DE4325855A1 - Novel benzoic acid derivatives, processes for their preparation and their use as medicaments - Google Patents

Abstract

The present invention relates to benzoic acid derivatives of the general formula 1 <IMAGE> processes for their preparation, and their use in the production of pharmaceutical preparations for the treatment of disorders of the CNS.

Description

The invention relates to new benzoic acid derivatives, Process for their preparation and their use as a medicine. The new benzoic acid derivatives according to the general formula I.

wherein
R¹ is O- (C₁-C₆alkyl), NH₂, NH (C₁-C₆alkyl);
X is oxygen, sulfur, or a single bond;
a is a number 0, 1, 2, 3, 4, 5 or 6;
b is a number 2, 3, 4, 5 or 6;

A is aryl, heteroaryl;
c is a number 2 or 3;
R² is hydrogen, fluorine, chlorine, bromine, iodine, nitro, amino, mercapto, S- (C₁-C₆alkyl), C₁-C₆alkyl, cyclopropyl, haloalkyl, hydroxy and O- (CH₁-C₆alkyl) - wherein R² can be a multiple substituent of A and the same or different;
d is a number 1, 2, 3, 4 or 5
can mean.

Preference is given to compounds of the general formula 1 embedded image in which
R¹ is methoxy, ethoxy, amino, methylamino, ethylamino, n-propylamino, iso -propylamino;
X is oxygen or a single bond;
a is a number 0, 1, 2, 3 or 4;
b is a number 2, 3 or 4;

A is aryl, heteroaryl;
c is a number 2;
R² is hydrogen, fluoro, chloro, bromo, C₁-C₄ alkyl, trihalomethyl, nitro, amino, hydroxy and O- (C₁-C₂ alkyl);
d is the number 1 or 2
can mean.

Particular preference is given to compounds of the general formula 1 embedded image in which
R¹ is amino, methylamino;
X oxygen;
a is a number 0, 1, 2 or 3;
b is a number 2, 3 or 4;

A is aryl, heteroaryl;
c is the number 2;
R² is hydrogen, fluorine and methoxy;
d is the number 1
can mean.

Very particularly preferred are:

2- [3- (4-phenyl-1-piperazinyl) propoxy] benzoic acid amide, 2- {3- [4- (2-pyridyl) -1-piperazinyl] propoxy} benzoic acid amide,
2- {3- [4- (1,3-diazin-2-yl) -1-piperazinyl] propoxy} benzoic acid amide,
2- {3- [4-phenyl-1- (1,2,3,6-tetrahydropyridyl)] - propoxy} benzoic acid amide,
2- {3- [4- (2-pyridyl) -1- (1,2,3,6-tetrahydropyridyl)] - propoxy} benzoic acid amide,
2- {3- [4- (1,3-diazin-2-yl) -1- (1,2,3,6-tetrahydropyridyl)] propoxy} benzoic acid amide.

The invention also relates to the corresponding physiologically suitable Acid addition salts with inorganic or organic Acids. For example, salts with are preferred Hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, Lactic acid, malonic acid, succinic acid, maleic acid, Fumaric acid, malic acid, tartaric acid, citric acid or Benzoic acid.

Unless different details are given become the general definitions in the used the following sense:

C₁-C₆-Alkyl is generally a branched or unbranched hydrocarbon radical having 1 to 6 carbon atoms, which may be optionally substituted with one or more halogen atom (s) - preferably fluorine - which may be the same or different. As examples, the following hydrocarbon radicals may be mentioned:
Methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl , 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyne, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise indicated, preferred are lower alkyl radicals having 1 to 4 carbon atoms, such as. For example, methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

Aryl is generally an aromatic radical with 6 to 10 carbon atoms - also in Compositions, wherein the aromatic with one or a plurality of lower alkyl group (s), alkoxy group (s), Nitro group (s), amino group (s) and / or one or a plurality of halogen atom (s) - equal to one another or different - can be substituted. preferred Aryl radical is phenyl.

Heteroaryl is generally a 5- to 6-membered aromatic ring, called heteroatoms May contain oxygen, sulfur and / or nitrogen and to one or more other aromatic (s) Ring (s) can be condensed / can - how to Example: pyrrolyl, furyl, thienyl, indolyl (Benzo [b] pyrrolyl), isoindolyl (benzo [c] pyrrolyl), Indolizinyl (pyrrolo [1,2-a] pyridyl), carbazolyl, Coumaronyl, thionaphthenyl, dibenzofuranyl, Dibenzothiophenyl, pyrazolyl (1,2-diazolyl), imidazolyl (1,3-diazolyl), oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, benzimidazolyl, benzoxazolyl, Benzothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, Tetrazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl. Unless otherwise stated, preference is given to Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, Quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, Quinazolinyl, 1,2,3-benzotriazinyl and 1,2,4-Benzotriazinyl, the - as under the definition given for aryl - may be substituted.

The compounds possess valuable pharmacological Properties and have effects on blood pressure, Heart rate and especially to the central nervous system on. The compounds of the invention show a novel profile of action that these substances for Treatment of central nervous disorders, such as  Psychosis, depression, anxiety and in particular Schizophrenia as well as sedatives suitable.

The conventional treatment of schizophrenia occurs with dopamine antagonists, such as. Haloperidol or Chlorpromazine. The effect of these substances is based on the blockade of postsynaptic dopamine receptors in the limbic system. In addition, these substances cause but also a blockade of presynaptic Autoreceptors, resulting in an increased Dopamine synthesis and increased distribution of dopamine from the presynaptic nerve endings leads. These side effects are for Side effects of neuroleptics, especially the Dyskinesia blamed [cf. Lit .: J.H. Gordon et al., Pharmacology, Biochemistry and Behavior 26 (1987) 223]. In contrast, presynaptic Dopamine agonists, such as. Apomorphine, a reduction the synthesis of dopamine and a reduction of Dopamine release from the presynaptic Nerve endings. In higher doses they stimulate Substances, however, the postsynaptic Dopamine receptors, resulting in patient psychosis would cause.

The compounds according to the invention show a new, the dopaminergic system influencing effect profile. These substances have a postsynaptic one dopamine antagonist effect while they are presynaptically inhibit dopamine synthesis, ie presynaptic as dopamine agonists act. by virtue of These new effects are the side effects classical antipsychotics (neuroleptics) in these Not to fear substances.  

The biological properties of the following listed compounds of the invention was with Using the following methods tested:

The affinity for dopamine D₂ receptors was due to Displacement experiments with [3 H] -SND 919 (2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazol dihydrochloride, INN: pramipexole). The methodology is carried out according to J. Mierau: Three male Rats (strain ChBB: Thom, ca. 200 g) decapitated. The brains are removed, the striata prepared and placed in ice-cold 0.05 M Tris buffer. The wet weight of Striata is determined, with 15 ml 0.05 M Tris buffer and 20 seconds in one Polytron (position 5) homogenized. The homogenate will 10 minutes at 40 000 g in a refrigerated centrifuge centrifuged. The supernatant is decanted and after Add the calculated amount of buffer (to 50 mg Wet weight 8.0 ml buffer) homogenized again.

The amount of 0.8 ml of the buffered tissue homogenate (= 5 mg wet weight) is treated with 0.1 ml of a solution of [3 H] -SND 919 (about 0.5 nmol / l final concentration) and with 0.1 ml of a solution of the test substance (increasing concentration: 10 ^-10 to 10 ^-4 mol / l) for 180 minutes at 25 ° C incubated. The incubation is stopped by filtering through a Whatmann GF / B filter; it is rinsed three times with 5 ml of ice-cold buffer. The filters are then transferred to vials and mixed with 10 ml of scintillation fluid. The vials are shaken in a shaker for 20 minutes and the radioactivity of the samples is measured in a liquid scintillation counter. The nonspecific binding is carried out in the presence of 10 ^-5 mol / l B-HT 920 CL2 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5d] azepine dihydrochloride, INN: Talipexol ).

The specific binding results from the Total binding, less nonspecific binding. The averages of the 3-fold determination are in Coordinate cross drawn in [abscissa (log.)] Test substance concentration (mol / l), ordinate (lin.): Radioactivity of the sample (dpm)]. The IC₅₀ value is the concentration that the specific binding of [3 H] -SND 919 inhibited by 50%.

The following table shows the IC₅₀ values of compiled compounds of the invention:

substance IC₅₀ (Example No.) [NM] | 2.1 19 2.3 2.0 2.4 17 2.5 2.7 2.6 20 3.1 12:45 3.2 19 3.3 2.8 3.4 1.8 3.5 5.2 3.6 8.2 3.7 0.76 3.8 12:19 3.9 12:43 3.10 0.96 3.11 15 3.12 11 3.13 2.3 3.14 4.3 3.15 2.9 3.16 21 3.17 3.6 3.18 9.3   3.19 16 3.21 20 3.23 15 8.1A 6.5 8.1b 69 8.2 16 9.1 23 12.1 9.8 18.1 6.2 18.2 35

The Presynaptic Dopaminagonistic Effect of Compounds of the invention can be in the model show the "dopamine synthesis inhibition". The methodology will according to J.R. Walters and R.H. Roth [Naunyn-Schmiedeberg's Arch. Pharmacol. 296 (1976) 5] carried out: 5 animals each receive 10 mg / kg s.c. the substance to be examined. After 5 minutes the administration of 750 mg / kg i.p. γ-butyrolactone, about the blockade of the presynaptic impulse line the influence of postsynaptic feedback loops to exclude the dopamine synthesis rate. The Gift of γ-Butyrolactone leads to a considerable Increase in DOPA or dopamine synthesis. To the inhibition the decarboxylation of DOPA become further 5 Minutes 200 mg / kg i.p. 3-Hydroxybenzylhydrazine hydrochloride (NSD 1015) applied. 40 minutes after substance administration, the Animals were killed and the corpus striatum prepared. The Measurement of the DOPA content is carried out with the aid of HPLC electrochemical detection (standard: Dihydroxybenzylamine).

Presynaptic dopamine agonists [e.g. Apomorphine, 5-OH-DPAT (5-hydroxy-2-dipropylamino-1,2,3,4-tetra hydronaphthalene) etc.] show one in this test  pronounced inhibition of DOPA accumulation while Dopamine antagonists [e.g. Haloperidol] Stimulate DOPA accumulation.

The compounds of the invention show in this Model, as well as presynaptic dopamine agonists, an inhibition of DOPA accumulation. So was for the Compounds of the invention, for example the % inhibition of DOPA accumulation compared to control animals with 0.9 percent. Saline were treated, determined. The results are in the following table:

In addition, the effect of the invention Compounds on postsynaptic dopamine neurons determined in the MPTP model on the monkey.

By 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enters humans and monkeys irreversible, neurological disease triggered, that in its biochemical and pharmacological Expression largely of idiopathic parkinsonian Disease resembles [S.D. Markey, J.N. Johannessen, C.C. Chivek, R.S. Burns and M.A. Herkenham, Nature 311 (1984) 464]. The cause of this match is the The fact that MPTP selectively targets small groups dopaminergic Nerve cells in the substantia nigra of the brain destroyed, which also occurs naturally Parkinson's disease due to degenerative processes be destroyed.

The MPTP model realized in rhesus monkeys is therefore, the effect of postsynaptic dopamine agonist substances.

For this purpose, rhesus monkeys receive MPTP in total doses of up to about 6 mg / kg body weight until the following symptoms occur:
The animals become akinetic and are unable to absorb water and food. They show a typical, stooped posture; occasionally cataleptic states occur. The extremities have a rigor, which is broken by passive movements of clonic convulsions.

Dopamine agonists, such as apomorphine, levodopa, B-HT 920 or 5-OH-DPAT lead to a temporary Cancellation of this conditional image for the period from 4 to 5 hours, with a single dose of 100 μg / kg intramuscularly. After that, re-enter the above  described symptoms. The extra gift of a dopamine antagonist (eg haloperidol) those caused by the dopamine agonist Improvement. The animals remain bradykinetisch and are still unable to water and feed take.

