solution of 24 g of potassium carbonate. A solution of 18 g of 2- (3,4-dimethoxy-phenyl) -ethyl-N-methyl-amine in 50 ml of dimethylformamide was added dropwise with stirring to the reaction mixture over 2 hours. The reaction mixture was stirred for a further 2 hours. The salts formed are then filtered off. The filtrate is evaporated at a bath temperature of 50 ° C and the residue is dissolved in 200 ml of 0.5 M citric acid solution and the solution is extracted with tert-butyl methyl ether to remove unreacted ⁸ bromochloropropane. The aqueous phase is then easily basified by the addition of sodium bicarbonate and extracted several times with ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulphate and evaporated. 21 g of 3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylamino] -propyl chloride are obtained as a residue.

E) 17 g of 5- (3,4-dimethoxy-phenyl) -pyrazolin-3-one are dissolved in 200 ml of dimethylformamide. To the solution was added 11 g of potassium carbonate and the reaction mixture was heated at 100 ° C for 0.5 h under a nitrogen atmosphere. A solution of 21 g is then added dropwise

3- N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -N-methylamino] -propyl chloride in 150 ml of dimethylformamide. After 2 hours, the salts formed are filtered off, the filtrate is evaporated to dryness and the residue is dissolved in ethyl acetate. The solution was then washed with 7% aqueous sodium hydroxide solution to remove unreacted 5 (3,5-dimethoxyphenyl) pyrazolin-3-one, dried with sodium sulfate and evaporated to dryness. 35 g of oily crude product are obtained as a residue. This was purified by chromatography on fine-grained silica gel under slightly increased pressure (Flash Chromatography) using 10: 1 tert-butyl methyl ether / methanol as eluent. 22.3 g of the title compound are obtained as an oil.

IR spectrum of a base (film): 1523 cmp ^"1, 1260 ^cm-1, 1236 cm" ^first

To form the salt, 2.6 g of the above oily title compound are dissolved in isopropanol, this solution is mixed with 3.7 ml of isopropanolic 2 N hydrochloric acid solution and the reaction mixture is evaporated to dryness under reduced pressure. The salt which remains is recrystallized from isopropanol and dried at 80 ° C under high vacuum. 2.1 g of 3- {3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylamino] -propyloxyl} -5- (3,4-dimethoxy-phenyl) -pyrazole hydrochloride are obtained, mp 189-192 ° C.

Example 2

3- {3- / N- (3,4-Dimetoxifenyl) ethyl) -N-methylamino / propyloxy} -5- (3,4-dimetoxifenyl) pyrazole

1.31 g of triphenylphosphine are dissolved in 15 ml of tetrahyfrofuran. 1.6 ml of a solution of 0.8 ml of ethyl azodicarboxilic acid in 0.8 ml of toluene is added dropwise to the solution at 5 ° C. After 5 minutes, a solution of 1.1 g of 5- (3,4-dimethoxy-phenyl) -pyrazolin-3-one in 10 ml of dimethylformamide was added dropwise. After 20 minutes, a solution of 1.26 g of 3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylamino] -propanol in 10 ml of tetrahyrofuran was added dropwise. The reaction mixture is then stirred at C.C for 48 hours. The reaction mixture was then evaporated to dryness. The crude product obtained is purified by flash chromatography as described in Example 1. 1.14 g of the title compound is obtained as an oil base. This was converted by the method described in Example 1 (E) to the hydrochloride having a melting point of 189-192 ° C.

Example 3

3 - {/ N- (2- (3,4-Dimetoxifenyl) ethyl) -piperidin-3-yl / methoxy} -5- (3,4-dimetoxifenyl) pyrazole

A) A mixture of 5.75 g of 3- (hydroximethyl) -piperidine, 13.8 ml of triethylamine and 10 g of 2- (3,4-dimethoxy-phenyl) -ethyl chloride was heated under reflux for 4 hours. After cooling, the reaction mixture was acidified with about 30 ml of an aqueous solution of 2N hydrochloric acid and the unreacted 2- (3,4-dimethoxy-phenyl) -ethyl chloride was separated by extraction with tert-butyl methyl ether. The aqueous phase is then made alkaline by addition of sodium hydroxide solution and extracted with dichloromethane. The organic phase was separated, dried and evaporated. 5.3 g of N- [2- (3,4-dimethoxy-phenyl) -ethyl] -3- (hydroximethyl) -piperidine are obtained.

B) 5.3 g of the product obtained above were dissolved in 70 ml of dichloromethane, to which 0.1 ml of dimethylformamide was added, and the solution was mixed with 5 ml of thionyl chloride. The reaction mixture was stirred at room temperature for 12 hours, evaporated and evaporated twice with toluene. The residue was dissolved in a mixture of sodium carbonate solution and ethyl acetate. The organic phase was separated, dried over sodium sulfate and evaporated. 6.6 g of N- [2- (3,4-dimethoxy-phenyl) -ethyl] -3- (chloromethyl) -piperidine are obtained as a residue.

C) 6.6 g of the product obtained are reacted with 4.4 g of 5- (3,4-dimethoxyphenyl) -pyrazolin-3-one by the method described in Example 1 (E). The title compound is purified as described in Example 1 (E). 4.1 g of the title compound are obtained in base form.

For salt formation, 4.1 g of the title compound is dissolved in ethanol and mixed with a solution of 1.07 g of oxalic acid in ethanol. 3.4 g of 3 - {[N- (2- (3,4-dimethoxy-phenyl) -ethyl) -piperidin-3-yl] -methoxy] -5- (3,4-dimethoxy-phenyl) -pyrazole monohydrooxalate, m.p. 147-150 ° C.

Example 4

3- {3- [N- (2- (3-Methylphenyl) -ethyl) -N-methylamino] -propyloxy} -2-methyl-5- (2-fluorophenyl) -pyrazole

A) To a solution of 100 g of 2-fluorobenzoylacetic acid ethyl ester in 400 ml of ethanol was added dropwise 32 g of methylhydrazine with ice-cooling. After the reaction is complete, the reaction mixture is allowed to stand at room temperature for 2 days. The crystallized 2-methyl-5- (2-fluorophenyl) pyrazolin-3-one is then filtered off.

