DD294706A5 - PROCESS FOR THE PREPARATION OF AMINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of compounds of general formula (I) or salts thereof, wherein E represents a hydrogen atom, a lower alkyl group or a group Ar1-Al -; Ar and Ar 1 represent the same or different aryl groups (including heteroaryl groups) which are optionally substituted by one or more substituents commonly used in pharmaceutical chemistry; A and A1 represent the same or different alkylene groups having one or two carbon atoms which link Ar or Ar1 to N and optionally substituted by lower alkyl and / or optionally substituted aryl; B represents an alkylene group having 3 to 4 carbon atoms which may be substituted by a lower alkyl group; D1 represents a hydrogen atom, CH 3, CR 1 R 2 NH 2, SO 3 H or SO 2 NR 6 R 7, wherein each of R 1 and R 2 independently represents a hydrogen atom or a lower alkyl group, and R 6 and R 7 each represents a hydrogen atom, a lower alkyl or aralkyl group having 7 to 12 carbon atoms, or R 6 and R 7 together with the nitrogen atom to which they are attached denote a 5- or 6-membered ring. These compounds are useful for treating depression, cerebral insufficiency or dementia of mammals including humans. Formula (I) {method; manufacture; Amine derivatives; pharmaceutical agents; Gamma-aminobutyric acid; senile dementia; Depressions}

Description

M / 31 102

Process for the preparation of amine derivatives

Field of application of the invention

The invention relates to a process for the preparation of amine derivatives which have new pharmacological properties. Furthermore, the invention relates to a process for the preparation of pharmaceutical agents containing these compounds. The amines prepared according to the invention are suitable for the treatment of depression.

Characteristic of the known state of the art

In the UK, an average of 300-400 out of 10 people suffer from depression, with 10-15% requiring hospitalization. Currently, the most effective and safest treatment for major depression is electroconvulsive therapy (ECT), where the patient receives a series of controlled electric shocks. Understandably, such treatment produces atavistic anxiety states in many patients. Such treatment also has undesirable side effects, especially memory disorders.

An ECT is also costly and time consuming and requires the presence of

Specialists, such as psychiatrists and anesthesiologists. As an alternative to ECT, drug therapy allows more tolerable treatment for the patient. At present, however, such therapy can not replace ECT as an optimal treatment method in severe cases, as it is not always effective. There is therefore a need to find new drugs for the treatment of depression, in particular drugs that have new mechanisms of action and more or less mimic an ECT.

The mechanism of action of an ECT is unknown, but in recent years many details have been learned about the biological effects of electroconvulsive shocks (ECS) on animals. In particular, changes in monoamine functions were found in rodents when ECS was repeatedly administered following clinical ECT therapy. These features include: enhanced 5-HT mediated behavior, enhanced dopaminergic behavior, and decreased beta-adrenoreceptor binding and coupled adenylate cyclase sensitivity. The latter is also observed in chonic treatment with a variety of antidepressant drugs.

The effects of repeated ECS are believed to be an answer to or adaptation to the acute effects of seizures. One of these acute effects is a marked change in the release, synthesis and content of gamma-aminobutyric acid (GABA) in the brain (see ARGreen et al, British J. Pharmacol., 92, 5-11 and 13-18 (1987) and Bowdler et al, ibid, 76, 291-298 (1982)).

GABA is one of the most abundant and abundant transmitters in the mammalian central nervous system and plays a central role in controlling the excitability of the brain. Similarly, he is involved in the benzodiazepine mediated relief of anxiety. Recently

Evidence has been provided that GABA transmission may be involved in the therapeutic effects of some antidepressant treatments. In particular, it has been shown in preliminary clinical tests that novel compounds designed as GABA agonists have an antidepressant effect (fengabine and progabide). The results therefore indicate that interventions directed specifically to GABA transmission may provide a basis for new therapeutic methods for the treatment of manic-depressive psychoses.

To date, three GABA receptors have been identified in the central nervous system. These are:

1. a GABA receptor that predominantly postsynaptically occurs and mediates an inhibition of neuronal signal transmission - cf. e.g. F.A. Stephenson, Biochem, J., 249, pages 21-32 (1988);

2. a presynaptic GABA receptor which inhibits the release of a variety of neurotransmitters, e.g. Norepinephrine and aspartic acid, but not mediated by GABA - cf. e.g. N. G. Bowery et al, Nature, 283, 92-94 (1980); and

3. a GABA autoreceptor that modulates the release of GABA by neurons - cf. e.g. P.R. Mitchell and I. L. Martin, Nature, 274, 904-905 (1978); S.Arbilla, J.L.Kanal and S.Z. Langer, Eur.J. Pharmac., 57, 211-217

(1979) and M. J. W. Brennan et al, Molec. Pharmac. 19, 27-30 (1981).

The pharmacological significance of these receptors is currently the subject of investigations, a major part of which is the search for anticonvulsant drugs.

is involved in the action of GABA _A ~ receptors involved. For two acts on GABA receptors substances Progabide and Fengabine, antidepressant effects in vorlä "fi • could be shown gen clinical studies - cf. PL Morselli et al, LERS, Volume 4 (1986), pages 9-126 χ and B. Scatton et al., Journal of Pharm. And Exp. Therapeutics., 241, 251-257 (1987).] The latter investigators were able to show that fengabine exhibited a biologic effect that differs from conventional antidepressants.The antidepressant mechanism of action of Fengabine was however, it was not clear that the idea was developed that it might be linked to GABAergic effects, probably at GABA _a receptors.

In the case of progabide, Morselli et al attributed the antidepressant effect of increased GABAergic transmission.

In the co-pending UK Pat.Anm. 8813185.9, there is evidence that the antidepressant effect of progabide and fengabine is indeed due to their agonistic activity on the GABA autoreceptor. The GABA autoreceptor regulates the release of GABA from GABAergic neurons, meaning that an agonist on the autoreceptor reduces GABA release and thus decreases GABA function, i. reduce the effect opposite the GABA agonist

would. It used to be thought that the autoreceptor has the same pharmacology as the GABA site - cf. Molec. Pharm, 19, 27-30 (1981). It has now been found that the GABA autoreceptor has its own pharmacology and that there are compounds which possess selective agonist activity on the GABA autoreceptor. These compounds can be used to advantage in medicine.

There is also evidence that compounds acting as inverse agonists at the benzodiazepine receptor

Reduce GABA function in the brain and thus increase acetylcholine transmission. In addition, they foster memory, possibly as a consequence of these effects, in animals and humans (see M.Sarter et al., Trends in Neuroscience, 11, 13-17 (1988)). Compounds that act selectively as GABA autoreceptor agonists probably show similar effects, e.g. a nootopic activity (e.g., increased alertness and cognition) and are therefore useful in the treatment of cerebral insufficiencies and dementia.