After intramuscular administration of the invention Compounds (0.1 to 3.0 mg / kg) failed Improvement, or even cancellation of the condition of the observed with MPTP treated monkeys. At a Row of compounds of the invention could even an antagonization of those caused by B-HT 920 Reversal of Parkinson's Symtomatik observed become. The animals remain at the dose of 0.3 to 3.0 mg / kg Compounds of the invention together with 0.1 mg / kg B-HT 920 is bardykinetic and still is not able to absorb water and food. That's it to a postsynaptic dopamine antagonizing effect to close these substances.

For example, in the following Table Compound Links One Antagonization of the effect of 0.1 mg / kg B-HT 920 im MPTP model found:

The compounds according to the invention are according to postsynaptic Dopaminantagonisten, the presynaptic but a dopamine agonist effect demonstrate. Therefore, the substances possess for therapy schizophrenia has significant advantages, as with the classic dopamine antagonists Side effects are excluded here.

production method

The compounds 1 can be different, in themselves known methods are produced. Depending on the structure of the link

- (CH₂) _a -X- (CH₂) _b -

can be different synthesis strategies apply. These are described individually below:

3.1. X = O, a = 0, b = 2, 3, 4, 5 or 6

Starting from o-, m- or p-Hydroxybenzoesäurealkylester Type 2 and a α, ω-haloalkyl halide - such as the Chloroalkyl bromide 3 - is based on a Williamson ether synthesis the corresponding Methoxycarbonylphenoxyalkylchlorid 4 prepared [Author Collective, Organikum, 17th Edition, VEB German publishing house of the sciences, Berlin 1988, S. 198; H. Feuer and J. Hooz, in Patai (Ed.), "The  Chemistry of the Ether Linkage ", Interscience, New York, 1967, pp. 446-450 and pp. 460-468; Houben / Weyl, Methods of Organic Chemistry, 4th Edition, Georg Thieme Verlag, Stuttgart Volume VI / 3, p. 62; C. Ferri, Reactions of Organic Synthesis, Georg Thieme Verlag, Stuttgart, 1978, p. 397 and cit. Lit.].

In this case, the corresponding Hydroxybenzoe acid alkyl esters - preferably the corresponding Methyl ester (R¹ = OCH₃) - of type 2 in one suitable solvent - preferably in a ketone and most preferably in acetone - with the desired ω-haloalkyl halide - preferably one corresponding ω-chloroalkyl bromide of type 3 - in Presence of a basic compound - preferably  an alkali carbonate, more preferred Potassium carbonate - reacted [C.F.H. Allen and J.W. Gates Jr., Org. Synthesis, Coll. Vol. III (1955) 140].

However, it is also possible for the benzoic acid derivative 2 first enter into an alkali colloid solution. Suitable alkali metal alkoxides are, for example Sodium methylate, sodium ethylate and Potassium tert-butoxide. Suitable alcohols provide z. B. Methanol, ethanol and butanol, wherein the Alkoholatrest expediently used Alcohol meets, but not necessarily must correspond. Analogous to the one described above Procedure will then be the desired one Added alkylating agent.

The resulting from the alkylation reaction Type 4 phenol ether is used in the following Synthesis stage with the desired heteroaryl or 4-aryl-1,2,3,6-tetrahydropyridines or heteroaryl or 4-arylpiperazines or the corresponding Azepines or Polyhydroazepinen the general formula 5 to the benzoic acid derivatives of the general formula 6a implemented. The implementation takes place in inert Solvents, preferably in the presence of a Auxiliary base and a catalyst instead.

As inert solvents are preferably Solvents used, which are among the do not change the reaction conditions used, such as Ether - for example, glycol dimethyl ether or Diglycol dimethyl ether - or cyclic ethers - such. B. Tetrahydrofuran or dioxane - or acid amides - such as For example, dimethylformamide (DMF), acetamide or Hexamethylphosphoric triamide (HMPT).

The auxiliary bases which are suitable for this reaction are known from the prior art. Prefers are alkali or alkaline earth carbonates and especially  preferably used alkali metal bicarbonates, wherein Sodium hydrogencarbonate is very particularly preferred.

The catalyst substances suitable for this reaction are also known in the art. Alkali halides are preferably used, wherein Sodium iodide is particularly preferred.

Optionally, on the subsequent Synthesis of the alkoxy substituent against another be replaced. This happens expediently by way of transesterification by z. B. first the corresponding hydroxybenzoic acid methyl ester (R¹ = OCH₃) is used in the process, the in the last reaction step of transesterification under Replacement of the alkoxy radical is subjected.

Such transesterifications of carboxylic acid esters are known from the prior art - per se - [C. Ferri, reactions of organic synthesis, Georg Thieme Verlag, Stuttgart, 1978, p 449 and cit. Lit .; J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 351, and cit. Lit.]. For the transesterification, it is expedient to use that alcohol whose alkoxy _radical is to form the new alkoxy substituent R _alkoxy . The transesterification can be catalysed both acidic and basic.

Corresponding catalysts - such. B. mineral acids or alkali hydroxides - are known in the art known. However, it is also possible that Transesterification reaction in neutral media [S. Bittner, Z. Barneis and S. Felix, Tetrahdron Lett. 1975, 387; S. Hashimoto I. Furukova and T. Kuroda, Tetrahedron Lett. 21 (1980) 2857; G.A. Olah, G.F. Salem and B.G.B. Gupta, Synthesis 1981, 142].  

The corresponding ethyl ester can be obtained by direct Transesterification of the methyl ester 6a with Titanium tetraethylate / ethanol analogous to one of D. Seebach et al. described transesterification are prepared [Synthesis 1982, 138]. In another alternative the ester of type 6a may initially be free Saponified carboxylic acid and the thus obtained intermediately Acid with the desired alcohol - preferably Ethanol - esterified.

Furthermore, there is at this stage of the reaction Possibility by the aminolysis of the benzoic acid ester of type 6a the corresponding acid amides 7, the in turn fall under the general formula 1, manufacture.

Such reactions are also from the prior Technique known [A.L.J. Beckwith in J. Zabicky, "The Chemistry of Amides, Interscience, New York 1970, p. 96-105; Houben / Weyl, Methods of Organic Chemistry, 4th edition, Georg Thieme Verlag, Stuttgart, Volume VIII, P. 658; W. A. Jacobs and M. Heidelberger, Org. Synth. Coll. Vol. I (1941) p. 153; B. B. Corson, R.W. Scott and C.E. Vose, Org. Synth. Coll. Vol. I (1941) p. 179; C.J. Kibler and A. Weissberger, Org. Synth., Coll. Vol. III (1955) 108; W. P. Ratchford and C.H. Fisher, J. Org. Chem. 15 (1950) 317; W. P. Ratchford and C.H. Fisher, ibid. 326; J. Kleinberg and L.F. Audrieth, Org. Synth., Coll. Vol. III (1955) 516; M. Gordon, J.G. Miller and A.R. Day, J. Am. Chem. Soc. 71 (1949) 1245].

Preferably, the benzoic acid ester is in one inert solvent with the desired amine to the corresponding acid amide implemented. inert Solvents are in general Solvents that are below the given Do not change reaction conditions. These include preferably ethers - such as. B. Glycol dimethyl ether (Glyme)  or diglycol dimethyl ether (diglyme) or cyclic Ether - such. As tetrahydrofuran (THF) or dioxane - or hydrocarbons - such. Benzene, toluene, Xylene or petroleum fractions - or Halogenated hydrocarbons - such. For example dichloromethane, Trichloromethane or carbon tetrachloride. Prefers are alcohols - such. Methanol or ethanol - used. However, it is also possible to use mixtures to use the said solvent.

In the reaction, a reaction temperature in Range from 0 ° C to the boiling point of Reaction mixture preferred, wherein the selected Temperature down by one too low Reaction rate and up through the Overreaction of side reactions is determined. Particularly preferred is the reaction in a Temperature in the range of 100 to 200 ° C and under pressure carried out, with temperatures in the range of 140 ° C. up to 160 ° C are very particularly preferred.

3.2.1 X = O, a = 1, 2, 3, 4, 5 or 6, b = 2

Starting from o-, m- or p-Halogenphenylalkylalkoholen type 8 (E = halogen) - preferably o-, m- or p-Bromalkylphenylalkoholen type 8 with a = 1, the corresponding Halogenphenylalkoxyessigsäureester Type 10 in the context of a Williamson'schen Ethersynthese by reaction of 8 with a Halogenessigsäurealkylester 9 - preferably methyl bromoacetate (Hal = Br, R _s = CH₃) - prepared.

In this case, the phenylalkyl alcohol - preferably one Benzyl alcohol of type 8 - in an inert Solvent first reacted with a base.

Under inert solvents are here in the first Line understood such solvents, among the selected reaction conditions of the base not be attacked significantly. Such solvency be of hydrocarbons - such. Benzene, Toluene, xylene or petroleum fractions - or ethers - such as z. B. glycol dimethyl ether (glyme) or Diglycol dimethyl ether (diglyme) - or cyclic Ethern - such. B. tetrahydrofuran or dioxane - with tetrahydrofuran being preferred.

As bases, alkali hydrides - such as sodium hydride or Potassium hydride - used, with sodium hydride is preferred.  

The resulting from this implementation Type 10 phenylalkoxy derivative is disclosed in US Pat subsequent synthesis step to the corresponding alcohol 11 reduced.

Such reductions of carboxylic esters to alcohols are known in the art [J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, 3 ^rd Edition, p. 1101 and cit. Lit .; C. Ferri, reactions of organic synthesis, Georg Thieme Verlag 1978, p. 99 and cit. Lit .; Houben / Weyl, Methods of Organic Chemistry, 4th Edition, Volume XIII / 4, p. 216]. Preference is given to reduction with complex alkali metal or alkali aluminum hydrides, optionally in the presence of a catalyst [NG Gaylord, Reduction with Complex Metal Hydrides, Wiley, New York, 1965, pp. 391-531; J. Malek and M. erny, Synthesis 1972, 217; J. Malek and M. Cerny, ibid. P. 226; A. Hajos, Complex Hydrides, Elsevier, New York, 1979; V. Baant, M. apka, M. erny, V. Chvalovsky, K. Kochloefl, M. Kraus and J. Malek, Tetrahedron Lett. 9 (1968) 3303], with lithium aluminum hydride (Lithiumtetrahydridoalanat) is particularly preferred.

Suitable solvents here are all inert Solvents that are below the given Do not change reaction conditions. These include preferably ethers - such as. For example, di-n-butyl ether, Glycol dimethyl ether (glyme), diglycol dimethyl ether (Diglyme) - and cyclic ethers - such. B. dioxane and Tetrahydrofuran - with tetrahydrofuran being especially is preferred.

The subsequent implementation with the desired 4-heteroaryl or 4-aryl-1,2,3,6-tetrahydropyridines or 4-heteroaryl or 4-arylpiperazines or -azepines or polyhydroazepines succeed after  Activation of the reduction reaction resulting alcohol 11. Such indirect Reactions are known in the art [R.C. Larock, Comprehensive Organic Transformations - a Guide to Functional Group Preparations, VCH Verlagsgesellschaft m.b.H., D-6940 Weinheim, 1989, P. 419 and cit. Lit .; J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 367 and zit. Lit.].

However, the implementation can also take place via the intermediate stage the corresponding halide - preferably the corresponding chloride or bromide - take place, which, for example, by reaction of the alcohol of Type 11 with thionyl chloride or - preferably - Phosphorus tribromide can be produced.

However, there is also the option of alcohol activate the amination in a different way. Particularly preferred is the activation in the form of Mesylate or tosylate of the respective alcohol, which - as well as the subsequent implementation of such activated alcohols - to the corresponding Amino compounds - from the prior art per se is known [s. z. B. Author collective, Organikum, VEB German publishing house of the sciences, Berlin, 1988, S. 559; R.C. Larock, Comprehensive Organic Transformations - a Guide to Functional Group Preparations, VCH Verlagsgesellschaft m.b.H., D-6940 Weinheim, 1989, P. 397 and cit. Lit.].