B) 5 g of the product obtained above are dissolved in 60 ml of dimethylformamide. 0.86 g of sodium hydroxide (as an 80% solution in paraffin) was added to the solution, and the reaction mixture was stirred at 80 ° C for one hour. It was then cooled to room temperature and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated, the residue was taken up in water and extracted with diethyl ether. The ethereal solution was separated and purified by flash chromatography over silica gel. 4.8 g of 3- (3-chloropropyloxy) -2-methyl-5- (2-fluorophenyl) pyrazole are obtained.

C) 2.4 g of the product obtained and 1.5 g of N-methyl-2- (3-methylphenyl) ethylamine are dissolved in 75 ml of dimethylformamide. 2.5 g of finely ground, anhydrous potassium carbonate are added to the solution. The reaction mixture was stirred at a bath temperature of 100 ° C for 11 hours. The mixture was evaporated and the reaction product was extracted with ethyl acetate. The organic phase was separated and extracted twice

M citric acid solution. The aqueous solution of the product in citric acid was then basified by the addition of sodium carbonate and the reaction product was extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulphate and evaporated. 1.0 g of the title compound is obtained as an oil base.

IR spectrum of the base (as a film): 1555 cm ^-1 , 1508 cm ^-1 ,

64 cm ^-1 .

To form the salt, 0.9 g of the title compound is dissolved in ethanol, a molar amount of L - (+) - tartaric acid is added and evaporated. 1.25 g of 3- {3- [N- (2- (3-methylphenyl) -ethyl) -N-methylamino] -propyloxi} -2-methyl-5- (2-fluorophenyl) -pyrazole x 1,1hyrotartrate is obtained as an amorphous solid. material.

Example 5

3- {3- [N- (2- (4-Nitrophenyl) ethyl) -N-methylamino] propyl} -5- (2-fluorophenyl) -2-methylpyrazole

A) 260 ml of 1-bromo-3-chloropropane are dissolved in 400 ml of acetone. 230 g of potassium carbonate are 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 over 30 minutes at a bath temperature of 40 ° C. The reaction mixture was then stirred at 40 ° C for 4 hours. The precipitated salts are then filtered off. The filtrate was evaporated at 40 ° C under reduced pressure. The residue was acidified with 16% hydrochloric acid solution to pH 1 and washed 3 times with tertiary butyl methyl ether to remove unreacted 1-bromo-3-chloropropane. The aqueous phase is then adjusted to pH 8 by addition of 16% aqueous sodium hydroxide solution and extracted several times with ethyl acetate. The combined ethyl acetate phases are dried over magnesium sulfate and evaporated. 71 g of 3- (N-benzyl-N-methylamino) -propyl chloride are obtained.

B) 3.3 g of 2-methyl-5- (2-fluorophenyl) -pyrazolin-3-one are dissolved in 50 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone. 0.55 g of sodium hydroxide (as an 80% solution in paraffin) was added to the solution, and the reaction mixture was stirred for 30 minutes. 3.3 g of 3- (N-benzyl-N-methylamino) -propyl chloride are added to the reaction mixture and stirred for a further 2 hours at 80 ° C. After cooling, 10 ml of isopropanolic solution were added to the reaction mixture

N hydrochloric acid and the mixture is then added dropwise to 2 liters of a 1: 3 mixture of acetone and tertiary butyl methyl ether. The precipitate formed is filtered off and dissolved in a mixture of saturated aqueous sodium carbonate solution and ethyl acetate. The organic phase is separated and the aqueous phase is extracted several times with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and evaporated. The crude base obtained is purified by chromatography on silica gel. 4.4 g of 3- [3- (N-benzyl-N-methylamino) -propyloxy] -2-methyl-5- (2-fluorophenyl) -pyrazole are obtained.

C) 4.4 g of the above product are dissolved in aqueous methanol. The solution was acidified with hydrochloric acid. A catalytic amount of palladium on carbon was then added and the reaction mixture was hydrogenated with hydrogen at 6 bar pressure for 24 hours at room temperature. Then the catalyst is filtered off, the filtrate is evaporated under reduced pressure. The residue was dissolved in a mixture of saturated sodium carbonate solution and ethyl acetate. The organic phase is separated and the aqueous phase is extracted several times with ethyl acetate. The combined ethyl acetate phases are dried and evaporated. 3.2 g of 3- [3- (N-methylamino) -propyloxy] -2-methyl-5- (2-fluorophenyl) -pyrazole are obtained.

D) 3.1 g of the product obtained above are dissolved in 30 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone. To the solution was added 3 g of potassium carbonate, and the reaction mixture was stirred at 80 ° C for 30 minutes. Then 2.5 g of 2- (4-nitrophenyl) ethyl bromide is added, the reaction mixture is stirred for 5 hours at 50 ° C, then 0.25 g of 2- (4-nitrophenyl) ethyl bromide is added once more and stirred for another 13 hours at 80 ° C. ° C The reaction mixture is then worked up as described in Example 5 B). 2.6 g of the title compound are obtained as an oil base.

IR spectrum (as film): 1555 cm ^-1 , 1515 cm ^-1 , 1345 cm ^-1 .

The main compound is then converted to its hydrotartrate as described in Example 4 (C). 3.54 g of the title compound monohydrate is obtained as an amorphous solid.

Example 6

3- {3- / N- (3,4-dimethylbenzyl) -N-methylamino / 2-hydroxipropyloxi} -5- (2-fluorophenyl) -2-methylpyrazole

A) 50 g of 3,4-dimethylbenzoic acid are mixed with 78 g of thionyl chloride and the reaction mixture is heated at reflux temperature for 3 hours. The reaction mixture was evaporated and the residue was taken up in toluene twice and evaporated again. 53 g are obtained

3,4-dimethylbenzoyl chloride.