Object of the invention

The aim of the invention is the provision of amines with novel pharmacological activity, which are particularly suitable for the treatment of depression.

Explanation of the essence of the invention

The invention is based on the object of a process for the preparation of amines of the following general formula:

Era..

NBD ¹ _(I)

or salts of these compounds, wherein E represents a hydrogen atom, a lower alkyl group or a group Ar -A -;

Ar and Ar are the same or different aryl groups (including heteroaryl groups) which are optionally substituted, e.g. by one or more substituents commonly used in the pharmaceutical

Chemistry can be used, such. a lower alkyl, lower alkoxy, halo, halo lower alkyl, halo lower alkoxy, cyano, amino (including substituted amino, such as, for example, mono- or di-lower alkylamino) and nitro substituents; A and A are the same or different alkylene groups having one or two carbon atoms connecting Ar or Ar to N and which are optionally substituted by a lower alkyl and / or an optionally substituted aryl;

B represents an alkylene group having 3 to 4 carbon atoms which may be substituted by a lower alkyl group;

D ^{1 is} halogen, CH ,, SO, H, CR ¹ R ² NH ₉ or SO ₉ NR ⁶ R ⁷ ,

12

wherein R and R each independently represent a hydrogen atom or a lower alkyl group, and R and R each independently represent a hydrogen atom, a lower alkyl or aralkyl group having 7 to 12 carbon atoms, or R and R together with the nitrogen atom to which they are bonded Form a 5- or 6-membered ring, such as Pyrrolidine or piperidine. These compounds are useful as pharmaceutical agents. By the term "low" is meant a group of 1 to 6 carbon atoms. Examples of lower alkyl are methyl, ethyl, propyl, butyl

 examples for

or bromine radical.

Examples of D are halogen radicals, such as a fluorine, chlorine

Examples of Ar and Ar are mono- or bicyclic aryl radicals, such as e.g. carbocyclic aryl groups having from 6 to 10 carbon atoms (eg, phenyl or naphthyl radicals) and heteroaryl groups having from 5 to 10 ring atoms, wherein the heteroatom is an oxygen, nitrogen or sulfur atom (eg, pyridine, furan, thiophene) or aromatic groups which are two or more Heteroatoms contain (eg a Thiazolylgruppe). Bicyclic heteroaryl groups are, for example, quinoline and benzcfuran.

Examples of A and A are each independently of one another - (CH ") -, optionally substituted by a lower alkyl and / or aryl radical, wherein m is 1 or 2. Preferably, A and A are each independently -CHR -, wherein R represents a hydrogen atom, a lower alkyl group such as a methyl or ethyl group, or an optionally substituted aryl group as defined for Ar such as a phenyl group. Examples of B are -CHPCH ₇ CH ₇ - and such a group which is substituted by a lower alkyl, such as a methyl radical. B is, for example, -CH (CH ₃ ) CH ₂ CH ₂ - or -CH ₂ CH (CH ₃ ) CH ₂ -.

1 2

Examples of R and / or R are hydrogen and methyl.

According to another embodiment of the present invention there is provided a compound of general formula I or a salt thereof as defined above. The present invention also provides pharmaceutical compositions containing a compound of general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of general formula I defined above have pharmacological activity. In particular, they affect the nervous system. In particular, the compounds of general formula I are inhibitors of gamma-aminobutyric acid (GABA) release by the nerve endings by acting on the GABA autoreceptor

 30

Several compounds have already been shown to act as agonists on the GABA autoreceptor. This is for example for muscimol, isoguvacine and THIP (see Merck Index 1983 No. 9214); however, these compounds are nonselective and also act on other GABA receptors (i.e., GABA

and / or GABA _n ). As far as known, no medical application has been attributed to the compounds mentioned above because of their GABA autoreceptor activity.

Compounds with selective properties towards the GABA autoreceptor are desirable because additional activity against other GABA receptors results in a variety of side effects, such as, e.g. sedation and adverse muscle tone effects.

The compounds of general formula I act on GABA autoreceptors and are particularly effective as agonists, which can be demonstrated by means of standardized in vitro tests. Advantageously, the compounds of general formula I appear to be selective in that they show little or no activity against GABAj.- or GABA receptors. The following test methods are used to determine activity

(a) GABA autoreceptors and GABA _D receptors by inhibition of potassium-stimulated GABA and norepinephrine release from rat cortex in vitro (Method 1); and (b) GABA.-receptors by depolarizing the isolated rat vagus nerve (Method 2).

Method (1) Cerebral rat cortical slices (0.25 x 0.25 x 2.0 mm) are prepared using a Mcllwain tissue slicer. The pieces are ligated in a Krebs-Henseleit solution, the [ ³ H] -GABA (10 ~ ⁷ M) and [ ¹⁴ C] -or-

(10 ^-6 M) adrenalin (10 M) in the presence of aminooxyacetic acid (AOAA) (10 ^"5 M), ascorbic acid and pargyline (10 ~ ⁴ M),

Incubated at 37 ^° C. for 20 minutes, with 5 ml portions of the crayfish

Rinsed Henseleit solution and transferred to 10 superfusion chambers (volume 300 μΐ). The pieces are continuously overgrown with Krebs-Henseleit solution (0.4 ml min) containing AOAA (10 M). Fractions of the superfusate are taken every 4 minutes. Transmitter release is induced after 68 (S,) and 92 (S) minutes of superfusion by treatment with Krebs-Henseleit solution containing 25 mM potassium (with concomitant reduction of sodium to maintain osmolarity) for 4 minutes. The tested compound is added to the superfusion medium 20 min before the second potassium stimulation. The remaining radioactivity in the tissue pieces is measured at the end of the experiment along with the radioactivity in the superfusate fractions by liquid scintillation counting in the tritium / carbon 14 channel.

Calculations : The amount of radioactivity (either tritium or carbon-14) is expressed in each fraction as a percentage of total tissue radioactivity at the beginning of each collection. The amount of radioactivity released by the increased potassium levels and above the basal level is calculated to give the ratio S2 / S1. The S2 / Sl ratio of drug-treated sections is expressed as a percentage of the S2 / Sl control ratio. For compounds which cause an inhibition of 30% or more, the pD values are calculated from plots of inhibition of release versus drug concentration. If no inhibition is observed, this indicates that the molecule has no GABA agonist activity.

Method (2)

Male Sprague-Dawley rats (250-400 g) are killed by a blow to the head and cervical dislocation.