For this purpose, the type 11 alcohol, for example, in dissolved absolute pyridine and - optionally under Cooling - mixed with p-toluenesulfonyl chloride.  

The resulting p-toluenesulfonic acid ester is used in the following synthesis step in an inert Solvent with the desired aryl or Heteroaryl-1,2,3,6-tetrahydropyridine or aryl or Heteroaryl or the corresponding azepine derivatives 4-Arylpiperazinderivat type 5 in the presence of a Alkali hydrogencarbonates - preferably potassium hydrogen carbonate - implemented.

Under inert solvents here are solvents to understand who are among the ruling ones Do not change the reaction conditions or the Do not interfere with the reaction.

These solvents are primarily cyclic ethers - such as tetrahydrofuran or dioxane - or acid amides - such as dimethylformamide or Hexamethylphosphoric triamide (HMPT), wherein Dimethylformamide is preferred. The Reaction temperature is in a wide range variable and will be down by too little Reaction rate and up through the Overreaction of side reactions limited. Prefers is a temperature interval from room temperature to Boiling point of the reaction mixture, with the interval from 80 to 120 ° C particularly preferred and - in the Use of DMF as solvent - the Temperature range from 90 ° C to 100 ° C very special is preferred.

The resulting from this reaction amines of the type 12 (Hal is preferably Br) are in the on it following reaction step - in a known manner - with copper (I) cyanide in the corresponding Conversion of type 13 nitrile compounds. When Reaction media are preferred inert solvents, the above-mentioned acid amides being especially to be favoured. Very particularly preferred Dimethylformamide.

The resulting cyanides of type 13 can be found in the subsequent reaction step - depending on the selected reaction compounds - to the corresponding carboxylic acid amides of the general formula 14a or to the corresponding carboxylic acids of type 15 being transformed. Such saponification reactions of  Nitriles are - in themselves - from the prior art known [P.L. Compagnon and M. Mioque, Ann. Chim. (Paris) [14], 5 (1970) 11-22; P. L. Compagnon and M. Mioque, ibid. 23-37; E. N. Zil'berman, Russ. Chem. Rev. 31 (1962) 615].

So the saponification reaction can be conducted in such a way that is preferably the amide of the general formula 14a is formed by the nitrile 13 within a short period of time with one base - preferably one anhydrous alkali hydroxide and more preferably with anhydrous potassium hydroxide - treated. - When Solvents are alcohols - especially preferably tert-butanol - used.

If a free carboxylic acid of type 15 is desired, can this by hydrolysis of the nitrile 13 with a aqueous solution of a base in the presence of a Alcohols are obtained, with the reaction time of the reactivity of the phenyl cyanide used in each case 13 depends. The base used is aqueous solutions of Alkali metal hydroxides used, wherein potassium hydroxide is preferred. Alcohols used are polyols, wherein diols are preferred and ethylene glycol is particularly preferred.

The thus obtained carboxylic acid of type 15 can under Application of known methods in the corresponding type 16 carboxylic acid ester transferred become [C. Ferri, reactions of organic synthesis, Georg Thieme Verlag Stuttgart, 1978, page 447 and cit. Litt; R.C. Larock, Comprehensive Organic Transformations, A Guide to Functional Group Preparation, VCH Verlagsgesellschaft m.b.H., Weinheim, 1989, p. 966; J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 348; E. Haslam, Tetrahedron 36 (1980) 2409].  

For this, the carboxylic acid 15 in the presence of an acid or an acid catalyst with the desired one Alcohol reacted. Suitable acids or catalysts are from the above-mentioned prior art known. In addition, it is possible to get the desired Carboxylic ester 16 by means of suitable Dimethylformamide acetals [H. Brechbühler, H. Büchi, E. Hatz and A. Eschenmoser, Helv. Chim. Acta 48 (1965) 1746] or by transesterification [Houben / Weyl, Methods of Organic Chemistry, 4th Edition, Georg Thieme Verlag, Stuttgart, Volume VIII, p 526) or by Reaction of the carboxylic acid derivatives 15 with the corresponding acid esters or orthoesters manufacture. Furthermore, the methyl esters can be by reacting the carboxylic acid of type 15 with Produce diazomethane [Houben / Weyl, Methoden der Organic Chemistry, 4th Edition, Georg Thieme Verlag, Stuttgart, Vol. VIII, p. 533 and Vol. X / 4, p. 664; S. M. Hecht and J.W. Kozarich, Tetrahedron Lett. 1973 1397].

By reacting the methyl ester of type 16 with the desired amines can be under analogous application the method described under 3.1 the corresponding carbamoyl compounds of type 14 produce.

Furthermore, the carboxylic acid amides 14 alternatively in a variant to the so-called Ritter reaction represent [J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 860 and cit. Lit.].

The nitrile compound 13 is initially with powdered potassium hydroxide in tert-butanol to the saponified corresponding amide anion and then with the desired alkyl halide - in excess - to the corresponding type 14 carbamoyl compound [S. Linke, Synthesis 1978, 303].

3.2.2 X = O, a = 1, 2, 3, 4, 5 or 6; b = 3, 4, 5 or 6

Such benzoic acid derivatives of the general formula 12b can by conversion of o-, m- or p-Halogenphenylalkylalkoholen type 8 - preferably o-, m- or p-Bromophenylalkylalkoholen - with α, ω-haloalkyl halides - preferably with α, ω-bromoalkyl chlorides of type 3a, where n = 3 is very particularly preferred - by way of a Williamson's ether synthesis can be prepared [Lit. s. under 3.1!].

In this case, the corresponding Halogenphenylalkylalkohol - preferably bromophenylalkyl alcohol (E = Br) - in Presence of a base - preferably an alkali hydride and particularly preferably sodium hydride - in one inert solvent with the α, ω-dihalide of the Type 3a to the corresponding Halogenphenylalkoxyalkylhalogenid - preferably Chloride - type 12 implemented. As inert Solvents are all solvents that are suitable not under the prevailing reaction conditions change. These include hydrocarbons - such. B. Benzene, toluene, xylene or petroleum fractions - or ethers - such. B. di-n-butyl ether, glycol dimethyl ether (glyme) or diglycol dimethyl ether (diglyme) or cyclic Ether - such. As tetrahydrofuran or dioxane, wherein Tetrahydrofuran is preferred.

The reaction temperature can - depending from the reactivity of the reactants - in another  Range can be varied. She gets down through one too low reaction rate and up through limited the prevalence of side reactions.

The bromophenylalkoxyalkyl chlorides thus obtained 17 are subsequently followed by analogy with the reaction of 4 6 - as described in 3.1 with the desired aryl or Heteroaryl-1,2,3,6-tetrahydropyridines or aryl or Heteroarylpiperazines or -azepines or Type 5 polyhydroazepines to the corresponding Benzoic acid derivatives of type 12b reacted. These in turn, in analogy to that under 3.2.1 described method (reaction 12 to 14 or 14a) - In the corresponding benzoic acid esters or amides be transferred.

3.3.1 X = single bond, a = 0, b = 2

Compounds of general formula 1, which is a Dimethylene unit can, starting from the correspondingly substituted o-, m- or p-Bromomethylbenzoic acid methyl esters of type 18 being represented.

Based on the nitrile synthesis according to Kolbe [J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 429 and cit. Lit; K. Friedrich and K. Wallenfels in Rappoport, "The Chemistry of the Cyano Group ", pp. 77 ff .; C. Ferri Reactions of organic Synthesis, Georg Thieme Verlag, Stuttgart, 1978, p. 573 and zit. Lit .; Houben / Weyl, Methods of Organic Chemie, 4th Edition, Georg Thieme Verlag, Stuttgart, Volume VIII, 293; Author collective, Organikum, VEB German publishing house of the sciences Berlin 1988, S. 210] are thus first the corresponding ones Methyl cyanomethylbenzoate can be produced.

The reaction of methyl bromomethylbenzoate 18 with a cyanide - preferably an alkali metal cyanide and particularly preferred potassium cyanide - is in good solvating solvents - preferably in Presence of a Phase Transfer Catalyst - carried out. The solvents used are alcohols - such as z. As methanol or ethanol - or ketones - such. B. Acetone or methyl ethyl ketone - or acid amides - such as z. As dimethylformamide (DMF), acetamide or Hexamethylphosphoric triamide - or ether - such as. B. Glyme, diglyme, dioxane or tetrahydrofuran. It can also mixtures of said solvents or their Mixtures with water are used. It is preferred Acetonitrile used as a solvent.

As phase transfer catalysts from the Prior art known catalysts - such. B. Crown ethers or tetraalkylammonium salts - used. Crown ethers such as for example 1,4,7,10-Pentaoxacyclopentadecane (15-crown-5), 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-8), 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxa cyclooactadeca-2,11-diene (dibenzo-18-crown-6), 2,3,14,15-dibenzo-1,4,7,10,13,16,19,22-octaoxa-cyclo triaconta-2,17-diene (dibenzo-24-crown-8), 2,3,17,18-dibenzo-1,4,7,10,13,16,19,22,25,28-decaoxa cyclotriaconta-2,17-diene (dibenzo-30-crown-10), cis-2,3,11,12-dicyclohexano-1,4,7,10,13,16 hexaoxacyclooctadecane (dicyclohexano-18-crown-6), cis-Dicylclohexano 1,4,7,10,13,16,19,22- octaoxacyclotetracosane (dicyclohexano-24-crown-8), 18-crown-6 being particularly preferred. - In the The choice of crown ether is the alkali ion used account.

In carrying out the substitution reaction, the Reaction temperature in a wide range of Room temperature to the boiling point of the  Reaction mixture can be varied, the Temperature interval down by too low Reaction rate and up through the Overreaction of side reactions is restricted.

The nitrile thus prepared is subsequently catalytically with hydrogen to the corresponding amine reduced. Such reductions are in the state of Technique known [P.N. Rylander, "Catalytic Hydrogenation over Platinum Metals ", Academic Press, New York, 1967, p. 307; M. Rabinowitz in Rappoport, "The Chemistry of the Cyano Group", Interscience Publishers, New York, 1970, p. 203; C. Ferri reactions of organic synthesis, Georg Thieme Verlag, Stuttgart, 1978, p. 92 and cit. Lit.].

The reaction is in one of the prevailing Reaction conditions inert solvent preferably in the presence of a protic acid - carried out. As solvents are alcohols - like z. As methanol, ethanol, propanol or isopropanol - or ethers - such as. B. diethyl ether, tert-butyl methyl ether, di-n-butyl ether, Glycol dimethyl ether (glyme), Diethylene glycol dimethyl ether (diglyme) or Tetrahydrofuran (THF) or halogenated hydrocarbons - such as dichloromethane, trichloromethane, Tetrachloromethane - or carboxylic acid ester - such. B. Acetic acid methyl ester - or hydrocarbons - such as z. As petroleum fractions, benzene, toluene or xylene - or Amides - such as B. dimethylformamide, acetamide, Hexamethylphosphoric triamide - or carboxylic acids - such as For example, formic acid or acetic acid.  

Particularly preferred is methanol as a solvent used. As protonic acids are preferred Mineral acids - such as hydrochloric acid or Sulfuric or carboxylic acids having 1 to 6 carbon atoms, optionally substituted by fluorine, chlorine and / or bromine may be substituted, such as Formic acid, acetic acid, trifluoroacetic acid, Trichloroacetic acid or propionic acid. Under the group The preferred acids also include sulfonic acids C₁-C₄-alkyl radicals or aryl radicals, the optionally by one or more halogen atoms may be substituted - such. For example, methanesulfonic acid, Trifluoromethanesulfonic acid, ethanesulfonic acid, Benzenesulfonic acid or toluenesulfonic acid. - Especially hydrochloric acid is preferably used.