B) 108 ml of a 40% aqueous methylamine solution was dissolved in 300 ml of tetrahydrofuran. 53 g of 3,4-dimethylbenzoyl chloride are added dropwise to this solution under ice-cooling. The reaction mixture was then stirred at room temperature for 1 hour. Then, the reaction mixture was evaporated to half volume under reduced pressure and treated with saturated sodium chloride solution and acidified with concentrated hydrochloric acid. The precipitated extract is filtered off with suction and dried in a drying oven at 40 ° C over potassium hydroxide. 47 g of N-methyl-3,4-dimethylbenzamide are obtained.

C) 6.4 g of lithium aluminum hydride are placed in 200 ml of tetrahydrofuran and heated to boiling. A solution of 25 g of the amide prepared according to B) was added dropwise over one hour and the reaction mixture was heated under reflux for a further 3 hours. The reaction mixture was then stirred to remove excess lithium aluminum hydride with aqueous sodium hydroxide solution and diluted with water and ethyl acetate. The precipitated salts are filtered off, the organic phase is separated and dried over magnesium sulphate and evaporated. 22.55 g of N-methyl- (3,4-dimethylbenzyl) -amine is obtained.

(D) 10 g of the product obtained and 0.2 ml of water are added dropwise at 28 ° C to 5.25 ml of epichlorohydrin. The reaction mixture is stirred at about 30 ° C for 5 hours. After cooling to room temperature, a 60% aqueous sodium hydroxide solution was added dropwise to the reaction mixture, and then stirred for an additional 40 minutes. For working-up, the reaction mixture is poured into 26 ml of water. The resulting oil was separated and dried with potassium hydroxide. The aqueous phase is extracted with ethyl acetate, the ethyl acetate is dried, evaporated and the residual oil is combined with the bulk of the oil. separated as the main product. A total of 11.3 g of 2- [N- (3,4-dimethylbenzyl) -N-methylaminomethyl] oxirane is obtained.

E) 500 mg of 5- (2-fluorophenyl) -2-methylpyrazol-3-one is mixed with 360 mg of anhydrous potassium carbonate at 100 ° C in 10 ml of diphenylformamide for 15 minutes. After cooling the reaction mixture to 60 ° C, 535 mg of the oxirane obtained in D) are added. The reaction mixture is then stirred for 8 hours at 100 ° C. For working up, the reaction mixture was evaporated, the residue was taken up in water and extracted with ethyl acetate. The organic phase was separated and evaporated. The crude product obtained as a residue was purified by flash chromatography. 0.11 g of the title compound is obtained as an oil phase.

IR spectrum (as film): 1556 cm ^-1 , 1462 cm ^-1 , 754 cm ^-1 .

To form the base, 320 mg of the obtained main base was dissolved in ethanol / ethyl acetate 1: 1 and the solution was mixed with a molar amount of fumaric acid. The reaction mixture is evaporated to dryness and the salt obtained is dried at 50 ° C. 540 mg of 3- {3- [N- (3,441 dimethylbenzyl) -N-methylamino] -2-hydroxypropyl-oxo} -5- (2-fluorophenyl) 2-methylpyrazole monohydrofumarate is obtained as an amorphous solid.

Example 7

3- {2- [N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -N-methylamino] -1,1-dimethylethoxy] -5- (3,4-dimethoxy-phenyl) -pyrazole

A) 8.8 g of 5- (3,4-dimethoxy-phenyl) -pyrazolin-3-one are dissolved in 50 ml of dimethylformamide and mixed with 5.5 g of potassium carbonate. The reaction mixture was heated under nitrogen at 100 ° C for 0.5 hour. Then 8.9 g of 2-bromo-2-methylpropionecarboxylic acid in the form of ethyl ester are added dropwise at 80 ° C. Stir for 1 hour at 80 ° C, cool and filter out the precipitated salt. The filtrate was evaporated under vacuum and the residue was dissolved in tertiary butyl methyl ether. After insoluble matter was filtered off, it was washed with saturated sodium chloride solution and evaporated. 10 g of 3- (2-ethoxycarbonylpropyl-2-oxi) -5 (3,4-dimethoxyphenyl) pyrazole are obtained as an oil.

B) 10 g of the product obtained are dissolved in a mixture of 20 ml of 20% sodium hydroxide and 40 ml of ethanol and the reaction mixture is heated under reflux for 2 hours. After cooling, the pH was adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was extracted several times with tertiary butyl methyl ether. The combined extracts were dried (MgSO4) and evaporated. 9 g of 3- (2-hydroxycarbonylpropyl-2-oxi) -5- (3,4-dimethoxiphenyl) pyrazole are obtained.

C) 5 g of the product obtained are slurried in dichloromethane at room temperature with 4.5 ml of triethylamine, cooled to -30 ° C and mixed with 1.28 ml of methanesulfonic acid chloride. The reaction mixture is stirred at -30 ° C for 1 hour, then a spatula tip of pyrrolidino pyridine is added to the tip and warmed to room temperature. After 12 hours, dilute with dichloromethane. After removal of the basic portions by extraction with sodium chloride solution in acetic acid, the organic phase is washed with concentrated sodium bicarbonate solution, free of acid, dried over sodium sulphate and evaporated. 3.7 g of 2,2-dimethyl-6- (3,4-dimethoxy-phenyl) -pyrazolo (5,1) -oxazole are obtained. Melting point 120-130 ° C.

D) 3.5 g of the product obtained and 4.2 g of N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine are dissolved in diglyme and heated at 150 ° C under nitrogen for 2 h. After cooling, it is diluted with tertiary methylbutyl ether, the base is separated with a solution of sodium chloride in acetic acid and then washed with a saturated solution of soda to remove the acid. The organic phase is dried over magnesium sulphate and evaporated. 6 g of 3- {2- [N- (2 (3,4-dimethoxyphenyl) ethyl) -N-methylaminocarbonyl] -propyl-2-oxo} -5- (3,4-dimethoxyphenyl) pyrazole are obtained.