ίο

The cervical vagus nerves are transferred to a Krebs's solution at room temperature and the connective tissue envelope is removed. The vagus nerves are placed in two-part perspex baths to allow extracellular determination of agonist-induced depolarization. Each nerve extends from one compartment to the other via a gap filled with fat, the fat serving to isolate the compartments from each other. The DC potential between the compartments is determined using silver-silver chloride electrodes in saline agar bridges and recorded on a Grass polygraph. A compartment is continuous with Krebs'scher solution at 27 ⁰ C doused (5 ml min) In this solution there is the agonist and antagonist drugs. The second compartment is filled with Krebs's solution alone. Non-cumulative concentration response curves are obtained on GABA (10 to 3 χ 10 M) using a 5 minute contact time and a 10 to 20 minute wash interval. The influence of the test compound is compared with GABA.

Results

In the above-mentioned tests, representative compounds gave the following results: 26

connection

N-butyl-N-methyl-4-chlorobenzenemethanamine

N-butyl N-methylbenzenemethanamine

Ν, Ν-bis- (4-chlorobenzyl) butylamine

N-Butyldibenzylamin

Ν, Ν-bis (phenylmethyl) -1,4-diaminobutane

GABA autoreceptor

pD2 values

6.3 7.0 6.8 6.2

6.0

Inhibition of noradrenaline release

10 " ⁵ m

Depolarization of the rat vagus nerve at

10 " ⁴ m

no effect no effect

not tested

The invention also relates to the use of compounds of general formula I for the preparation of medicaments for the treatment of senile dementia and / or depression.

Furthermore, a process for the preparation of the compounds according to the invention is provided.

The compounds of the general formula I can be prepared by means of one of the following methods:

a) by alkylating a compound of general formula II, Ha or Hb

12 (ID Ar-A-NH-E (Ha) Ar-A-NH-BD ² (Lib) E-NH-BD ²

in which Ar, E and A have the abovementioned meanings and D denotes a methyl group, with a suitable compound of the general formula III, IIIa or IIIb:

hal-B-CN (III) E ¹ -hal (purple) Ar-A-hal (IIIb)

wherein B, Ar and A have the meanings given above, hai represents a chlorine or bromine radical and E is E except for a hydrogen C ₁ toms, to obtain a compound of general formula I, wherein D ^{1 is} CH ₃ or SO ₂ NR ⁶ R ⁷ ; or

b) by reductive alkylation of a compound of the above general formula II, Ha or Hb with a suitable compound of general formula IV, IVa or IVb

²⁶ "12

OHC-BD (IV) OHC-E ² (IVa) 0HC-A ² -Ar (IVb)

2 2

wherein D has the abovementioned meanings, E is an alkyl group having 1 to 5 carbon atoms or Ar ^{1 is} -CH ₂ -, A ^{2 is} CH ₃ and B ^{1 is} an alkylene chain having 2 or 3 carbon atoms, which by Substituted lower alkyl, in the presence of a reducing agent, such as

Sodium cyanoborohydride to obtain the corresponding compound of formula I wherein D is CH ₂ or SO ₂ NR ⁶ R ⁷ ; or

c) by reduction of a compound of general formula V

Ar-ANBD ³

4 '(V)

R-CO

wherein D ^{3 is} CH, CR ¹ R ² NH, or CONH ", R ^{4 is} a

12 alkyl group having 1 to 5 carbon atoms or Ar -A means; Ar, Ar, A and B are as defined above.

2 and A is a direct bond or an alkylene group having a carbon atom which is optionally substituted by a lower alkyl and / or aryl radical, to obtain the corresponding compound of the above-indicated formula I, wherein

D ^{1 is} CH, or CR ¹ R ² NH ₉ and E is R ⁴ CH ₀ ,

4 ^{e ll}

wherein R has the meanings given above; or

d) by reduction of a compound of general formula VI

Ar-AN-CO-B ¹ -D ³ E

wherein Ar, A, E and D ^{J have} the meanings given above and B is as defined in formula IV, to obtain the corresponding compound of general formula I wherein B is -CH ₂ B ¹ - and D ^{1 is} CH ₃ or CR ¹ R ² NH ₂ stand; or

e) by reacting a compound of general formula 35

Ar-A-OH (VII)

with an amine of the general formula

ENH-BD ¹ (VIII)

wherein Ar, A, E and B have the meanings given above and D is CH ₃ , in the presence of an acid, for example sulfuric acid, to give a compound of general formula I, wherein D is CH ₃ ;

^or

f) carrying out a Mannich reaction with an aryl anion of the formula Ar, formaldehyde and an amine of general formula VIII to obtain a compound of general formula I wherein D is CH ₁ ;

-> or

g) by halogenation of a compound of the general formula

Era

N-B-OH

(Ix)

in which Ar, A, B and E have the meanings given _above , for example with thionyl chloride, phosphoroxy

chloride, PBr ₃ or an acid HX, wherein X is halogen, to obtain a compound of general formula I wherein D is halogen; or

h) by reacting a compound of general formula X.

Ar-Av

NB-CR ¹ R ² -D ¹

E S (X)

15

wherein D represents a halogen atom, for example a chlorine atom,

(i) with an alkali metal azide, followed by hydrogenation with, for example, H _o / Pd; or

(ii) performing a Gabriel synthesis,

to obtain a compound of general formula I wherein D ^{1 is} NH ₂ ;

or

i) by reducing a compound of the general formula

Era

N-B-CN (XI)

^e

wherein Ar, A, E and B have the meanings given above, for example with lithium aluminum hydride, to obtain a compound of general formula I wherein D ^{1 is} -CH ₀ NH ₀ ;

^{2 2}

or

j) by oxidation of a compound of the general formula

Era. N-B-SH (XII)

wherein Ar, A, 3 and E have the meanings given above, wherein a compound of the general formula or

Formula I wherein D is SO ₀ H;

k) by reacting a reactive derivative of a compound of the general formula

Era

N-B-SO-H (XIII)

ie 194 ΪΟ (,

wherein Ar, A, E and B have the meanings given above, with an amine of the general formula

HNR ⁶ R ⁷ (XIV)

to obtain a compound of general formula I, or

where D ^{1 is} SO ₃ NR ⁶ R ⁷ ;

1) by acidification of a compound of general formula I to obtain an acid addition salt or by neutralization of an acid addition salt to give the free base of the compound; or m) by reacting a compound of general formula II as defined above with a sultone of the general formula

Γ \

· ° ^

wherein B has the meanings given above, to obtain a compound of general formula I, wherein D ^{1 is} SO 3 H, or a salt thereof.