To be used in such reactions Catalysts are also known in the art known o. a. Lit.!].

These include preferably Raney nickel or Raney nickel / cobalt catalysts, palladium or Platinum. Particularly preferred is palladium on carbon (10%) used.

Preference is given at a temperature of about 20 ° C. hydrogenated. Depending on the reactivity can but also the choice of a higher temperature to be required. - This is the hydrogen pressure in a range of 5 to 30, preferably 8 to 20 and more preferably at about 13 bar.  

The amines of type 19 are prepared in Analogy to one of N. Nicholas and B. Ganem designed method [J. Org. Chem. 54 (1989) 5998] with Trifluoroacetamide in the corresponding Trifluoracetamide transferred and then under Ice cooling with sodium nitrite in a mixture of Acetic acid and acetic anhydride diazotized and by Heat to a temperature in the range of 20 ° C to 30 ° C - preferably to a temperature of about 25 ° C - to the corresponding acetates decomposed, from which means methanolic potassium carbonate solution the corresponding Alcohols of type 20 can be released which - as described under 3.2.1 (Reaction 11 to 12a) - in the corresponding 4-aryl or 4-heteroaryl-1,2,3,6-tetrahydropyridine derivatives or in the corresponding 4-aryl or 4-heteroarylpiperazine derivatives or azepine derivatives of type 21 transferred become. The thus obtained Benzoic acid methyl ester derivatives can - as under 3.1 described (reaction 6a to 7 or reaction 6a to 6b) - to the corresponding amides of type 22 or to the corresponding esters of type 23 are implemented.  

3.3.2 X = single bond, a = 1, b = 2

Compounds of this type are by reaction suitable o, m or p-Cyanobenzaldehyde type 24 with malonic acid 25 can be produced. This condensation of Type of so-called Knoevenagel reaction is from the state of Technique well known [G. Jones, Org. React. 15 (1967) 204; Author collective, Organikum, VEB Deutscher Verlag of the Sciences, Berlin 1988, p. 459].

For the preparation of Propencarbonsäurederivates 26 the cyanobenzaldehyde 24 and the malonic acid 25 are in Dissolved pyridine and heated to reflux until the carbon dioxide evolution is over. In the next reaction step, the carboxylic acid 26 with known methods in the corresponding Acid halide transferred - wherein the reaction with Thionyl chloride to the corresponding propenoic acid chloride is preferred. - In addition, however, others can  Halogenating agents - such as Phosphorus trichloride or phosphorus pentachloride - be used. The reaction can be "in substance" be performed. Preferably, however, for the Halogenation one among the prevail Reaction conditions selected inert solvent. When Solvents become chlorinated hydrocarbons - such as For example, dichloromethane, trichloromethane or Carbon tetrachloride or mixtures of said Solvent particularly preferred.

The subsequent conversion of the acid chloride in the Propenol of type 27 takes place by reduction of the Acid halide or acid chloride. When Reducing agents are preferably complex Hydrides - such. Sodium borohydride, Lithium aluminum hydride, diisobutylaluminum hydride, Natriumdiethylaluminiumhydrid - used. Besides it is possible to pass the alcohol 27 through catalytic reduction of the acid halide accessible close. Such implementations - especially under Use of Complex Hydrides as Reducing Agents - are known in the art [O.H. Wheeler in Patai, "The Chemistry of Acyl Halides, Interscience Puplishers, New York, 1972, p. 231; H. Schenker, Angew. Chem. 73 (1961) 81; D.C. Iffland and H. Siegel, J. Am. Chem. Soc. 80 (1958) 1947].

Particularly preferred is sodium borohydride as Reducing agent used.

Suitable solvents are all inert organic Solvents chosen among the Reaction conditions unchanged or at least remain largely unchanged and not detrimental intervene in the reaction process. This includes  preferably diethyl ether, tert-butyl methyl ether, Di-n-butyl ether, glycol dimethyl ether (glyme), Diglycol dimethyl ether (diglyme), tetrahydrofuran and Dioxane - and alcohols - for example, methanol, Ethanol, propanol or isopropanol.

In a particularly preferred process variant is the acid chloride dissolved in tetrahydrofuran and with a suspension of sodium tetrahydridoboranate in Ethanol added.

It has proved to be advantageous, the Cool reaction mixture. Preferably, the Addition of the reducing agent in a temperature range from -50 ° C to 0 ° C. most preferably in the range of -25 ° C to -20 ° C.

Depending on the reactivity of the reactants can but also the choice of a higher or lower one Temperturniveaus be necessary.

At the subsequent reaction stage is the Nitrile 27 saponified to the benzoic acid derivative 28.

Such saponification reactions of nitriles are - on itself - known from the prior art [P.L. Compagnon and M. Mioque, Am. Chim (Paris) [14], 5 (1970) 11; P. L. Compagnon and M. Mioque, ibid. 23; E. N. Zil'berman, Russ. Chem. Rev. 31 (1962) 615]. Preference is given to saponification with the aqueous solution an alkali metal hydroxide, wherein potassium hydroxide is particularly preferred.

The preferred solvents are water or alcohols - such. As methanol, ethanol, glycol, glycerol or Triethylene glycol - or mixtures of the above Solvent used, wherein Ethanol / water mixtures are particularly preferred.  

The reaction temperature is in a range of about 20 ° C to the boiling point of the reaction mixture. Preferred is a temperature in the range of 20 ° C to 90 ° C, with a temperature of about 70 ° C throughout is particularly preferred.

The subsequent hydrogenation of the thus obtained Hydroxypropenylbenzoic acid derivative 28 provides the corresponding 3-hydroxypropyl-benzoic acid derivative of Type 29.

Such hydrogenations are - in itself - from the state known to the art [C. Ferri, reactions of Organic Synthesis, Georg Thieme Verlag, 1978, p. 79 ff. and cit. Lit.].

The catalysts used are, for example, Raney nickel [R. Schröter, New Method Prep. Org. Chem., 1 (1948) 61], so-called nickel boride [R. Paul, P. Buisson and N. Joseph, Ind. Eng. Chem. 44 (1952) 1006; D.J. Brown, J. Chem. Soc., Chem. Commun. 1973, 553], platinum metal or platinum oxide, rhodium, ruthenium or zinc oxide [P.N. Rylander, Organic Synthesis with Noble Metal Catalysts, Academic Press., New York 1973; P.M. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press, New York, 1967] or palladium on carbon.

Especially preferred is Raney Nickel.

The hydrogenation of the double bond takes place in inert organic solvents. As inert solvency inert organic solvents are suitable here, not under the given reaction conditions change and not detrimental in the self Intervene reaction sequence. These are preferably  Alcohols - such as methanol, ethanol, propanol or isopropanol - or ether - such as Diethyl ether, tert-butyl methyl ether, di-n-butyl ether, Glycol dimethyl ether (glyme), Diethylene glycol dimethyl ether (diglyme), tetrahydrofuran - or halogenated hydrocarbons - such as Dichloromethane, trichloromethane, carbon tetrachloride - or Carboxylic acid esters - such as Acetic acid methyl ester and ethyl acetate - or Hydrocarbons - such as petroleum fractions, Benzene, toluene, xylene or amides - such as Dimethylformamide, acetamide, Hexamethylphosphoric triamide - or carboxylic acids - such as formic acid or acetic acid - or also mixtures of the solvents mentioned. Especially methanol is preferably used as the solvent.

The hydrogenolysis of the double bond takes place preferably at room temperature (about 20 ° C) under a Hydrogen pressure in the range of 2 to 12 bar preferably 4 to 7 bar and more preferably at 5 bar. Depending on the reactivity of the However, double bond can also make the choice more drastic Reaction conditions - especially the choice of a be necessary higher reaction temperature.

In the next reaction step, the Benzoic acid derivative 29 - known per se Way - in the corresponding halide - preferably in the corresponding chloride - transferred, where - as desired - the hydroxyl function also by the corresponding halide is substituted. When Chlorinating agents are suitable for all those Chlorinating agent, already at the o.a. presentation of the acid chloride (reaction step 26-27) were. Thionyl chloride is preferably used.  

Suitable solvents for this reaction in primarily halogenated hydrocarbons - such as. B. Dichloromethane, trichloromethane, carbon tetrachloride - or acid amides - such. B. dimethylformamide (DMF), Acetamide or hexamethylphosphoric triamide (HMPT), also mixtures of said solvents can be used. Preference is given to a mixture from dichloromethane and dimethylformamide.

The reaction temperature is variable in the range of 0 ° C to the boiling point. Preferred is a reaction temperature in the range of 5 ° C to 20 ° C, and more preferably 10 ° C to 15 ° C. In the subsequent reaction _step , the benzoic acid chloride either by reaction with alcohols (HA = HR _alkoxy ) in the corresponding benzoic acid ester of type 30 or by way of aminolysis with the desired amines (HA = HNH₂ or HNH (C₁-C₆-alkyl)) in the corresponding Benzoesäureamide 30 transferred.

Both reactions are - in itself - from the state of Technique known [ester formation: Houben / Weyl, Methoden of Organic Chemistry, 4th Edition, edited by E. Müller, Georg Thieme Verlag, Stuttgart, Volume VIII, P. 543, C.R. Hauser, B.E. Hudson, B.Abramovitch and J.L. Shivers, Org. Synth., Coll. Vol. III (1955) 142; AH. Ford Moore, Org. Synth., Coll. Vol. IV (1963) 84; N.O.V. Sunday, Chem. Rev. 52 (1953) 237; amide formation: B.C. Challis and J. Butler in Patai, "The Chemistry of the Amino Group, Interscience Publishers, New York, 1968, p. 279; C. Ferri, reactions of organic Synthesis, Georg Thieme Verlag Stuttgart, 1978, p. 222 ff. u. zit. Ref. J. March, Advanced Organic Chemistry, 3rd Ed., John Wiley and Sons, New York 1985, p. 370 ff. and zit. Lit .; R.C. Larock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, VCH Verlagsgesellschaft, D-6940 Weinheim,  1989, p. 963 et seq. And cit. Ref., A.L.J. Beckwith in J. Zabicky, "The Chemistry of Amides", Interscience Publishers, New York 1970, p. 73].

The subsequent reaction of propyl bromide 31 with Heteroaryl or aryl-1,2,3,6-tetrahydropyridine derivatives or corresponding piperazine or Azepine derivatives of type 5 provides - in analogy to the corresponding implementation described in 3.3.1. the amine of type 31. Such reactions correspond the reactions described under 3.1 (Reaction 4 after 6) and are carried out under analogous conditions.

3.3.3 X = single bond, a = 0, b = 4

Starting material for benzoic acid derivatives of these Structure form propanediol monoacylester type 32 their synthesis also from the prior art is known [N.J. Huang and L.-H. Xu, synth. Commun. 20 (1990) 1563].

(R _E = lower alkyl). The oxidation of such alcohols makes the corresponding type 33 aldehydes accessible. The prior art discloses a variety of suitable reagents for the oxidation of primary alcohols to the corresponding aldehydes. P, Muller in Patai, The Chemistry of Functional Groups, Supplement E, Wiley, New York, 1980, p. 469; CF Cullis and A. Fish in Patai, "The Chemistry of the Carbonyl Group", Vol. 1, Interscience, New York, 1966, p. 129; W. Carruthers, "Some Modern Methods of Organic Synthesis," 2nd ed., Cambridge University Press, Cambridge, 1978, p. 338; TS Lee in RL Augustine and DJ Trecker, "Oxidation", Marcel Dekker, New York, 1969 and 1971].