E) A solution of 6 g of the obtained product in dry tetrahydrofuran was added dropwise to 20 ml of a solution of (1 molar) lithium aluminum hydride in tetrahydrofuran. The reaction mixture was heated at reflux for 2 hours. Under ice-cooling, 0.57 ml of water, 0.75 ml of 15% sodium hydroxide solution and one additional 2.5 ml of water are then added successively. The precipitated aluminum hydroxide was filtered off and the filtrate was evaporated. The residue was dissolved in 1 M aqueous citric acid solution. The solution was washed with ethyl acetate. The citric acid solution was then separated, basified by addition of aqueous sodium carbonate solution, and the reaction product was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated. 4.1 g of crude product are obtained, which product is purified by chromatography on silica gel. It will be obtained

2.7 g of the title compound as an oil phase.

IR spectrum (as film): 1512 cm ^-1 , 1464 cm ^-1 , 1261 cm ^-1 .

The main compound is then reacted according to the method described in Example 4 (C) to form a salt with a molar amount of L - (+) - tartaric acid. 3.56 g of 3- {2- / N (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylamino / -1,1-dimethylethoxy} -5- (3,4-dimethoxy-phenyl) -pyrazole x 1 are obtained. 2-hydrotartrate as an amorphous solid.

Example 8

3- {6- / N- (2- (3,4-Dimetoxifenyl) ethyl) -N-methylamino / hexyloxy} -5- (3,4-dimetoxifenyl) pyrazole

A) 10 ml of 6-bromohexanoyl chloride were dissolved in a mixture of 100 ml of absolute dichloromethane and 100 ml of absolute toluene. A solution of 13.6 g of N-methyl-N- [2- (3,4-dimethoxy-phenyl) -ethyl] -amine and 9.5 ml of triethylamine in 25 ml of absolute toluene is added dropwise to the solution under ice-cooling. The reaction mixture was then stirred at room temperature for 12 hours. The precipitated salts are filtered off and washed with toluene. The filtrate was washed with 1 molar citric acid solution and then with sodium bicarbonate solution, dried with magnesium sulfate and evaporated. 19.3 g of 5- {N- [2- (3,4-dimethoxy-phenyl) -ethyl] -N-methylaminocarbonyl} -pentyl bromide are obtained as an oil.

B) 3.85 g of 5- (3,4-dimethoxy-phenyl) -pyrazolin-3-one is dissolved in 50 ml of aqueous dimethylformamide. 3.15 g of finely ground potassium carbonate are added to the solution, and the reaction mixture is heated to 100 ° C under stirring under nitrogen. A solution of 5.6 g of 5-N- [2- (3,4-dimethoxy-phenyl) -ethyl] -N-methylaminocarbonyl) -pentyl bromide in 10 ml of anhydrous dimethylformamide (slowly) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 100 'for a further 2 hours. C. After cooling, the precipitated salts are filtered off and the filtrate is evaporated. The oily residue was dissolved in ethyl acetate and washed with sodium hydroxide solution to remove unreacted 5- (3,4-dimethoxy-1,4-phenyl) -pyrazolin-3-one. The organic phase was separated and dried with sodium sulfate and evaporated. 6.5 g of 3- {5- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylaminocarbonyl] -pentyloxy} -5- (3,4-dimethoxy-phenyl) -pyrazole are obtained as an oil.

C) 6.5 g of the product obtained above are reduced with lithium aluminum hydride according to the method described in Example 7 B). The reaction mixture is then worked up as described in Example 7E). 2.5 g of the title compound are obtained as an oil base.

IR spectrum (as film): 1509 cm ^-1 , 1465 cm ^-1 , 1261 cm ^-1 .

The main compound is then reacted to form a salt by the method described in Example 4 (C) with a molar amount of L - (+) - tartaric acid. 3.25 g of 3- {6- [N- (2- (3,4-dimethoxiphenyl) ethyl) -N-methylamino] -hexyloxi} -5- (3,4-dimethoxiphenyl) pyrazole x 1,1-hydrotartrate is obtained. as an amorphous solid.

Example 9

3- {2- / N- (2- (4-Chloro-phenyl) -ethyl) -N-methylamino / -ethyl-oxo} -5- (4-hydroxy-phenyl) -2-methyl-pyrazole

1.8 g of 3- {2- / N- (2- (4-chlorophenyl) ethyl) -N-methylamino / ethyloxyl} -5- (4-methoxyphenyl) -2-methylpyrazole (see Example 24) are dissolved in 100 ml dichloromethane. The solution was mixed with 10 ml of a 1 molar solution of bromide boron in dichloromethane. The reaction mixture was allowed to stand for 12 hours, then water was added and extracted with dichloromethane. The aqueous phase was separated, basified, extracted three times with a mixture of dichloromethane and methanol, and the combined organic phases were dried and evaporated. The crude title compound obtained as an oil was purified by chromatography on silica gel using dichloromethane / methanol. For salt formation, the purified title compound is reacted with a molar amount of L - (+) - tartaric acid by the method described in Example 4 (C) and the salt obtained is crystallized from a mixture of diethyl ether and isopropanol. 1.15 g of 3- {2- [N- (2- (4-chlorophenyl) ethyl) -N-methylamino] -ethyl-oxo} -5- (4-hydroxyphenyl) -2-methylpyrazole x 1,3-hydrotartrate is obtained, m.p. 90-91 ° C.

Example 10

3- {2- / N- (2- (4-chlorophenyl) ethyl) -N-methylamino / ethyloxy} -5- (4acetoxifenyl) -2-methylpyrazole

100 mg of 3- {2- / N- (2- (4-chlorophenyl) ethyl) -N-methylamino / ethyloxi} -5- (4-hydroxyphenyl) -2-methylpyrazole (see Example 9) are dissolved in 2 ml of dichloromethane. To the solution was added 0.15 mL of pyridine and 1 mL of acetic anhydride, and the reaction mixture was stirred at room temperature for 24 hours. Then, the reaction mixture was evaporated under reduced pressure, the residue was taken up in aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated, dried and evaporated. The title compound obtained as a residue is taken up in tertiary butyl methyl ether. A 2 N isopropanolic hydrochloric acid solution was added to form the salt. The precipitated salt is separated. 80 mg of the hydrochloride of the main compound having a melting point of 160-175 ° C is obtained.