The reaction according to process a) can be carried out in the conventional manner in the presence of an inert solvent and a base, e.g. a tertiary amine (e.g., diisopropylethylamine) and optionally with heating. Examples of suitable inert solvents are dimethylformamide, acetonitrile and dimethyl sulfoxide.

16a

The reductive alkylation according to process b) is carried out in a conventional manner, depending on the reducing agent in an inert solvent and without heating. If the reducing agent is sodium cyanoborohydride, the solvent may be an aqueous alcohol such as aqueous ethanol. It is also possible to carry out a catalytic hydrogenation, for example using Pd / C and an alcoholic solvent, for example ethanol .

The methods c) and d) can both by means of suitable

Reducing agents are carried out. For example, an ionic hydrogenation can be carried out, cf. Kursanor et al, Synthesis 1974, Vol. 9, 633-651. Other reducing agents such as diborane, Raney nickel or LiAlH ₄ can also be used.

The process k) can be carried out in situ in an inert solvent to form a reactive derivative of the acid of the formula XIII (for example the preparation of a sulfonyl halide by addition of PCl ₅ ). In order to avoid internal quaternization, the reactive intermediate formed first is not purified but treated immediately with the amine of general formula XIV. Method m) can be carried out by reacting the starting compounds in an inert solvent without heating.

The starting materials of general formula II which are used in process a) are known compounds or can be prepared by analogous methods, for example

Example by reduction of an amide of the general formula Ar-A-NHCO-E, wherein E has a CH ₂ group less than E, can be prepared.

Compounds of general formula V may be acylated by acyl-25

tion of a corresponding compound of general formula Ar-A-NH-B-D using an acid chloride of the formula

4 R COCl are produced. Compounds of the formula Ar-A-NH-BD can in turn be prepared by alkylating amines of the general formula NH ₉ -BD with the aid of ^

Halides of the general formula Ar-A-hal are produced.

Compounds of the general formula VI can be obtained by acylation of amines of the general formula Ar-A-NH-E under Ver-1 -ι

use of acid chloride of the general formula ClCO B-D, wherein B has the meanings given in connection with method d).

is 19 (f? 0C

Compounds of general formula XII can be prepared by hydrolysis of the corresponding isothiouronium salt in the presence of a base such as NaOH. The isothiouronium salt may be prepared from a compound of general formula I wherein D is halo.

wherein D is halogen, with the aid of thiourea

Starting materials for the processes described herein are known compounds or can be prepared by analogous methods for known compounds.

In each of the reactions described above, compounds of the formula I can be isolated either in the form of the free base or as an acid addition salt. Examples of such salts are salts with pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric, phosphoric, nitric, acetic, citric, tartaric, succinic, malonic, formic, fumaric and maleic acid or organosulfonic acids , such as methanesulfonic acid or tosyl

acid.

If acidic substituents are present, salts with strong bases, e.g. Alkali metals (such as sodium) are produced. Such salts of compounds of general formula I are also the subject of the present invention.

Compounds of the general formula XII and the isothiouronium precursors (ie compounds of the general formula I in which D ^{1 is} -SH or -SC (NH) NH ₂ ) are likewise provided by the present invention.

The present invention also provides pharmaceutical

A preparation containing a compound of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 5

Any suitable carrier known in the art may be used for the pharmaceutical agents. In the compositions, the carrier can be in solid or liquid form or in a mixture of solid and liquid form. Solid agents include powders, tablets and capsules. A solid carrier may consist of one or more substances which also act as flavorants, lubricants, solubilizers, suspending agents, binders or tablet disintegrators. The carrier may also be an encapsulating material. In powders, the carrier is in the form of a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is in admixture with a carrier having the required binding properties and is contained in suitable proportions and tableted to the desired shape and size. Powders and tablets contain 5 to 99%, preferably 10 to 80% of the active ingredient. Suitable solid carriers are magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "agent" also includes the formulation of the active ingredient with a carrier in the form of an encapsulating material to give capsules in which the active solid portion (with or without carrier) is coated by carriers and thus combined with them. Similarly, cachets are encompassed by the present invention.

Sterile liquid agents are sterile solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier. Examples include sterile water, a sterile organic solvent or a mixture of both. The active ingredients are often dissolved in a suitable organic solvent. For example, an aqueous propylene glycol solution containing 10-75% by weight of glycol is generally suitable. Other agents may be prepared by dispersing the finely divided active ingredient in an aqueous starch or sodium carboxymethylcellulose solution or in a suitable oil, e.g. Arachis oil, are produced. The agents may be administered by oral, nasal, rectal or parenteral route.

Preferably, the pharmaceutical agent is in unit dosage form, the agent being divided into dosage units containing appropriate amounts of the active ingredient. The dosage unit may be a packaged agent, which package contains certain amounts of the agent, e.g. packaged powders or vessels or ampoules.

The dosage unit may be a capsule, a cachet, a tablet or a suitable number of these packaged forms. The amount of the active ingredient in a unit dose of the agent may be varied or adjusted to levels of 1-500 mg or more, for example 25 mg to 250 mg, depending on the particular requirement and activity of the active ingredient. The present invention also includes agents in which the compounds are present without a carrier in unit dosage form. Based on the results of the animal experiments it can be stated that the dose range for the treatment of humans with compounds of the general formula I is in the range from about 1 mg to 2 g per day, depending on the activity of the respective compound.

toc,

The following examples illustrate the present invention and the methods of preparing the compounds of the invention.

applications

Example 1 N-butyl-4-chlorobenzenemethanamine

A solution of N-butyl-4-chlorobenzamide (2.26 g, 0.011 mol) in dry THF (25 mL) is added slowly to an ice-cooled solution of the B ₂ H ₆ -THF complex (1.0 M, 45 mL 0.045 mol) under a nitrogen atmosphere. After completion of the addition, the mixture is stirred and heated at reflux for 3 hours, cooled and decomposed by the dropwise addition of a 1: 1 mixture of concentrated aqueous HCl and water (10 ml). The mixture is then evaporated in a rotary evaporator within half an hour at 60 ⁰ C, which decomposes the boron-amine complex. The residue is taken up in water, rendered strongly basic with aqueous NaOH and extracted with CH 2 Cl 2 (3 × 25 ml). The combined extracts are washed with water, dried (MgSO 4), filtered and evaporated to give n-butyl-4-chlorobenzenemethanamine (1.79 g) as an oil. The oil is concentrated to give the hydrochloride salt of the title compound (1.98 g) by crystallization from ethanic HCl and ethyl acetate; Smp 250 - 252 ° C after melting and solidification at 203 - 207 ⁰ C.