Common oxidants are, for example, by Potassium permanganate, bromine, manganese dioxide, Ruthenium tetroxide, etc. [T. Lee and M. van the Engh in W.S. Trahanovsky, "Oxidation in Organic Chemistry, Academic Press, New York, Part D, 1982, p. 197]. In addition, preferably chromium-VI compounds - such. B. Chromium-VI-oxide (Collins reagent), Pyridiniumchlorochromat (Coreys reagent) used [J. March, Advanced Organic Chemistry, 3rd Edition, Wiley & Sons, New York, 1985, p. 1057 and cit. Lit]. About that In addition, reagents such. B. Ceric ammonium nitrate [W.S. Trahanovsky and L.B. Young, J. Chem. Soc. 1965, 5777, W.S. Trahanovski, L.B. Young and R.W. Brown, J. Org. Chem. 32 (1967) 3865], Sodium dichromate in water [T.S. Lee and U.A. Sharpener, J. Org. Chem. 35 (1970) 3589; Y. S. Rao and R. Filler, J. Org. Chem. 39 (1974) 3304], silver carbonate on Celite [M. Fetizon and M. Golfier, C.R. Acad. Sci., Ser. C., 267 (1968) 900], nitric acid in aqueous glyme [A. Mc. Killop and M.E. Ford, synth. Commun. 2 (1972) 307], the complex of N-methylmorpholine N-oxide and ruthenium [K. B. Sharpless,  K. Akashi and K. Oshima, Tetrahedron Lett. 1976, 2503], the system oxygen / pyridine / copper-I-chloride [C. Jallabert and H. Riviere, Tetrahedron Lett, 1977, 1215], lead IV acetate / pyridine [R. Partch, Tetrahedron Lett. 1964, 3071; R. Partch and J. Monthomy, Tetrahedron Lett. 1967, 4427; T.J. Brocksom and J.T.B. Ferreira, J. Chem. Res., Synop. 1980, 412] and the System Benzoyl Peroxide Nickel Bromide [N.P. Doyle, W.J. Patrie and S.B. Williams, J. Org. Chem. 44 (1979) 2955] for the preparation of the aldehydes of the invention.

In addition, there is the possibility of aldehydes on the Pathways for catalytic oxidation [K. Heyns and H. Paulsen, Angew. Chem. 69 (1957) 600; K. Heyns and H. Paulsen, Newer Methods Prep. Org. Chem. 2 (1963) 335; M.Y. Sheikh and G. Eadon, Tetrahedron Lett. 1972 257]. Furthermore, it is from the prior art known that such aldehydes in a selective manner by means of N-bromosuccinimide and its derivatives can be prepared (for example, iodosuccinimide and Tetrabutylammonium iodide) [R. Filler, Chem. Rev. 63, 21-43 (1963) 22; S. Hanessian, D.H. Wong and M. Therien, Synthesis 1981, 394].

Besides this is the indirect oxidation with the systems Dimethyl sulfoxide / oxalyl chloride or tosyl chloride on the basis of a Pfizner-Moffatt reaction [J.G. Moffatt in R.L. Augustine and D.J. Tracker, "Oxidation", Marcel Dekker, New York, Vol. 2, 1971, 1].

The subsequent reaction with the phosphonium salt 34, which from the corresponding o-, m- or p-Brommethylbenzoesäuremethylester 18 with from the state easily prepared by the technique known methods can be delivered as part of a Wittig reaction  [C, Ferri, Reactions of Organic Synthesis, Georg Thieme Verlag, Stuttgart, 1978, p. 354 and cit. Lit .; J. March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1985, p. 845 and cit. Lit.] the corresponding Olefin of type 35.

For this, the carbonyl compound 33 becomes a solution or suspension of the phosphonium salt 34 and in Presence of a base implemented.

Suitable reaction media are all solvents which do not adversely affect the course of the reaction, among which ethers - such as. For example, di-n-butyl ether, Glycol dimethyl ether, diglycol dimethyl ether, Tetrahydrofuran - or sulfoxides - such as Dimethyl sulfoxide or tetrahydrothiophene 1,1-dioxide (Sulfolane). It is also possible to mix the to use said solvent.

The bases are preferably alkali metal hydrides or Alkali used, with sodium hydride or Sodium methoxide are particularly preferred.

The reaction temperature can - depending on the respectively used reaction medium - in a wide Range will be varied and will go down through one too low reaction rate and up through limited the prevalence of side reactions.

Since the Wittig reaction in a very large number of Variants is feasible, is thereby - depending on Type of selected variant - the choice of others Reaction media, bases and others Reaction conditions allows.  

The subsequent hydrogenation of the thus obtained Benzoesäurederivates 35 to diester 36 takes place preferably - analogous to that described under 3.3.2 Hydrogenation Step - Catalytic.

As catalysts are preferably Raney nickel, with Sodium boranate reduced nickel (II) chloride (so-called. Nickel boride), platinum metal, platinum oxide, rhodium, Zinc oxide, or palladium on carbon use.

Besides, it is possible to apply the reduction to carry out the homogeneous catalysis. As catalysts are suitable u. a. Rhodium complexes - such. B. Chlorotris (triphenylphosphine) rhodium (RhCl (Ph₃P) ₃) [F. H. Jardine, prog. Inorg. Chem. 28 (1981) 63].

In addition, systems such. For example, sodium in ethanol, Sodium and tert-butyl alcohol in Hexamethylphosphoric triamide [P. Angibeaud, M. Larcheveque, H. Normant and B. Tchoubar, Bull. Soc. Chem. Fr. 1968, 595; G.M. Whitesides and W.J. Ehmann, J. Org. Chem. 35 (1970) 3565], lithium and aliphatic Amines [R.A. Benkeser, G. Schroll and D.M. Sauve, J. Am. Chem. Soc. 77 (1955) 3378), zinc in the presence of Acids, NaTeH [K. Ramasamy, S.K. Kalyanasundaram and P. Shanmugam, Synthesis 1978, 545; M. Yamashita, Y. Kato and R. Suemitso, Chem. Lett. 1980, 847], Trifluoroacetic acid and triethylsilane [J. March, Advanced Organic Chemistry, J. Wiley and Sons, New York, 1985, p. 693 and cit. Lit.], hydrazine in Presence of small amounts of oxidizing agents [E. Corey, W.L. Mock and D.J. Pasto, Tetrahedron Lett. 1961, 347; S. Hünig, H.R. Müller and W. Thier, Tetrahedron Lett. 1961, 353; A. Furst, R.C. Berlo and S. Hooton, Chem. Rev. 65 (1965) 51; G. Nagendrappa and  D. Devaprabhakara, Tetrahedron Lett. 1970, 4243; Hoffmann and Schlesinger, J. Chem. Soc., Chem. Commun. 1971, 1245; K. Kondô, S. Murai and N. Sonoda, Tetrahedron Lett. 1977, 3727], hydroxylamine and Ethyl acetate [P.A. Wade and N.V. Amine, synth. Commun. 12 (1982) 287] and hydroxylamine-O-sulfonic acid (NH₂OSO₃H) [R. Appel and W. Büchner, Liebigs Ann. Chem. 654 (1962) 1; W. Dürckheimer, Liebigs Ann. Chem. 721 (1969) 240; R.G. Wallace, Org. Prep. Proced. Int. 14 (1982) 265].

In addition, the reduction of the double bond succeeds under Preservation of the two ester functions in the diester 36 with AlH₃ [H.J. Jorgenson, Tetrahedron Lett. 1962, 559; W. L. Dilling and R.A. Plepys, J. Org. Chem. 35 (1970) 2971; H.C. Brown and H.M. Hess J. Org. Chem. 34 (1969) 2206] and with sodium borohydride in the presence of Salts - preferably chlorides - the lanthanides - like z. B. LaCL₃, CeCl₃, SmCl₃ - [A.L. Gemal and J. Luche, J. Am. Chem. Soc. 103 (1981) 5454] as well as 9-Borabicyclo [3.3.1] nonane (9-BBN) [V.V. Krishanamurthy and H.C. Brown, J. Org. Chem. 42 (1977) 1197], Triethylsilane [I. Ojima and T. Kogure, Organometallics 1 (1982) 1390].

The type 36 diesters thus obtained become preferably using methanolic solutions of alkali or alkaline earth metal salts in the corresponding type 37 alcohols are converted, wherein Alkali carbonates are particularly preferred and Potassium carbonate is very particularly preferred.

The alcohols 37 thus prepared are - as under 3.2.1 (reaction 11 to 12a) - into the corresponding 4-aryl or Heteroaryl-1,2,3,6-tetrahydropyridines or in the corresponding aryl or heteroarylpiperazines or Azepine of type 38 transferred.  

The Benzoesäureester 38 can - if desired - again by means of the method described under 3.1 (Reaction 6a to 7 or Reaction 6a to 6b) to the corresponding amide derivatives 39 or by way of Transesterification converted into type 40 benzoic acid ester become.

Examples Example 1.1: 3- (3-Chloropropoxy) benzoic acid methyl ester (Reaction 2 to 4)

50.0 g (329 mmol) of 3-hydroxybenzoic acid methyl ester and 123.9 g (787 mmol) of 1-bromo-3-chloropropane are combined with 69.0 g (500 mmol) of potassium carbonate in 1 liter of acetone resolved and over a period of 9 hours Reflux temperature heated. Then you leave on Cooling room temperature, soaks of the inorganic Salting off and concentrating i. Vak. on. The residue is with 400 ml of water and twice with 200 ml of ether extracted. The organic phase is dried and the solvent i. Vak. deducted. Subsequently, will the residue i. Vak. distilled.

74.9 g (99.6% of theory) of the title substance are obtained a boiling point of 193-197 ° C (17.33 mbar).

Analogous to Example 1.1 are the following Benzoic acid ester derivatives accessible:

Example 1.2

2- (3-chloropropoxy) -benzoic acid methyl ester
Yield: 71%, b.p .: 185-187 ° C (17.33 mbar).

Example 1.3

4- (3-chloropropoxy) -benzoic acid methyl ester
Yield: 92%, b.p .: 204-206 ° C (17.33 mbar).

Example 1.4

3- (4-chlorobutoxy) -benzoic acid methyl ester
Yield: 99%, b.p .: 134 ° C (1.33 mbar).

Example 1.5

2- (4-chlorobutoxy) -benzoic acid methyl ester
Yield: 69%, b.p .: 198-199 ° C (16 mbar).

Example 2.1

1- [3- (2-Methoxycarbonyl) phenoxypropyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (Reaction 4 to 6a)
13.7 g (60 mmol) of 2- (3-chloropropoxy) -benzoic acid methyl ester 9.7 g (50 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride 16.0 g (100 mmol) of potassium iodide and 30 g of potassium bicarbonate are stirred for 8 h at 50 to 60 ° C in 100 ml of dimethylformamide. Then allowed to cool to room temperature, filtered off from the inorganic salts and concentrated i. Vak. on. The residue is mixed with 300 ml of water and extracted twice with 250 ml of ethyl acetate. The organic phase is dried and the solvent i. Vak. deducted. The remaining residue is adsorptively filtered on silica gel (solvent: cyclohexane: ethyl acetate, 2: 1), the purified fractions are combined and the hydrochloride is precipitated with ethereal hydrochloric acid. 17.6 g (91% of theory) of the title substance are isolated with a melting point of 161.degree.-162.degree.

Analogously to Example 2.1 are the following Tetrahydropyridine derivatives and piperazine derivatives accessible:

Example 2.2

1- [3- (4-Methoxycarbonylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine
Yield: 72%, mp: 85-86 ° C.

Example 2.3

1- [3- (3-Methoxycarbonylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 65%, mp: 166 ° C.

Example 2.4

1- [3- (3-Methoxycarbonylphenoxy) propyl] -4-phenylpiperazine hydrochloride
Yield: 73%, mp: 195-197 ° C.

Example 2.5

1- [4- (3-Methoxycarbonylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 82%, mp: 167-168 ° C.