Example 11

3- {3- [N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propyloxy} -2-benzyl-5- (3,4-dimethoxy-phenyl) -pyrazole

A) 6.6 g of 3,4-dimethoxibenzoylacetic acid ethyl ester are slurried in ethanol and mixed with 3.5 g of benzylhydrazine added dropwise over 1.5 hours under ice-cooling. The reaction mixture was stirred at room temperature for 12 hours. The precipitated product is filtered off and washed first with ethanol, then with tertiary butyl methyl ether. 4.36 g of 5- (3,4-dimethoxiphenyl) -2-benzylpyrazolin-3-one are obtained, m.p. 164-166 ° C.

B) 5.5 g of the product are dissolved in 50 ml of dimethylformamide. The solution is mixed with 0.5 g of sodium hydride and stirred for 0.5 hour at 80 ° C under a nitrogen atmosphere. Then 1.97 ml of 1-bromo-3-chloropropane was added dropwise at room temperature and the reaction mixture was stirred for 14 hours. The reaction mixture was then evaporated under reduced pressure, taken up in tert-butyl methyl ether and the insoluble residue was filtered off. The filtrate was evaporated and purified by chromatography over fine-grained silica gel under slightly increased pressure (= flash chromatography). 7 g of 3- (3-chloro-propyloxy) -5- (3,4-dimethoxy-phenyl) -2-benzyl-pyrazole are obtained.

C) 6 g of the product obtained and 7 g of homoveratrylamine are dissolved in 20 ml of dimethylformamide, mixed with 10 ml of triethylamine and heated at 120 ° C for 4 hours. The reaction mixture was evaporated, taken up in ethyl acetate and extracted with 2M citric acid. The aqueous solution of the product in citric acid was then basified by the addition of sodium bicarbonate and the reaction product was extracted with ethyl acetate. The extract is purified by chromatography over fine-grained silica gel under slightly increased pressure (= flash chromatography). 4.9 g of 3 {3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyloxy} -2-benzyl-5- (3,4-dimethoxy-phenyl) -pyrazole are obtained.

IR spectrum (as a film): 1524 cm ^{@ -1} , 1260 cm @ ^-1 , 1236 cm @ ^-1 .

Example 12

3- {3- / N- (2- (3,4-Dimetoxifenyl) ethyl) amino / propyloxy} -5- (3,4dimetoxifenyl) pyrazole

4.9 g of 3- {3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyloxy} -2-benzyl-5- (3,4-dimethoxy-phenyl) -pyrazole is dissolved in glacial acid acetic acid, mixed with 0.5 g of palladium on carbon and hydrogenated for 24 hours under a hydrogen pressure of 80 bar and at 80 ° C. After filtering off the catalyst, it is evaporated, basified with sodium hydroxide (pH = 10) and the product is extracted with ethyl acetate. The organic phase was separated, evaporated and purified by flash chromatography over silica gel. 1.1 g of 3- {3- [N- (3,4-dimethoxy-phenyl) -ethyl] -amino] -propyloxyl} -5- (3,4-dimethoxy-phenyl) -pyrazole are obtained. IR spectrum (as a film): 1511 cm ^{@ -1} , 1465 cm ^{@ 4} , 1262 cm ^{@ -1} .

For salt formation, 1.1 g of the title compound was dissolved in ethanol, mixed with a molar amount of L - (+) tartaric acid and evaporated. 1.46 g of 3- {3- [N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propyloxy} -5- (3,4-dimethoxiphenyl) -pyrazole monohydrotartrate is obtained as an amorphous solid.

Example 13

3- {3- / N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -N-methylamino / -propyloxyl} -5 (3,4-dimethoxy-phenyl) -2-benzyl-pyrazole

A) 5 g of 5- (3,4-dimethoxy-phenyl) -pyrazolin-3-one (for preparation see Example 1C) are stirred in 100 ml of toluene. To the mixture is added dropwise first 3 ml of collidine and then 3.6 ml of benzyl bromide. After heating at reflux for 6 hours, the precipitated crystals are filtered off and washed with isopropanol, then with 2 M citric acid. The organic phase is dried over magnesium sulphate and evaporated. Purified by recrystallization from isopropanol. 4 g of 5- (3,4-dimethoxy-phenyl) -2-benzyl-pyrazolin-3-one are obtained, having a melting point of 165 ° C.

B) 62 g of the product are dissolved in 500 ml of dimethylformamide. 31 g of potassium carbonate are added to the solution and the reaction mixture is heated at 100 C for 0.5 h. After dropwise addition of a solution of 56 g of 3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylamino] -propyl chloride in 70 ml of dimethylformamide, the solution is heated at 100 DEG C. for a further 4 hours. The precipitated salts are filtered off and the filtrate is evaporated to dryness. The residue is taken up in 350 ml of 0.75 N hydrochloric acid and extracted with ethyl acetate. The aqueous phase was made basic by the addition of aqueous sodium hydroxide and extracted with ethyl acetate. After drying and evaporation of the organic phase, the crude product obtained is purified by flash chromatography. 68 g of 3- {3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methylamino] -propyl-oxo} -5- (3,4-dimethoxy-phenyl) -2-benzyl-pyrazole are obtained.

IR spectrum of a base (such as film) 1524 ^cm-1, 1260 ^cm-1 '1236 cm' ^first

7.1 g of the dissolved base in 100 ml of acetone are added dropwise

1.63 g of oxalic acid dihydrate, dissolved in 20 ml of acetone. The precipitated crystals are filtered off and dried. 7.7 g of 3- {3- / N- (2- (3,4-dimethoxyphenyl) ethyl) -N-methylamino / propyloxi} -5- (3,4-dimethoxiphenyl) -2-benzyl-pyrazole hydrooxalate are obtained. having a melting point of 135-137 ° C.