Analysis for C ₁₁ H ₁ -ClN-HCl: 11 Io

About: 56 , 4 7, 3 6 , 0% gef. : 56 , 4 7, 4 6 , 2%

²² ZSt? 0G

Example 2 N- (1-methylbutyl) -4-chlorobenzenemethanamine

In a similar manner to Example 1, a solution of N- (1-methylbutyl) -4-chlorobenzamide (2.26 g, 0.01 mol) in dry THF (25 ml) in an ice-cooled solution of B ₂ H ₆ . THF complex (1.0 M, 45 ml, 0.045 mol) reacted under a nitrogen atmosphere to give the title compound as an oil.

The oil was set to the hydrochloride salt (1.58 g) by crystallising from ethanolic HCl to and ethyl acetate, mp 170-171 ⁰ C.

Analysis for C ₁₂ H ₁₈ C ¹ N

CHN

About: 58 ,1 7 , 7 5 6% gef. : 58 2 8th , 0 6 , 0%

Example 3 N-Buty1-N-methyl-4-chlorobenzenemethanamine

In a similar manner to Example 1, a solution of N-butyl-N-methyl-4-chlorobenzamide (4.49 g, 0.02 mol) in dry THF (50 ml) is charged with an ice-cooled solution of diborane THF. Complex (1.0 M, 90 mL, 0.09 mol) to give the title compound, which is reacted with hydrochloric acid and crystallized from ethyl acetate (1.51 g, 65.7%), mp 136-138 ° C ,

Analysis for C ₁₀ H ₁₀ ClN-HCl:

1Δ Io

CHN

About: 58 1 7, 7 5 6% gef. : 58 3 7, 7 5 ,8th%

Example 4 N-butyl N-methylbenzenemethanamine

Benzyl chloride (1/15 ml, 0.01 mol) is added dropwise to a vigorously stirred, ice-cold solution of il-methylbutylamine (10 ml, large excess) in ethanol (30 ml). The clear solution is then stored for 2 h at room temperature and evaporated to dryness. The residue is taken up in water and dilute HCl and washed with ether (2 × 25 ml) and the combined extracts (MgSO.sub.4) are dried. After filtration and evaporation, a yellow oil (1.68 g), which is converted into the HCl salt with ethereal HCl. The solvents are evaporated off and the residue is recrystallised twice from ethyl acetate to give the title compound in the form of the hydrochloride-quaterhydrate (0.6 g), mp 115-118 ° C.

Analysis for C ₁₂ H ₁₉ N ^ ₂

CHN 20

About: 66 , 0 9 , 5 6 4% gef. : 65 , 6 9 , 5 6 4%

Example 5

Ν, Ν-bis- (4-chlorobenzyl) butylamine

² A solution of Nn-butyl-N- (4-chlorobenzyl) -4-chlorobenzamide (2.9 g, 8.6 mmol) in dry tetrahydrofuran (25 mL) is added to a 1.0 M solution of diborane Tetrahydrofuran (43 ml, 43 mmol). The mixture is stirred for half an hour at 0 ⁰ C and then heated with stirring for 3 h at reflux temperature. After cooling, the mixture is added by careful addition of a 1: 1 mixture of water and concentrated hydrochloric acid (20 ml) at ⁰ ° C. The solvents are evaporated off and stirred, and the white, boron-complexed residue is heated in a liter. l solution of water and concentrated HCl (70 ml) for 7 1/4 h at reflux temperature.

After cooling, a heavy oil separates. The oil is extracted into dichloromethane (3 × 25 ml) and the combined extracts are washed with brine and dried (MgSO ₄ ). After filtration and evaporation, a pale yellow syrup (1.41 g) is obtained.

The syrup is reacted with aqueous NaOH to the free base and extracted into dichloromethane. After drying (MgSO 4) and evaporation, the product (1 g) is obtained by chromatography over silica gel and elution with toluene in the form of an oil as the first isolated product. This is converted into the HCl salt with hydrochloric ether. The solvent is evaporated and the residue is crystallized from ethyl acetate-ether to give, in two portions, the title compound and the hydrochloride salt (0.93 g). Mp 174 - 178 ⁰ C.

Analysis for C ₁₀ H ₀₁ Cl ₀ -HCl:

10 ΔLZ

ber. ge f.

60.3 60.3

6.2 6.2

3.9% 4.2%

Examples 6 to 10

By analogous methods, the following compounds of general formula Ib are obtained:

Ar-CH

CH.

N-nC ₄ H ₉

(Ib)

where Ar has the following meanings:

25

Example no.

Ar

melting point

4-hydroxyphenyl

2-methoxyphenyl

4-chloro-2-methoxyphenyl

2,6-Dimethy! Phenyl

10 4-Amino-5-chloro-2-methoxyphenyl

135-137 ° C (hemioxalate hemihydrate)

121 - 123 ⁰ C (oxalate, hydrate)

142 - 144 ⁰ C (oxalate)

83 - 84.5 ° C (maleate)

167-174 ⁰ C (dec.) (Dihydrochloride)

Example 11 N-butyldibenzylamine

A solution of Ν, Ν-dibenzylbutyramide (2.67g) in tetrahydrofuran (10ml) is added dropwise over 10 minutes to a stirred suspension of lithium aluminum hydride (1.52g) in tetrahydrofuran (40ml) at 90 ^° C , The mixture is heated to reflux for 14 hours and stopped by dropwise addition of water (1.61 ml), 2 N aqueous sodium hydroxide (3 ml) and water (3 ml). The white mixture is stirred for 1 h at room temperature and then filtered off. The residue is washed with tetrahydrofuran (2 × 10 ml) and the combined filtrates and washings are concentrated in vacuo. Diisopropyl ether (50 ml) is added to the mixture and washed with saturated aqueous sodium chloride solution (1 × 10 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give an orange oil (2.43 g) , The product is chromatographed on silica gel with diisopropyl ether as eluent and distilled flask for

Flask to give the title compound in free base form (1.82 g, 72%, bp 160 ° C / 0.5 mm Hg). Then add ether (20 ml) and hydrochloric ether (5 ml). The mixture is concentrated in vacuo and the product is slowly crystallized in ether at room temperature to give the hydrochloride hemihydrate salt (1.79 g), mp 131-133 ° C.

analysis for C ₁₈ I • 0 , 5 H _? O: C 35 8th H 4 N 72 6 8th ,1 4 7% About: 72 3 6% gef. : I ₃₃ N-HCl