Example 2.6

1- [4- (2-Methoxycarbonylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 51%, mp. 138-139 ° C

Example 3.1

1- [3- (2-Carbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (Reaction 6a to 2)
3.7 g (10 mmol) of 1- [3- (2-methoxycarbonylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine are dissolved in 25 ml of methanol and in an autoclave with 25 ml of liquid ammonia added. The closed autoclave is heated to 150 ° C for 17 h. The reaction mixture is then allowed to cool to room temperature, the excess ammonia is blown off and the solution is filtered through 20 g of silica gel. The solution is i. Vak. concentrated, the precipitated crystals dissolved in methanol and the hydrochloride precipitated with ethereal hydrochloric acid. 2.9 g (78% of theory) of the title substance are obtained as crystals having a melting point of 218-220 ° C.

Analogously to Example 3.1 are the following Tetrahydropyridine derivatives and piperazine derivatives accessible:  

Example 3.2

1- [3- (2-Methylcarbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 83%, mp: 206-208 ° C.

Example 3.3

1- [3- (4-carbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine methanesulfonate
Yield: 63%, mp: 201-202 ° C.

Example 3.4

1- [3- (4-Methylcarbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine methanesulfonate
Yield: 69%, m.p .: 174-176 ° C

Example 3.5

1- [3- (2-Carbamoylphenoxy) propyl] -4- (4-chloro) -phenyl-1,2,3,6-tetrahydropyridine methanesulfonate
Yield: 61%, mp: 207-209 ° C

Example 3.6

1- [3- (2-Carbamoylphenoxy) propyl] -4- (4-fluoro) -phenyl-1,2,3,6-tetrahydropyridine methanesulfonate
Yield: 59%, mp: 181-183 ° C.

Example 3.7

1- [3- (3-carbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine oxalate
Yield: 74%, mp: 94-99 ° C.

Example 3.9

1- [3- (3-Ethylcarbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 62%, mp: 178-180 ° C.

Example 3.10

4-phenyl-1- [3- (3-propylcarbamoylphenoxy) propyl] -1,2,3,6-tetrahydropyridine hydrochloride
Yield: 53%, m.p .: 177-178 ° C.

Example 3.11

1- [3- (3-carbamoylphenoxy) propyl] -4-phenyl-piperazine hydrochloride
Yield: 69%, mp: <250 ° C.

Example 3.12

1- [3- (3-Methylcarbamoylphenoxy) propyl] -4-phenylpiperazine hydrochloride
Yield: 73%, mp: 201-204 ° C.

Example 3.13

1- [4- (3-carbamoylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 51%, mp: 196-198 ° C.

Example 3.14

1- [4- (3-methylcarbamoylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine oxalate
Yield: 52%, mp: 144-145 ° C.

Example 3.15

1- [3- (3-Ethylcarbamoylphenoxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine oxalate
Yield: 45%, mp: 113-115 ° C.

Example 3.16

1- [2- (3-Methylcarbamoylphenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 64%, mp: 158-160 ° C.

Example 3.17

1- [3- (2-carbamoyl) phenoxy] -4-phenyl-piperazine methanesulfonate
Yield: 64%, m.p .: 184-186 ° C.

Example 3.18

1- [2- (3-carbamoylphenyl) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine (Reaction 21 to 22)
Yield: 0.4 g (44%), 145-147 ° C.

Example 3.19

1- [2- (3-methylcarbamoylphenyl) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine
Yield: 62%, mp: 115-117 ° C.

Example 3.20

1- [4- (2-carbamoylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 63%, mp: 190-193 ° C.

Example 3.21

1- [4- (2-methylcarbamoylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine
Yield: 53%, mp: 168-169 ° C.

Example 3.22

1- [4- (2-ethylcarbamoylphenoxy) butyl] -4-phenyl-1,2,3,6-tetrahydropyridine
Yield: 61%, mp: 139-141 ° C.

Example 3.23

1- [3- (2-carbamoyl) phenoxy] propyl 4- (2-pyridyl) piperazine methanesulfonate
Yield: 64%, mp: 137-138 ° C.

Example 3.24

1- [3- (2-carbamoyl) phenoxy] propyl-4- (2-pyrimidinyl) -piperazine dihydrochloride
Yield: 67%, mp: 206-208 ° C.

Example 3.25

1- [2- (2-carbamoyl) phenoxy] ethyl-4-phenyl-piperazine
Yield: 68%, mp: 161-163 ° C.

Example 3.26

1- [2- (2-carbamoyl) phenoxy] ethyl-4-phenyl-1,2,3,6-tetrahydropyridine
Yield: 65%, mp: 137-138 ° C.

Example 4.1

2-bromophenylmethoxyacetic acid ethyl ester (reaction 8 to 10)
10.7 g (0.27 mol) of 60% sodium hydride are washed twice with 50 ml of absolute petroleum ether and suspended in 125 ml of absolute tetrahydrofuran. A solution of 50.0 g (0.27 mol) of o-bromobenzyl alcohol in 125 ml of absolute tetrahydrofuran is added dropwise at 0 to 10 ° C. to this suspension. The mixture is stirred for 1 h at room temperature, added dropwise at 5 ° C 32.7 ml (0.29 mol) of methyl bromoacetate in 100 ml of absolute tetrahydrofuran, stirred for a further hour at room temperature and then heated over a period of 4 h to 50 ° C. Then allowed to cool the reaction mixture to room temperature, the solvent draws i. Vak. and the residue is taken up in 100 ml of ethyl acetate and 100 ml of water. The organic phase is separated, dried and the solvent after filtering off the desiccant i. Vak. deducted. The remaining residue is i. Vak. distilled.

42.5 g (58% of theory) of the title substance are obtained a bp .: 178-182 ° C (17.33 mbar).

Example 5.1

2- (2-bromophenylmethoxy) ethanol (10 to 11 reaction)
5.9 g (0.16 mol) of lithium aluminum hydride are suspended in 60 ml of absolute tetrahydrofuran and added dropwise at room temperature 42.5 g (0.16 mol) of 2-bromophenylmethoxy-ethyl acetate in 30 ml of absolute tetrahydrofuran. The mixture is stirred for 2 h at room temperature, mixed with 60 ml of 40% diammonium tartrate solution, filtered off with suction from the resulting precipitate and washed thoroughly with ethyl acetate. The solvent is i. Vak. deducted. Then 50 ml of water and 150 ml of ethyl acetate are added, the organic phase separated, dried and the solvent after filtering off the desiccant i. Vak. deducted. The residue is processed raw.

This gives 34.5 g (94% of theory) of the title substance as an oil with a calculation index of n _D ²⁰ = 1.548.

Example 6.1

1- [2- (2-Bromophenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine (Reaction 11 to 12a)
29.2 g (0.13 mol) of 2- (2-Bromophenylmethoxy) ethanol are dissolved in 290 ml of absolute pyridine, cooled to -5 ° C and treated with 47.0 g (0.225 mol) of p-toluenesulfonyl chloride. The reaction mixture is allowed to warm to room temperature and stirred at this temperature for 3 h. The mixture is mixed with 400 ml of cold water and 400 ml of dichloromethane, the organic phase is separated and washed twice with 50 ml of cold 2N hydrochloric acid. The organic phase is dried and the solvent i. Vak. deducted. The residue is dissolved in 600 ml of dimethylformamide and treated with 20.1 g (0.13 mol) of 4-phenyl-1,2,3,6-tetra hydropyridine and 50 g of potassium bicarbonate. Subsequently, the reaction mixture is stirred for 3 h at a temperature in the range of 90 to 100 ° C. The mixture is allowed to cool, sucks from the potassium bicarbonate and the solvent is drawn i. Vak. from. The residue is mixed with 200 ml of water and 400 ml of ethyl acetate. The organic phase is separated, dried and the solvent i. Vak. deducted.

The residue is added to 10 times the amount of silica gel purified [eluent: cyclohexane-ethyl acetate 1: 1).

The appropriate fractions are pooled and the Solvent is i. Vak. deducted.

This gives 31.9 g (66% of theory) of the title compound in Form of an oil.

Example 7.1

1- [2- (2-cyanophenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine (Reaction 12 to 13)
29.9 g (80 mmol) of 1- [2- (2-bromophenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine and 10.5 g (117 mmol) of copper (I) cyanide are stirred for 3 hours at 150 ° C in 75 ml of dimethylformamide. Then allowed to cool the reaction mixture to room temperature, filtered off with suction from the precipitate and draws the solvent i. Vak. from. The residue is added to ice-cooled aqueous ammonia solution and extracted three times with 200 ml of ethyl acetate. The organic phase is dried and the solvent i. Vak. deducted. The residue is purified by means of low pressure chromatography on 20 times the amount of silica gel [MN K 60, 230-400 mesh ASTM, from Macherey and Nagel eluent:
Cyclohexane-ethyl acetate 3: 1 to 1: 1]. The appropriate fractions are combined and the solvent i. Vak. deducted.

This gives 12.7 g (50% of theory) of the title compound in Form of an oil.

Example 8.1

1- [2- (2-Methylcarbamoylphenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine oxalate [A] and 1- [2- (2-carbamoylphenylmethoxy) ethyl] -4-phenyl 1,2,3,6-tetrahydropyridine oxalate [B] (Reaction 13 to 14)
20 g (6 mmol) of 1- [2- (2-cyanophenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine and 2.1 g (31 mmol) of powdered potassium hydroxide are dissolved in 78 ml of absolute tert. Butanol dissolved and heated to reflux over a period of 2.5 h. It is allowed to cool to room temperature and treated with 0.4 ml (6 mmol) of iodomethane, heated for 2 h at 50 ° C, allowed to cool again to room temperature, treated with a further 0.4 ml of iodomethane and heated for a further 2 h at 50 ° C. It is then cooled to room temperature and filtered from the residue, the solvent i. Vak. removed and the remaining residue with 100 ml of ethyl acetate and 50 ml of water. The phases are separated, the aqueous phase extracted again with 50 ml of ethyl acetate. The organic phases are combined, dried and the solvent i. Vak. deducted. The residue is adsorptively purified by means of low-pressure chromatography on 20 times the amount of silica gel [MN K 60, 230-400 mesh ASTM, by Macherey and Nagel; eluent:
Dichloromethane-ethyl acetate-methanol 7: 2: 1]. The appropriate fractions are combined and the solvent i. Vak. deducted. There are then obtained 1- [2- (2-methylcarbamoyl) -phenylmethoxy] ethyl-4-phenyl-1,2,3,6-tetrahydropyridine (R _f = 0.27, TLC: Kieselgel 60, the above-mentioned solvent) and 1 - [2- (2-carbamoyl) phenylmethoxy] ethyl-4-phenyl-1,2,3,6-tetrahydropyridine (R _f = 0.20). The respective residues are dissolved in ethanol and the corresponding oxalates are precipitated with oxalic acid. The title compounds are obtained as crystals in the following yields: [A]: 0.4 g (17% of theory) mp: 203-206 ° C.
[B]: 0.8 g (32% of theory) mp: 154-157 ° C

Example 8.2

In analogy to Example 8.1, 1- [2- (3-carbamoyl) phenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine produced. However, it is - deviating from Example 8.1 - not mixed with iodomethane, but immediately worked up.

The title compound is obtained in a yield of 51%, in the form of crystals of mp. 101-103 ° C.

Example 9.1

1- [2- (2-Methoxycarbonylphenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine oxalate (Reaction 13 to 16)
2.0 g (6 mmol) of 1- [2- (2-cyanophenylmethoxy) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine are dissolved in a solution of 0.8 g (12 mmol) of potassium hydroxide in 5 ml of water and 20 ml of ethylene glycol added over a period of 20 h at a temperature of 100 ° C stirred. Subsequently, the solvent is i. Vak. removed and the residue in a mixture of 30 ml of methanol, 5 ml of trimethyl orthoformate and 5 ml of conc. Sulfuric acid for 2 h at reflux temperature. The solvent is i. Vak. removed and the residue is combined with 100 ml of ethyl acetate and 100 ml of cold 2N sodium hydroxide solution. The organic phase is separated, dried and the solvent i. Vak. deducted. The residue is purified by means of low pressure chromatography on 30 times the amount of silica gel [MN K 60, 230-400 mesh ASTM, from Macherey and Nagel; Eluent: cyclohexane-ethyl acetate 1: 1]. The appropriate fractions are combined and the eluent i. Vak. deducted. The remaining residue is dissolved in acetone and the oxalate is precipitated with oxalic acid.