Example 14

3- {3- / N- (2- (3,4-Dimetoxifenyl) ethyl) -N-methylamino / propyloxy} -5- (3,4-dimetoxifenyl) pyrazole

A) 2.g 3- {3- / N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -N-methylamino / propyloxyl) -5- (3,4-dimethoxy-phenyl} -2-benzyl-pyrazole ( production (see Example 13) is dissolved in 10 ml of methanol and 2 g of palladium black are added under nitrogen, 5.5 ml of 98% formic acid are added to the stirred solution under a nitrogen atmosphere, after stirring for 3 hours under a nitrogen atmosphere. Saturated sodium carbonate solution was added to the oily residue and extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and evaporated to give 1.6 g of 3- {3- / N- (2- (3,4-dimethoxyphenyl) - ethyl) -N-methylamino / propyl-oxo} -5- (3,4-dimethoxy-phenyl) -pyrazole as an oily base, which was converted to the hydrochloride analogously to Example 1E). The resulting substance has a melting point of 189-192 ° C.

The compounds of formula I shown in the following table can be prepared by the methods described in the preceding examples. The IR-bands in cm ^-1 reported in the table are characteristic bands of IR spectra of the respective free bases (unless otherwise indicated as a film).

-μ '(d

- · ' H B at • « LO r4 f “· * WHAT r4 y— OJ what IN) • WHAT o m • cn 0 to The M id '(D ch Pl r-1 OJ O '·' S 04 m ej H 'ίΟ ώ S OJ • T “ H P OÍ. . it • CM H ? .. '·. . OJ · H .04 -to -m -WHAT cn y ta ¹⁰ C! E E ' " E- E T N ABOUT ch · «» at about «it <ľô ω «£ ï • J <O <·· 10 ^ω οί -in- .. m Am: am 1553, • h- X- 1- t- U- x - 1.1 (L <r T · to -j o £ ^ cc T n 1 04 the x X < * d xV ABOUT and n X about x Γ) * 04 X 0 1 x 0 1 n x 0 0 1 X 0 04 X 0 I x from 1 from « from 1 from 1 from 1 from 1 C - IN" OJ OJ OJ T " about 0 about D D D x x x 0 1 The M The about « about 1 -J 0 F 4-Cl CC y Tt x about about 0 D Γ x 0 x tO CC 3-Cl ABOUT what 0 1 WHAT from 4 0 T WHAT 0 1 WHAT D ‘D D x x x x tfl CC ABOUT about 1 0. F x ' x 0 1 CM ol 01 OJ * X X X x x x x o _n ABOUT D 0 D □ f x x about T 0 0 n QC about « x 4 4 x about y 0 ABOUT D ABOUT, D x X x x x ABOUT 1 WHAT about ABOUT 0 0 0 CC WHAT what ' WHAT WHAT M * • ^: M CM .i > u · it T · (ABOUT ▼ - h- WHAT cn about 04

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f-f 1 e at > 1 w "(Ti . and ·· P < (T) M S U C « N ABOUT · Pi -P • -P m σ> 'eo p. « P X ABOUT IR: 1670, 1514, 1327 T ± r- WHAT N- p r- i é x WHAT in- 1 ABOUT what w p * p X about σ> about IR: 1604, 1517, 1343 m 9> P; +4 · CO E (Those < I- in-' IR: 1513, 1463, 1265 WHAT about r * · P P x about T r-l. ABOUT · from e CTI < H OJ_ • r- OJ WHAT OJ t CD what in δ m i ' r-J about ώ e . "J < h in- r- CM ABOUT T about' what CM cm ' m Ύ- X en in in*- p *. ' P X ABOUT R-1 o · ČQ e CTI δ u. CM IR: 1518, 1464, 1262 about <73 » P · P X about in 1.1 TA: am IR: 1517, 1466, 1265 E (0 < H IR: 1511, 1465, 1262 J 1 TA: am IR: 1259, 1374, 1517, 1595 < 1 o> cm X about T r. x about 1 n X about 1 you x about ( (M * ci X about 1 n x about OJ x about « oi x about F ro OJ X about 1 o> x about 1 n cm x about 1 * r x about. « ' o> CM x about n x about 1 C7 CM X about 1 o> x ABOUT ( n w x about 1 about x about 1 about about· x about 1 r x about J o> 04 X about 1 M X about 1 about oi x about 1 x T r> CM x about 1 X — N r) x about from 1 from 1 'with-** from 1 from 1 from 1 from 1 'from 1 FROM 1 from 1 from 1 from 1 from 1 from 1 C OJ OJ OJ OJ OJ OJ OJ OJ CM CM CM CM OJ ABOUT about) T ABOUT 01 x ABOUT ABOUT 01 x ABOUT 01 x about T about X about about Ν ' M- in -N- The CC x X x X x X X X CJ about from C about from u_ ABOUT about n x about LL about about x about LL ABOUT n x about ABOUT n X ABOUT 1 about 01 x about 1 CC 4 x 1 in X M · 4 what what in WHAT WHAT WHAT m CC x x. · s x x X x X x X X X X x * CC x x x x X r) x υ x · x x X x X X, Z about about about about ABOUT ABOUT x T n x about 01 x o. x about 1 Tt x about x about 1 T 1 M- X M · M · Tt x x x x x x n CC already about 4 · x x about 01 x 9 what ó r M ¹ ABOUT, x ABOUT and WHAT about r » X ABOUT what x x already 9 • M- § 3 9 x % § ä • 1M · (M> U r- OJ -t g 5 m • e WHAT XF •in WHAT cn in about m in and CM and with

B — base, ol = oily, am — amorphous solid, TA = hydrotartrate, FU = hydrofumarate, OX = hydrooxalate,

Example I

Tablets containing 3-3- [N- (2- (3,4-dimethoxiphenyl) ethyl) -N-methylamino] -propyloxy-5- (3,4-dimethoxiphenyl) -pyrazole hydrochloride

Tablets of the following composition are made for one tablet:

3-3 / N- (2- (3,4-dimethoxiphenyl) -ethyl (-N-methylamino) -propyloxi-5- (3,4-dimethoxiphenyl) -pyrazole hydrochloride 20 mg corn starch 60 mg milk sugar 135 mg gelatin (as a 10% solution) 6 mg

The active substance, corn starch and milk sugar are covered with a 10% gelatin solution. The paste is crushed and the resulting granulate is applied to a suitable sheet and dried at 45 ° C. The dried granulate is passed through a crusher and mixed with other excipients in a blender:

talc 5 mg magnesium stearate 5 mg corn starch 9 mg and then compressed to 240 mg tablets.