Example 12 Ν , Ν-Dibenzyldiaminobutane

A solution of 4- (Ν, Ν-dibenzylamino) -butyramide.HCl (0.01 mol) in dry fine THF (50 mL) is added dropwise to a solution of LiAlH ₄ (3.25 g, 0.0855 mol) in dry THF (50 ml). The mixture is stirred and heated to reflux for 2 hours, cooled and then decomposed by the dropwise addition of water (3 ml), 15% aqueous NaOH (3 ml) and water (9 ml). After filtration, the filtrate is dried (MgSO ₄ ), filtered off and evaporated to give an oil (2.95 g). The oil is dissolved in hot ethanol (5 ml) and treated with oxalic acid (1.0 g, 1 equivalent). The solution is filtered while hot, diluted with ethyl acetate, cooled and filtered from the crystals. After two recrystallizations from ethanol-ether to obtain the 3/4 Ethandionatsalz (1.34 g) in the form of very pale cream crystals, mp 156-167 ⁰ C (decomposition, softening above 150 ⁰ C).

analysis for C ₁₈ H 24 ^N 2 4 ^(COOH) 2 ^: ' C 7 7 H 8th N 69, 3 7 , 7 8th , 3% About: 69th , 7 ,1% gef. :

Example 13 N, N-bis- (4-chlorobenzyl) -1,4-diaminobutane

A solution of 4- [Ν, Ν-bis (4-chlorobenzyl) amino] butyronitrile (2.2 g, 0.0066 mol) in dry THF (25 mL) is added dropwise to an ice-cold solution of 1.0 M BH - THF (40 mL, 0.04 mol) under a nitrogen atmosphere. The mixture is then heated at reflux for 7 hours. After cooling, the mixture is decomposed by the dropwise addition of a 1: 1 mixture of concentrated HCl and water (30 ml). The solvents are evaporated in vacuo and the residue is boiled for 4 h with water (50 ml) and concentrated H ₃ SO ₄ (20 ml). After cooling, the mixture is basified with aqueous NaOH and extracted with CH "C1" (3 × 30 ml). The combined extracts are washed with water and dried (MgSO ₄ ). After filtration and evaporation, a gummy product (1.59 g) is obtained, which is chromatographed on silica gel by elution with pure ethyl acetate. Further elution with a solution of 2% Et ₃ N-20% EtOH-78% ethyl acetate gives 1.52 g of a gummy product, which is dissolved in hot ethanol and treated with 1 equivalent of oxalic acid, diluted with ether and cooled. After slow crystallization, a solid is obtained, which is recrystallized from ethanol to give the title compound as the 3/4 oxalate salt (0.76 g), mp 158-166 ° C (decomposition).

Analysis for C _1Q H ₀₀ C1 ₀ N ₀ '4 (COOH) _o :

HN

About: 57 , 9 5 85 6 , 9% gef. : , 57 , 9 6 , 0 7 , 0%

28 Example 14

N- (3-chloropropyl) dibenzylamine

The title compound in the form of the hydrochloride salt is prepared by halogenation of N- (3-hydroxypropyl) dibenzylamine using thionyl chloride forth, mp 118-121 ⁰ C (dec.).

Analysis for C ₁₇ H ₅

CHN 10

About: 65 ,8th 6 ,8th 4 , 5% gef. : 65 , 7 6 , 9 4 7%

Example 15 S- [4- (Ν, Ν-D i benzyl) aminobutyl] isothiourea

A mixture -. N- (3-Chloropropyl) -dibenzylamine (1.98 g, 7.2 "MoI), prepared according to Example 14, and thiourea (0.55 g, 7.2 mmol) in ethanol (25 ml) are stirred and heated at reflux for 17 hours. The solution is then cooled off and the solvent is evaporated off, giving one

gets oily residue. The oil is triturated with ether, forming crystals overnight. The crystals are filtered off and crystallized from isopropanol-ethyl acetate to give crystals of the title compound in the form ° of the hydrochloride-quaterhydrates (1.09 g), mp 139- 141 ° C.

Analysis for ^C ₁₈ ^H ₂ 3 ^N 3 ^S 30

1. 2 C 0 7 H N 9% 4 61, 8th 6 , 0 11 9% About: 60 , 9 11 gef. :

Example 16 3- [Ν, Ν-Bis-benzyl] aminopropanesulfonic acid

a) S- [(Ν, Ν-Dibenzyl) -aminobutyl] -isothiourea hydrochloride (prepared according to Example 15) is hydrolyzed in aqueous ethanolic sodium hydroxide. The solvents are evaporated off and the residue is taken up in water and extracted three times with methylene dichloride. The extracts are dried (MgSO 4), filtered and evaporated to give N- (3-mercaptopropyl) -dibenzylamine.

b) A solution of the prepared in Stufp a) mercapto compound (4.18 g, 0.015 mol) in acetic acid (50 ml) and water (50 ml) is cooled to 0 ⁰ C (ice bath), then stirred vigorously with dropwise addition of a Solution of bromine (7.84 g, 0.049 mol) in acetic acid (50 ml). The resulting gas is introduced into a water trap. After completion of the addition of the bromine solution, the mixture is stirred for 1 h at room temperature. The solvent is evaporated in vacuo and the residue is washed twice with water. The remaining gummy product is boiled with water for 4.75 h, the mixture being completely dissolved. The solution is cooled and evaporated to dryness to give 3- [Ν, Ν-bis-benzyl] -aminopropanesulfonic acid as an oil.

This is purified by C-18 reverse phase HPLC with 2.5 M ammonium acetate in 25-75% acetonitrile / water buffered to pH 3.5. An organically pure product containing 1 molar equivalent of ammonium acetate is obtained.

³⁰ AS?

Example 17

2- [N-butyl-N-methyl] -naphthalinmethanamin

a) 2-Naphthoyl chloride (3.81 g, 0.020 mol) dissolved in dichloromethane (10 ml) is added dropwise to an ice-cooled solution of N-methylbutylamine (1.74 g, 0.020 mol) and diisopropylethylamine (4.5 ml, 0.025 mol) in dichloromethane (40 ml). The mixture is stirred for 18 h at room temperature and evaporated in vacuo. The residue is taken up in dichloromethane (50 ml), washed with 2M HCl (2 × 25 ml), dried (MgSO 4) and then concentrated by evaporation in vacuo to give N-butyl-N-methylnaphthalene-2-carboxamide (4 , 6 g, 0.019 mol) in the form of a yellow oil.

b) A 1M solution of borane / methyl sulfide in tetrahydrofuran (5 ml, 0.05 mol) is added dropwise to a solution of the product from step a) dissolved in anhydrous tetrahydrofuran (75 ml). The mixture is heated 18 h to reflux temperature, cooled to 2O ⁰ C and is then added dropwise a 5M solution of sulfuric acid (20 ml) added over 1 h. The mixture is stirred for 1 h and then distilled Dimethylsu ¹ fid and tetrahydrofuran from the reaction mixture at 80 ⁰ C from. Another 5M sulfuric acid is added (10 ml) and the mixture is heated at reflux temperature for 1 1/2 h and then stirred at room temperature for 16 h. The mixture is basified with 2M sodium bicarbonate, extracted with dichloromethane (2 × 50 ml), dried (MgSO 4) and evaporated in vacuo to give the title compound (3.95 g, 0.017 mole) as a yellow oil. Tosylic acid (3.23 g, 0.017 mol) is dissolved in isopropanol (20 ml) and the solution is subsequently added to the product prepared above. After evaporation in vacuo and crystallization

₃₁ 19 * / 10t

from ethyl acetate / toluene, the toluene-4-sulfonic acid salt (4.15 g, 52%) is obtained in the form of a white solid.