The title compound is obtained in a yield of 0.6 g (22% of theory) of mp: 163 ° C.

Example 10.1 (Reaction 18 to 19)

151.6 g (0.66 mol) of methyl 3-bromomethylbenzoate, 56.2 g (0.86 mol) of potassium cyanide and 15.2 g (0.06 mol) 18-crown-6 (1,4,7,10,13-pentaoxacyclopentadecane) over a period of 32 h in 700 ml of acetonitrile and 70 ml of water heated to reflux. Then allowed to the reaction mixture Cool room temperature, soak off the solid Components of the reaction mixture and concentrated i. Vak. on. The remaining residue is mixed with 300 ml of water mixed and twice with 250 ml of ethyl acetate extracted. The organic phase is dried, the Solvent after filtering off the desiccant i. Vak. deducted and the residue i. Vak. distilled [Bp .: 110-117 ° C (0.133 Pa)]. The distillate is in 1300 ml of methanol and 140 ml of conc. Hydrochloric acid dissolved, with 11 g of palladium / carbon (10%) and added via a Period of 5 h in an autoclave at 20 ° C and a Hydrogen pressure of 13 bar hydrogenated. The Hydrogen absorption is according to the consumption of  calculated amount finished. Man sucks the catalyst on silica gel and the filtrate concentrated i. Vak. on. The Residue is dissolved in ethanol and the hydrochloride precipitated with ethereal hydrochloric acid.

105.1 g (73.6% of theory) of the title compound are obtained as crystals of mp .: 140-142 ° C.

Example 11.1

Methyl 3- (2-hydroxyethyl) benzoate (Reaction 19 to 20)
147.0 g (0.68 mol) of methyl 3- (2-aminoethyl) benzoate hydrochloride and 15.0 g of dimethylaminopyridine are dissolved in 2500 ml of pyridine, cooled to -2 ° C and slowly added with 370 ml (2.46 mol ) Trifluoroacetic anhydride added. The mixture is allowed to react for 2 h at 0 to 7 ° C, the solvent draws i. Vak. , the residue is taken up in 900 ml of dichloromethane and washed twice with 300 ml of water. The organic phase is dried and i. Vak. concentrated. The residue is crystallized from a little ether / cyclohexane [mp. 87-89 ° C], then dissolved in a mixture of 1000 ml of acetic acid and 2000 ml of acetic anhydride and treated under ice-cooling with 385.6 g (5.59 mol) of sodium nitrite. The reaction mixture is allowed to warm to room temperature and stirred for 20 h at room temperature. The mixture is then added to 3 l of ice-water and extracted three times with 600 ml of dichloromethane. The combined extracts are dried and the solvent - after filtering off the desiccant - i. Vak. deducted. The remaining residue is dissolved in 500 ml of methanol, 77.2 g of potassium carbonate are added and the mixture is stirred at room temperature for 6 h. The mixture is then filtered off from the potassium carbonate, the solvent i. Vak. removed and the residue distilled under high vacuum. The title compound is obtained in a yield of 69.8 g (57% of theory) as oil of b.p .: 106-110 ° C. (0.133 Pa).

Example 12.1

1- [2- (3-Methoxycarbonylphenyl) ethyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (Reaction 20 to 21)
19.6 g (0.11 mol) of ethyl 3- (2-hydroxyethyl) benzoate are dissolved in 200 ml of dichloromethane and stirred with 7 ml (0.08 mol) of phosphorus tribromide for 3 hours at room temperature. The mixture is then added to 100 g of ice and extracted once with 100 ml of ice water. Thereafter, the organic phase is dried, the solvent after filtering off the desiccant - i. Vak. removed and the residue distilled under high vacuum. [Bp .: 100-106 ° C (0.133 Pa)]. The distillate is dissolved in 150 ml of dimethylformamide and treated with 12.7 g (0.06 mol) of 4-phenyl-1,2,3,6-tetra hydropyridine hydrochloride and with 10.9 g (0.13 mol) of sodium bicarbonate and stirred at a temperature in the range of 50 to 60 ° C for 20 h. Then the solvent is i. Vak. removed, the residue with 150 ml of dichloromethane and 150 ml of water. After separation and drying of the organic phase, the extractant - after removing the desiccant - i. Vak. deducted. The residue is adsorptively purified by means of low-pressure chromatography on 20 times the amount of silica gel [MN K 60, 230-400 mesh ASTM, by Macherey and Nagel; Eluent: cyclohexane-ethyl acetate 3: 1 to 1: 1). The appropriate fractions are combined and the solvent i. Vak. deducted. The residue is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

The title compound is obtained in a yield of 8.3 g (21% of theory) as crystals of mp: 203-206 ° C.

Example 13.1

3- (3-cyanophenyl) -propenoic acid (reaction 24 to 26)
25.0 g (0.19 mol) of m-cyanobenzaldehyde, 23.8 g (0.22 mol) of malonic acid and 1.6 ml of piperidine are dissolved in 33 ml of pyridine and heated under reflux for 2.5 h. Then the solution is added to 100 g of ice and treated with 100 ml of concentrated hydrochloric acid. The crystals are filtered off with suction and dried.

The title compound is obtained in a yield of 30.7 g (93% of theory) in the form of crystals of the formula: 243 ° C.

Example 14.1

3- (3-cyanophenyl) propeno 10095 00070 552 001000280000000200012000285910998400040 0002004325855 00004 09976l (Reaction 26 to 12)
30.5 g (176 mmol) of 3- (3-cyanophenyl) -propenoic acid and 26 ml (352 mmol) of thionyl chloride are dissolved in 60 ml of dichloroethane and heated at reflux temperature for 3 hours. Subsequently, the reaction mixture i. Vak. concentrated and the residue dissolved in 200 ml of tetrahydrofuran. This solution is added dropwise with stirring to a cooled to -20 to -25 ° C mixture of 12.7 g (334 mmol) of sodium borohydride in 600 ml of ethanol. The mixture is stirred for 15 minutes and then added 100 ml of 2N hydrochloric acid. The solvent is i. Vak. removed, the residue taken up in 200 ml of dichloromethane and extracted twice with 50 ml of water. The organic phase is dried and after filtering off the desiccant i. Vak. concentrated. The residue is then distilled under high vacuum to give the title compound in a yield of 21.0 g (75% of theory). The product crystallizes and has a mp of 55 ° C.

Example 15.1

3- (3-Hydroxypropenyl) benzoic acid (Reaction 27 to 28)
17.5 g (0.11 mol) of 3- (3-cyanophenyl) -propenol are stirred in a mixture of 100 ml of ethanol, 75 ml of water and 25.8 g of potassium hydroxide at a temperature of 70 ° C for 2 h. Subsequently, the ethanol is i. Vak. removed and the residue under cooling with 100 ml of conc. Hydrochloric acid added. The precipitated crystals are filtered off and washed once with 50 ml of cold water. Subsequently, the crystals are dissolved warm in 300 ml of ethyl acetate; The solution is mixed with 20 g of activated carbon and adsorptively filtered on silica gel. The filtrate is i. Vak. concentrated and the precipitated crystals are filtered off with suction and washed once with 50 ml of diethyl ether.

The title compound is obtained in a yield: 16.8 g (86% of theory) in the form of crystals of the m .: 122-124 ° C.

Example 16.1

3- (3-hydroxypropyl) benzoic acid (Reaction 28 to 29)
16.8 g (94 mmol) of 3- (3-hydroxy) propenylbenzoic acid are dissolved in 170 ml of methanol, admixed with 11 g of Raney nickel and hydrogenated for 2 h in an autoclave at 20 ° C. and under a hydrogen pressure of 5 bar. The hydrogen uptake is terminated after consumption of the calculated amount. The catalyst is suctioned off over silica gel and the filtrate is concentrated i. Vak. on. There remain 16.8 g of the title compound (99% of theory) in the form of an oil.

Example 17.1

3- (3-chloropropyl) benzoic acid methylamide (Reaction 29 to 30)
5.4 g (30 mmol) of 3- (3-hydroxypropyl) benzoic acid are dissolved in 10 ml of dichloromethane and admixed with 0.2 ml of dimethylformamide. While cooling, 10 ml of thionyl chloride are added dropwise at 10 to 15 ° C. Subsequently, the reaction mixture is stirred for 0.5 h at room temperature and for 1 h at reflux temperature. The reaction mixture is i. Vak. concentrated, the residue taken up in 50 ml of absolute toluene, again i. Vak. concentrated and dissolved in 30 ml of absolute dichloromethane. At a temperature in the range of 10 to 15 ° C then 20 ml of a mixture of methylamine and tetrahydrofuran (5:95) are added dropwise. Thereafter, stirring is continued for 30 minutes at room temperature. You narrow it down i. Vak. a, the residue is combined with 50 ml of water and 50 ml of ethyl acetate. The organic phase is separated, dried and the solvent i. Vak. deducted. The title compound is obtained in a yield of 4.4 g (69% of theory) in the form of an oil.

Example 18.1

1- [3- (3-methylcarbamoylphenyl) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine (Reaction 30 to 31)
4.3 g (20 mmol) of 3- (3-chloropropyl) benzoic acid methylamide, 3.9 g (20 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride, 6 g of potassium bicarbonate and 3.2 g Potassium iodide are stirred for 4 hours at a temperature in the range of 80 to 90 ° C in 70 ml of dimethylformamide. Subsequently, the solvent is i. Vak. concentrated, the residue is mixed with 300 ml of water and extracted twice with 200 ml of ethyl acetate. The organic phase is dried and the solvent i. Vak. deducted.

The residue is purified by low pressure chromatography purified on 20 times the amount of silica gel [MN K 60, 230-400 mesh ASTM, from Macherey and Nagel; Eluent: dichloromethane-ethyl acetate-methanol 70: 20: 10]. The appropriate fractions are pooled and the solution i. Vak. concentrated. The failed ones Crystals are sucked off and once with 30 ml Washed diethyl ether. The title compound is obtained in a yield of 3.1 g (46% of theory) as crystals of the m .: 115-116 ° C.

Analogously to Example 18.1 is shown:

Example 18.2

1- [3-carbamoylphenyl) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
Yield: 48%, mp: 230-233 ° C.

formulation

The benzoic acid derivatives of the general formula I and their acid addition salts with pharmacological Safe acids can in the known manner in the usual formulations - such as tablets, dragees, Pills, granules, aerosols, syrups, emulsions, Suspensions and solutions using inert pharmaceutically suitable excipients or Solvents are transferred. Here is the share the pharmaceutically active compound (s) in each case in Range from 0.5% to 90% by weight of the total composition lie, d. H. in amounts sufficient to the To reach below dosing range.

The formulations are for example through Stretching the active ingredients with solvents and / or Carriers, optionally using Emulsifiers and / or dispersants, for example, when using water as Diluent optionally organic Solvent as solubilizer or Auxiliary solvents can be used.

As auxiliaries, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (eg petroleum fractions), vegetable oils Origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg, ethanol or glycerol), Carriers, such. B. ground natural minerals (eg Kaolin, clays, talc, chalk), synthetic Minerals (eg fumed silica and minerals) Silicates), sugars (eg, pipe, dairy, and Dextrose), emulsifying agents (eg lignin, Sulfite liquors, methylcellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g. Magnesium stearate, talc, stearic acid and Sodium lauryl sulfate).  

The application is done in the usual way parental - especially by infusion - oral or transdermally. In case of oral administration, the Tablets of course except those mentioned Carriers also additives such. For example, sodium citrate, Calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably Potato starch, gelatin and the like. Furthermore, lubricants, such as magnesium stearate, Sodium lauryl sulfate and talc for tableting be used. In the case of aqueous suspensions can the active ingredients except the above Excipients with different flavor enhancers or dyes are added.