Claims (11)

PATENT Compounds of formula (I) wherein n is an integer from 1 to 5, A is a group of the formula wherein R ¹ is hydrogen or a lower alkyl group and Q is a (CH ₂ ) _m group wherein m is 2 to 8 and which may optionally be substituted by 1 to 2 alkyl groups at the oxygen atom or 2hydroxipropylene chain, or A is b. (0 ') (b) wherein p is 4 to 6 and B is (CH ₂ ) _{r -} , wherein r is 1 to 3, and which may optionally be substituted by 1 to 2 lower alkyl groups at the position of the oxygen atom, R ² is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro, or when A contains no OHskupinu and R ^3, R ⁶ and R ⁷ are hydroxide, also lower alkanoyloxy, R ³ is hydrogen, halogen, lower alkyl, without alkoxy, 26 hydroxy, or when A contains no OH-group and R, R and R ⁷ are not hydrogen, also lower alkanoyloxy; R ² and R ³ are attached to two adjacent carbon atoms and together represent an alkylene dioxy group having 1 to 2 carbon atoms, R ⁴ is hydrogen or lower alkyl, R ⁵ is in the 1 or 2 position and is hydrogen, lower alkyl or phenyl lower alkyl, R ⁶ represents hydrogen, lower alkyl, lower alkyloxy, hydroxy, halogen, trifluoromethyl or nitro, or when A contains no OH-group and R ² , R ³ and R ⁷ are not hydroxides, also lower alkanoyloxy and R ⁷ is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, or when A contains no OH-group and R ² , R ³ and R ⁶ are not hydroxy, also lower alkanoyloxy, or R ⁶ and R ⁷ are attached to adjacent carbon atoms and together form a C 1 -C 2 alkylenedioxy group, as well as their physiologically acceptable acid addition salts. Compounds according to claim 1, wherein A represents a group of formula (a), wherein R ¹ represents lower alkyl or hydrogen and Q. represents (CH ₂ ) _{m -} , wherein m represents 2 to 6, or A represents a group of formula (b), where p is 5. Compounds according to any one of the preceding claims, wherein R ⁴ is hydrogen and R ⁵ is hydrogen, alkyl of 1 to 2 carbon atoms or benzyl. Compounds according to any one of the preceding claims, wherein n is 2 or 3. Compounds according to any one of the preceding claims, wherein n represents 2 or 3, A represents a group of formula (a), wherein R ¹ represents hydrogen or lower alkyl and Q represents (CH ₂ ) _m -group wherein m is 2 to 4, or A is a group of formula (b) wherein p is 5, R is hydrogen, lower alkoxy or hydroxy, R ³ is hydrogen or lower alkoxy, R ⁴ is hydrogen, R ⁵ is hydrogen or benzyl, R ⁶ is hydrogen, lower alkoxy, hydroxy or nitro and R ⁷ is hydrogen or lower alkoxy. Compounds according to claim 5, wherein n represents 2, A represents a group of formula (a), wherein R ¹ represents methyl or hydrogen, Q represents a (CH ₂ ) _m group wherein m represents 3 or 4, R represents methoxy or hydroxy, R is methoxy, R is hydrogen, R is hydrogen or benzyl, ^R6 is methoxy, hydrogen or hydroxy, and R ⁷ represents methoxy or hydrogen. 7. 3- {3- / N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -N-methylamino / propyloxi} -5- (3,4-dimethoxy-phenyl) -pyrazole, 3- {3- / N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -N-methylamino / -propyloxy} -5- (4-hydroxy-3-methoxy-phenyl) -pyrazole and their physiologically acceptable acid addition salts according to claim 6. 8. 3- {N- (2- (3,4-Dimethoxiphenyl) -ethyl) -piperidin-3-yl] -methoxy} 5- (3,4-dimethoxiphenyl) -pyrazole and its physiologically acceptable acid addition salts according to claim 5. A medicament comprising a pharmacologically effective amount of a compound of claim 1 and conventional farinceutic excipients and / or carriers. A process for the preparation of compounds of formula I wherein n is an integer from 1 to 5, A is a group of formula a R ¹ I - N -Q wherein R ¹ is hydrogen or lower alkyl and Q is (CH ₂ ) _B where m is 2 to 8 and which optionally may be substituted by 1 to 2 lower alkyl groups at the oxygen atom or 2hydroxipropylene chain, or A represents a group of formula b (B) wherein p is from 4 to 6 and B is (CH ₂ ) _r -group, wherein r is 1, and which may optionally be substituted at the position of the oxygen atom 1 to 2 lower alkyl groups, R ² is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, or nitro, or when A contains no OH-group and R ³ , R ⁶ and R ⁷ are not hydroxides, also lower alkanoyloxy and R ³ is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, or when A contains no OH-group and R ² , R ⁶ and R ⁷ are not hydroxy, also lower alkanoyloxy or R ² and R ³ are attached to two adjacent carbon atoms and together represent an alkylene dioxy group having 1 to 2 carbon atoms, R ⁴ is hydrogen or lower alkyl, R ⁵ is located at the 1 or 2-position and represents hydrogen, lower alkyl or phenyl-lower alkyl, R ⁶ is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl or nitro, when A contains no OH group and R ² , R ³ and R ⁷ are not hydroxy also lower alkanoyloxy and R ⁷ is hydrogen, lower alkyl, lower alkoxy, hydroxi or 23 halogen, or when A contains no OH-group and R, R and R ⁴ are not hydroxi, also lower alkanoyloxy or R ⁶ and R ⁷ are attached to two adjacent carbon atoms and together form a C 1 -C 2 alkylenedioxy group, as well as their physiologically acceptable acid addition salts, characterized in that: a) for the preparation of compounds of formula Ia (Ia) wherein R ⁴ , R ⁵ , A and n are as defined above for R ⁵ , R ³ , R ⁶ and R ⁷ alkanoylox, are combined of formula II and R ² ', R ³ ', R ⁶ 'and R ⁷ with the exception of lower (II) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ are as defined above, but optionally free hydroxyl groups are protected with a hydroxy protecting group, react with compounds of formula III (III) wherein R ² f R ³ , A is as defined above, but all free hydroxy groups optionally present are