Analysis for C ₁ CH ₉₁ NC ₇ H ₀ SO.,

C 2 H 3 N About: 69, 2 7.32 3 , 51% gef. : 69, 7.18 , 47%

Example 18

1- [N-Butyl-N-methyl] -naphthalinmethanamin

a) A solution of 1-naphthoyl chloride (3.81 g, 0.020 mol) dissolved in dichloromethane (10 ml) is added dropwise to an ice-cooled solution of N-methylbutylamine (1.74 g, 0.020 mol) and diisopropylethylamine (4, 5 ml, ca. 0.025 mol), dissolved in dichloromethane (50 ml). The mixture is stirred for 18 h at room temperature and then evaporated in vacuo, taken up in dichloromethane (50 ml), washed with dilute hydrochloric acid (2 χ 25 ml), dried (MgSO.) And then evaporated in vacuo, taking 1 - (n-butyl-N-methyl) -naphthalenecarboxamide (4.46 g, 0.018 mol).

b) To the product of step a), dissolved in tetrahydrofuran (25 ml), add a 1M solution of borane / methyl sulfide in tetrahydrofuran (5 ml, 0.05 mol). The mixture is heated for 18 h at reflux temperature and then cooled to room temperature. Add 5M sulfuric acid (20 ml) dropwise and stir the mixture for 1 h and then distill off the solvents and methyl sulfide. Sulfuric acid (20 ml, 10M) is added and the mixture is heated to reflux for 1 1/2 hours. After cooling and

• Evaporate in vacuo and take the residue

aqueous sodium bicarbonate (50 ml), extracted with dichloromethane (2 × 100 ml), dried (MgSO 4) and then evaporated in vacuo to give the title compound (4.2 g, 0.017 mole) as an oil. To this is added toluene-4-sulfonic acid (3.23 g, 0.017 mol) and the mixture is heated in ethanol / ethyl acetate to give on cooling crystals of the toluene-4-sulfonic acid salt of the title compound (3.97 g), mp 126 -. 13O ⁰ C.

Analysis for C ₁₆ H ₂₁ NC ₇ HgSO ₃ :

CHN

About: 69, 1 7, 32 3, 51% gef. : 68 8th 7, 40 3, 40%

Example 19

3- (1,2-diphenylethylamino) -propanesulfonic acid, sodium salt

A solution of 12.2 g of 3-hydroxy-1-propanesulfonic acid Y- sultone, 19.7 g of 1,2-diphenylethylamine and 150 ml of methanol is allowed to stand at room temperature for 72 hours. The precipitate is separated off and suspended in boiling methanol. After cooling to room temperature, the solid is separated off and dried in vacuo. The resulting solid is stirred with one liter of methanol and 2.792 g of sodium hydroxide until a clear solution is formed. After removal

3Q of the solvent in vacuo gives 22 g of the title compound in the form of 1/4-hydrate. Smp 285 - 29O ⁰ C.

Analysis for C ₁₇ H ₂ INO ₃ SNa: 1 / 4H ₂ O: CHNS

Found: 58 , 46 5, 81 4 , 01 9 36 Calculated: 58 85 6 25 4 , 04 9 24

Example 20

3 - [(diphenylmethyl) amino] -1-propanesulfonic acid, sodium salt

A solution of 18.3 g of aminodiphenylmethane, 12.2 g of 3-hydroxy-1-propanesulfonic acid Y-sultone and 200 ml of methanol is allowed to stand at room temperature for 72 hours. The gummy precipitate is separated and dissolved in a mixture of isopropanol and ethanol. While standing, a crystalline precipitate forms. The solid is separated off and dissolved in 800 ml of methanol. The solution is evaporated to the crystallization point, cooled and filtered to give 12 g of a solid.

The solid is suspended in 300 ml of methanol and filtered with 2N sodium hydroxide solution. The solution is evaporated in vacuo to give 12.6 g of the title compound in the form of 2/3 hydrate. Mp 150 to 154 ⁰ C (decomposition).

Analysis for C ₁₆ H ₁₈ NO ₃ SNa: 2 / 3H ₂ O:

CHN

About: 56 , 64 5 , 73 4 13 gef. : 56 90 5 , 68  4 13

Example 21

3- (2,2-diphenylethylamino) -1-propanesulfonic acid, sodium salt

A solution of 12.2 g of 3-hydroxy-1-propanesulfonic acid sultone, 19.7 g of 2,2-diphenylethylamine and 270 ml of methanol is allowed to stand at room temperature for 58 hours.

10

25 30

The precipitated solid is filtered off and washed with methanol. The solid is dried in vacuo to give 15.3 g of 3- (2,2-diphenylethylamino) -1-propanesulfonic acid, mp 283-5 ⁰ C (dec.) Obtained.

Analysis for

C 98 6 H 4 N S 96 gef. : 63 92 6 , 87 4 , 49 9 04 About: 63 , 63 , 39 10

The sodium salt is prepared by dissolving 11.36 g of the acid and 1.424 g of sodium hydroxide in 500 ml of methanol. After removal of the solvent in vacuo, 8.6 g of the title compound, mp 283-285 ⁰ C.