In the case of parenteral use, solutions the active ingredients using suitable liquid Carrier materials are used.

The dosage for oral use is 1-300 mg preferably between 5 and 150 mg.

Nevertheless, it may possibly be necessary from to deviate from the said quantities, in Dependence on the body weight or the type of Application route, of individual behavior towards the drug, the kind of it Formulation and the time or interval, too which the administration takes place. So it can be in be sufficient in some cases, with less than that abovementioned minimum amount while in other cases exceeded the stated upper limit must become. In case of application of larger quantities It may be advisable to do this in several Distribute individual doses throughout the day.  

Furthermore, the compounds of general formula I can or their acid addition salts with other types Active ingredients are combined.

formulation Examples tablets

1. The tablet contains the following ingredients:

Active ingredient according to formula I. 0.020 parts stearic acid 0.010 parts dextrose 1,890 parts total 1,920 parts

manufacturing

The substances are mixed together in a known manner and the mixture is compressed into tablets, each of which Weighs 1.92 g and contains 20 mg of active ingredient.

ampoule solution composition Active substance according to formula I | 1.0 mg sodium chloride 45.0 mg Aqua pro inj. ad 5.0 ml

manufacturing

The active ingredient is added at intrinsic pH or optionally at pH 5.5 to 6.5 dissolved in water and with sodium chloride as isotonic added. The resulting solution is filtered pyrogen-free and the filtrate under aseptic Conditions are filled in ampoules, which subsequently sterilized and sealed. The ampoules contain 1 mg, 5 mg and 10 mg active ingredient.

suppositories

Each suppository contains:

Active ingredient according to formula I. 1.0 parts Cocoa butter (mp .: 36-37 ° C) 1200.0 parts carnauba 5.0 parts

manufacturing

Cocoa butter and carnauba wax melted together. At 45 ° C to give the active ingredient Add and stir until complete dispersion originated. The mixture is in shape poured appropriate size and the suppositories appropriately packaged.

Claims (8)

1. benzoic acid derivatives of the general formula I. wherein
R¹ is O- (C₁-C₆alkyl), NH₂, NH (C₁-C₆alkyl);
X is oxygen, sulfur, or a single bond;
a is a number 0, 1, 2, 3, 4, 5 or 6;
b is a number 2, 3, 4, 5 or 6; A is aryl, heteroaryl;
c is a number 2 or 3;
R² is hydrogen, fluorine, chlorine, bromine, iodine, nitro, amino, mercapto, -S- (CH₁-C₆-alkyl), C₁-C₆-alkyl, haloalkyl, hydroxy and O- (CH₁-C₆-alkyl), wherein R² may be a multiple substituent of A and the same or different;
d is a number 1, 2, 3, 4 or 5
may mean and their acid addition salts. 2. benzoic acid derivatives of the general formula I, wherein
R¹ is methoxy, ethoxy, amino, methylamino, ethylamino, n-propylamino, iso -propylamino;
X is oxygen or a single bond;
a is a number 0, 1, 2, 3 or 4;
b is a number 2, 3 or 4; A is aryl, heteroaryl;
c is a number 2;
R² is hydrogen, fluoro, chloro, bromo, C₁-C₄ alkyl, trihalomethyl, hydroxy and O- (C₁-C₂ alkyl);
d is a number 1 or 2
may mean and their acid addition salts. 3. benzoic acid derivatives of the general formula I, wherein
R¹ is amino, methylamino;
X oxygen;
a is a number 0, 1, 2 or 3;
b is a number 2, 3 or 4; A is aryl, heteroaryl;
c is the number 2;
R² is hydrogen, fluorine and methoxy;
d is the number 1
may mean and their acid addition salts. 4. Pharmaceutical preparation, characterized by a content of a compound according to one of Claims 1 to 3. 5. Use of compounds according to one of Claims 1 to 3 and their acid addition salts at the production of pharmaceutical preparations with a postsynaptic dopamine antagonist and a presynaptic dopamine agonist Effect. 6. Use of compounds according to one of Claims 1 to 3 and their acid addition salts in the manufacture of pharmaceutical Preparations for the treatment of central nervous Diseases. 7. Use of compounds according to one of Claims 1 to 3 and their acid addition salts according to one of claims 1 to 3 in the Production of pharmaceutical preparations for Treatment of psychosis, depression, Anxiety and schizophrenia.   8. A process for preparing compounds of general formula I. characterized in that - in the case
R¹, Y, Z, c, A, R² and d are as defined in claim 1 and

• a) X = oxygen, a = 0 and b is a number 2, 3, 4, 5 or 6 -
  • 1. Hydroxybenzoic acid alkyl ester or general formula 2 reacting with α, ω-haloalkyl halides under known reaction conditions, and
  • 2. the resulting benzoic acid derivative of general formula 4 with heterocyclic compounds of the general formula 5 - where N, R 'and R "are a 6- or 7-membered ring form - converted under known reaction conditions to the corresponding amines 6a and - either
  • 3. by means of a known transesterification - or by saponification of the ester 6a and reesterification of the resulting free carboxylic acid - produces the corresponding carboxy compounds 6b - or
  • 4. on the way of a known per se aminolysis of the benzoic 6a the benzoic acid amides 7 - which fall under the general formula 1 - produces isolated and optionally converted into the corresponding pharmacologically acceptable acid addition salts;
• b) X = oxygen, a = 1, 2, 3, 4, 5 or 6 and b = 2 -
  • 1. Halogenphenylalkylalkohole of the general formula 8 under conditions known per se with methyl haloacetate 9 implements and
  • 2. The resulting Phenylalkoxyessig ester derivative 10 - in a known per se - to the alcohol 11th reduced,
  • 3. the alcohol of general formula 11 after its conversion into the corresponding halide - by means of known methods - with heterocyclic compounds of general formula 5 - wherein N, R 'and R''form a 6- or 7-membered ring - in the corresponding Amine 12a transferred and
  • 4. this - with known per se methods in the corresponding nitrile compounds of the general formula 13 (n = 2) converts and these - either
  • 5. converted by known methods into the corresponding benzoic acid amides 14a (n = 2), isolated and optionally converted into the corresponding, pharmacologically suitable acid addition salts
    - or
  • 6. saponified in known manner to the corresponding benzoic acid derivatives 15 (n = 2) and
  • 7. esterifying the resulting carboxylic acid derivatives 15 to the corresponding benzoic acid ester 16 (n = 2) and
  • 8. subjecting the resulting benzoic acid ester 16 - under known reaction conditions - the aminolysis and the resulting benzoic acid amides 14 (n = 2), which fall under the general formula 1 isolated and optionally converted into the corresponding pharmaceutically suitable acid addition salts,
    - or
  • 9. the nitrile of general formula 13 saponified with an alkali metal hydroxide and then with an alkyl halide HalR _alkyl to the corresponding carbamoyl compound 14th reacted, this isolated and optionally converted into the corresponding pharmacologically acceptable acid addition salts.
• c) X = oxygen, a = 1, 2, 3, 4, 5 or 6 and b is a number 3, 4, 5 or 6 -
  • 1. Halogenphenylalkyl alcohols of the general formula 8 (E = halogen) with α, ω-Dihalogenidalkylverbindungen (general formula 3 or 3a) to the corresponding Halogenphenylalkyl oxyalyklhalogeniden 17 (n = b) and
  • 2. the resulting halogen compounds (E = halogen) by - methods known per se - with heterocyclic compounds of general formula 5 - wherein N, R 'and R''form a 6- or 7-membered ring - in the amine 12b, which among the general formula 1 falls, transfers, isolates and
  • 3. these - with known per se methods in the corresponding nitrile compounds of the general formula 13 - a and b as defined under c - transferred and these
    - either
  • 4. by means of known methods in the corresponding benzoic acid amides of the general formula 14a - a and b as defined under c - transferred, these isolated and optionally converted into the corresponding, pharmacologically suitable acid addition salts
    - or
  • 5. in a conventional manner to the corresponding benzoic acid derivatives of general formula 15 - a and b as defined under c - saponified and
  • 6. the resulting carboxylic acid derivatives 15 to the corresponding benzoic acid esters of general formula 16 - a and b as defined under c - esterified, these isolated and optionally converted into the corresponding, pharmacologically suitable acid addition salts.
• d) X is a single bond, a = 0 and b = 2
  • 1. Bromomethylbenzoate of the general formula 18 reacts with alkali metal cyanides according to known methods and then subjects the corresponding nitriles to reduction and
  • 2. the resulting amines of the general formula 19 are converted by known methods with trifluoroacetamide into the corresponding trifluoroacetamides, these diazotized and - after their conversion into the corresponding acetates - from these produces the alcohols of general formula 20 and
  • 3. the alcohols of general formula 20 by means of known methods - after their activation - with heterocyclic compounds of general formula 5 - wherein N, R 'and R''form a 6- or 7-membered ring - in the amine of general formula 21 transferred and the resulting benzoic acid esters 21 - either
  • 4. using known methods in the - corresponding benzoic acid amides of the general formula 22, which fall under the general formula 1, transferred, isolated and optionally converted into the corresponding pharmacologically acceptable acid addition salts
    - or
  • 5. with known methods - in the benzoic acid ester of the general formula 23, which fall under the general formula 1 transesterified, the reaction product isolated and optionally producing the corresponding pharmacologically acceptable acid addition salts;
• e) X represents a single bond, a = 1 and b = 2 -
  • 1. Cyanobenzaldehyde the general formula 24 - by means of per se known methods - transferred with malonic acid 25 in the Propencarbonsäurederivate the general formula 26 and
  • 2. the resulting carboxylic acids 26 after their activation - reduced by means of known methods - to the corresponding alcohols of general formula 27 and
  • 3. saponifies the resulting nitriles 27 by methods known per se to give the corresponding benzoic acid derivatives of general formula 28 and
  • 4. The corresponding unsaturated carboxylic acids 28 are hydrogenated by methods known per se to give the correspondingly saturated benzoic acid derivatives of general formula 29 and
  • 5. the resulting benzoic acid derivatives 29 - according to methods known from the prior art - with thionyl chloride and converted with alcohols or amines into the corresponding benzoic acid esters or - amides of the general formula 30 and
  • 6. The resulting benzoic acid derivatives 30 - by methods known per se - with heterocyclic compounds of general formula 5 - wherein N, R 'and R''form a 6- or 7-membered ring - into the amine 1, which falls under the general formula 1 convicted isolated and optionally converted into the corresponding, pharmacologically suitable acid addition salts;
• f) X represents a single bond, a = 0 and b = 4 -
  • 1. Propanediol monoacylester of the general formula 32 by means of per se known procedures to the appropriate aldehydes of the general formula 33 oxidizes and
  • 2. with phosphonium salts of the general formula 34 to the - known per se from the prior art methods - corresponding alkenyl benzoic acid derivatives of the general formula 35 and
  • 3. this - in a manner known per se - hydrogenated to the correspondingly saturated propanecarboxylic acid derivatives of general formula 36 and
  • 4. subjecting the resulting carboxylic acid ester 36 - according to known methods - the saponification, resulting in the corresponding alcohols of the general formula 37 result and
  • 5. by means of per se known methods, the resulting alcohols 37 - after their activation - with heterocyclic compounds of general formula 5 - wherein N, R 'and R''form a 6- or 7-membered ring - converted into the amine of general formula 38 and the resulting benzoic acid esters 38
    - either
  • 6. subjected to aminolysis according to methods known per se, resulting in the benzoic acid amides 39 which fall under the general formula 1, isolated and optionally converted into the corresponding pharmacologically acceptable acid addition salts
    - or
  • 7. Subjecting the transesterification according to known methods, resulting in the benzoic acid esters 40, which fall under the general formula 1, isolated and optionally converted into the corresponding pharmacologically acceptable acid addition salts.