protected with a hydroxy protecting group and X is a leaving group leaving a leaving group, and optionally protecting groups ydroxy is cleaved off again, or (b) for the preparation of the compounds of formula Ib <1, the meaning given for A, with the exception of the OH-containing radical, the compounds of formula II are reacted with triphenylphosphine in the presence of azodicarboxilic acid esters of formula XVIII R ¹⁰ OOC - N = N - COOR ¹¹ (XVIII) wherein R ¹⁰ and R ¹¹ are lower alkyl and the reaction product is reacted with compounds of formula IV (IV) wherein R ² , R ³ , to A are as defined above, however, all of the free NH groups in residue A are protected with an amino protecting group and the free hydroxy groups are protected with hydroxy protecting groups, and then the amino or hydroxy protecting groups present are cleaved again, or ... the text in which R ¹ , R is missing ² , R ³ , R ⁴ , R ⁶ , R ⁷ , Q and n are as defined above and R ⁵ is as previously defined for R ⁵ , however, when the chain length m is Q = 3, R ⁵ is lower alkyl; or a phenyl lower alkyl group located on a nitrogen atom adjacent to an oxygen atom is a compound of formula V (V) wherein R ¹ , R ² , R ³ and n are as defined above, but hydroxy groups present are provided with a protecting group for are reacted with compounds of formula VI (VI) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and Q are as defined above, but all free hydroxy groups are protected with a hydroxy protecting group and Y is an aminolytically cleavable group, and then the protective groups present are hydrolytically cleaved again, or d) for the preparation of compounds of formula Ia, the compound of formula VII * 2 n (VII) wherein R ^2, R ^3, the Y are as defined above, with all the remaining free hydroxislupiny protected by protective groups for the hydroxy groups, are reacted with compounds of formula VIII (VIII) Where R ⁴ , R ⁵ , R ⁶ , R ⁷ and A are as defined above, the free hydroxy groups are protected with a hydroxy protecting group and then the hydroxy protecting groups present are cleaved off again, or e) for the preparation of compounds of formula Id wherein R ^1, R ² _y R ^3, R ^4, R ^5, R ^6, R ⁷ and n are as defined above, compounds of formula IX (IX) wherein R ^4, R ^6, and R ⁷ are as defined above, but optionally free hydroxyl groups are protected with a hydroxy protecting group, Z is hydrogen or a 2,3-epoxipropyl radical, and R ⁵ is a lower alkyl or phenyl-lower alkyl group located on a nitrogen atom adjacent to the atom of the pyrazole ring oxygen or, when Z is hydrogen, has the meaning given for R ⁵ , reacted with compounds of formula X Wherein R, R, R, and n are as defined above, but wherein all free hydroxy groups are protected with a hydroxy protecting group, and Z is a 2,3-epoxipropyl radical when Z is hydrogen or Z is hydrogen, when Z is a 2,3-epoxipropyl radical, and then optionally present hydroxy protecting groups are cleaved, or f) for the preparation of compounds of formula Ie (Ie) wherein R ¹ , R ³ ', R ⁴ , R ⁵ , R ⁷ ' and n are as defined for alkanoyloxi, and Q represents «2 * 6 are as defined above, R, RR ² and R * with the exception of nitro and lower (CH ₂ ) n - a group wherein m is 1 to 7 and which is optionally substituted by 1 to 2 lower alkyl groups at the position of the oxygen atom with compounds of formula XI wherein R, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ on Q are as defined above, but all free hydroxy groups are protected with a hydroxy protecting group and R ¹ is lower alkyl or an amino protecting group are reduced and then any protecting groups present for amino and / or hydroxy groups, cleavage again, or g) for the preparation of compounds of the general formula If) wherein R ⁴ , on A are as defined above, R ⁵ has the meaning given for R ⁵ , but R ^{5 is} not benzyl if the residue A contains an NH group and R ² , R ³ have the meanings given for R, R, R and R with the exception of hydroxi, but at least one of R, R, R and R is lower alkanoyloxy, in compounds of formula XII (XII) where R ⁴ is as defined above R ^2IV , R ³ , R ^6IV and R ⁷ are as defined for R, R, R and R with the exception of lower alkanoyloxy, but at least one of R ^2IV , R ³ , R ^6IV and R ⁷ is hydroxy, R ^SIV is lower alkyl or phenyl lower alkyl and A is as defined for A, but the NH group present in residue A is protected with a benzyl protecting group, the free hydroxyl groups R, R, R and / or R are acylated and then the optional benzyl protecting group is again it splits off and falls in the wall twisted compounds of formula I, wherein R, R, R and / or R is metoxiskupinu, of which releases the hydroxyl group of and / or optionally the resulting compound of formula I, wherein R ⁵ is benzyl, cleavage of the benzyl and optionally free compounds of formula I, are converted to the free compounds of Formula I. Compounds of general formula XI wherein R ¹ represents a lower alkyl or amino protecting group R ² is hydrogen, halogen, lower alkyl, trifluoromethyl or lower alkoxy and R ³ is hydrogen, halogen, lower alkyl or lower alkoxy, or R and R are attached to two adjacent carbon atoms and together are alkylenedioxy, n is an integer from 1 to 5, Q is (CH ₂ ) _m -, wherein m is 1 to 7, and which is optionally in the a-position of the oxygen atom substituted with 1 to 2 lower alkyl groups, ^{R4-significant} hydrogen or lower alkyl, R ⁵ is in the 1 or 2 position and is hydrogen, lower alkyl or phenyl lower alkyl, 6 · «x R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; ' R ⁷ is hydrogen, lower alkyl, lower alkoxy or halogen; R ⁶ and R ⁷ are attached to two adjacent carbon atoms and together form an alkylene dioxy group having 1 to 2 carbon atoms.