Analysis for C ₁₇ H ₂ QNO ₃ SNa:

CHASE

gef. : 59 , 62 5, 98 4 , 01 9 , 01 About: 59 , 81 5, 91 4 10 9 , 39

35

Claims (10)

M / 31 102 1. Compounds of the general formula Era NBD ¹ (D. e ^ and the salts thereof / wherein E represents a hydrogen atom, a Ni ^^ igalkylgruppe or a group Ar -A -; Ar and Ar represent the same or different aryl groups (including heteroaryl groups) optionally substituted by one or more substituents commonly used in pharmaceutical chemistry; A and A are the same or different alkylene groups having one or two carbon atoms connecting Ar or Ar * to N and optionally substituted by lower alkyl and / or optionally substituted aryl; B is an alkylene group having 3 or 4 carbon atoms which may be substituted by lower alkyl; D ^{1 represents} a halogen atom, CH ₃ , CR ¹ R ² NH ₉ , SO, H or SO ₉ NR ⁶ R ⁷ , in which R ¹ and R ^z each independently represent a hydrogen atom or a lower alkyl group and R and R each represent a hydrogen atom, a lower alkyl group or an aralkyl group of 7 to 12 Represent carbon atoms or r ' and R together with the nitrogen atom to which they are attached form a 5- or 6-membered ring » 2. Compounds according to claim 1 of the general formula (I) / in which Ar and Ar are each independently of one another optionally substituted mono- or bicyclic aryl groups, the aryl groups being selected from carbocyclic groups having 6 to 10 carbon atoms and heteroaryl groups having 5 to 10 ring atoms, wherein the heteroatom (s) is (are) selected from oxygen, nitrogen and sulfur. 3. Compounds according to claim 2 of the general formula (I), wherein Ar and Ar are selected from an optionally substituted phenyl, naphthyl, pyridyl, furyl, thienyl, thiazolyl, quinolyl and benzofuranyl. 4. Compounds according to claim 2 or claim 3 of the general formula (I) wherein the substituents of Ar and Ar are selected from lower alkyl, lower alkoxy, halo, halo lower alkyl, halo lower alkoxy, cyano, amino and nitro radicals. 5. Compounds according to any one of claims 1 to 4 of general formula I, wherein A and A are each independently - (CH-) -, wherein the group is optionally substituted by lower alkyl and / or aryl and m is 1 or 2 , Compounds according to claim 5 of the general formula (I) / in which A and A are each independently of one another --CHR, in which R represents a hydrogen atom, a lower alkyl group or an optionally substituted aryl group as defined for Ar. 7. Compounds according to any one of claims 1 to 6 of the general formula I, wherein B is -CH ₂ CH ₂ CH ₂ - or is such a group having a methyl substituent 8. Compounds according to one of claims 1 to 7 of the general formula (I), wherein D is CH ₃ , SO ₃ H or SO ₂ NH. 9. Compounds according to claim 1, namely N-butyl-4-chlorobenzenemethanamine,
N- (1-methylbutyl) -4-chlorobenzenemethanamine, N-butyl-N-methyl-4-chlorobenzenemethanamine, N-butyl-N-methylbenzenemethanamine, Ν, Ν-bis (4-chlorobenzyl) -butylimine, N-butyldibenzylamine.
N, N-dibenzyl-1,4-diaminobutane,
N- (3-chloropropyl) dibenzylamine,
3- [Ν, Ν-benzyl] aminopropanesulfonic acid or the salts of these compounds. 10. A process for preparing a compound of general formula I as defined in claim 1, characterized in that
35 'Si' a) a compound of general formula II, Ha or Hb Ar-A-NH-E (II) Ar-A-NH-BD ² (Ha) E-NH-BD ² (Hb) wherein Ar, E and A have the meanings given in claim 1 and D is CH ₃ or SO ₂ NR R, with a suitable compound of the general formula HI, HIa or IHb hal-BD ² (HI) E ¹ -hal (IHa) Ar-A-hal (IHb) 15 wherein B, Ar and A have the meanings given in claim 1, hai is a chlorine or a bromine atom, and E has the meanings of E except hydrogen, alkylated, to obtain a compound of general formula I wherein D ¹ f or D ^{1 is} CH ₃ or SO ₂ NR ⁶ R ⁷ ; b) a reductive alkylation of one of the above-defined compounds of general formula H, Ha or Hb using a suitable compound of general formula IV, IVa or IVb 30 2
wherein D has the meanings given above, 2
E is an alkyl group having 1 to 5 carbon atoms or Ar ^{1 is} -CH ₂ -, A ^{2 is} CH ₂ and B ^{1 is} one - 39- Alkylene chain with 2 or J carbon atoms, which is optionally substituted by lower alkyl, in the presence of a reducing agent, such as sodium cyanoborohydride, to obtain a compound of general formula I wherein D is CH ₇ or SO ^ NR ⁶ R ⁷ ;
or c) a compound of general formula V Ar-ANBD ³ R ⁴ -C0 (V) wherein D ^{3 is} CH ₃ , CR ¹ R ² NH ₂ or CONH ₂ , R ^{4 is} an alkyl group having 1 to 5 carbon atoms or 12 1 Ar -A - means; Ar, Ar, A and B have the meanings given above and A is a direct bond or an alkylene group having one carbon atom which is optionally substituted by a lower alkyl and / or an aryl radical, reduced to a compound of general formula I, wherein D ^{1 is} CH ₇ or CR ¹ R ² NH ₉ and E is R ⁴ CH ₉ , wherein R has the meanings given above; or d) a compound of general formula VI Ar-AN-CO-B ¹ -D ¹ (VI) in which Ar, A and E have the meanings given above, D has the abovementioned meanings and B has the meanings given in connection with formula IV, to give a compound of the general formula reduced to my formula I, wherein B is -CH ₉ B - stands 1 and D is CH ₃ or CR R NH-; or e) a compound of the general formula Ar-A-OH (VII) with an amine of the general formula ENH-BD ¹ (VIII) wherein Ar, A, E and B have the meanings given above and D is CH ₃ , in the presence of an acid, to obtain a compound of general formula I, wherein D is CH ₃ ; or f) a Mannich reaction with an aryl anion of the general formula Ar ", formaldehyde and an amine of general formula VIII is carried out to obtain a compound of general formula I, wherein D ^{1 is} CH ₃ ; or 25 g) a compound of the general formula Era N-B-OH (IX) E ^ wherein Ar, A, B and E have the abovementioned meanings, for example with thionyl chloride, phosphorus oxychloride, PBr., or an acid HX, wherein X is a halogen atom, halogenated, to give a compound of general formula I, wherein D ¹ ei or D represents a halogen atom; h) a compound of general formula X. Era. NB-CR ¹ R ² -D ¹ (X) wherein D represents a halogen atom (i) with an alkali metal azide, followed by a Hydrogenation, or (ii) under the conditions of a Gabriel synthesis reacts, being a compound of the general Forme or Formula I wherein D is NH "; i) a compound of the general formula Era N-B-CN (XI) e ^ wherein Ar, A, E and B have the meanings given above, to obtain a compound of general formula I, wherein D is -CH _? NH _? stands; or j) a compound of the general formula Era. N-B-SH (XII) wherein Ar, A, B and E are as defined above have, to a compound of general formula I. oxidized, wherein D is SO, H; or k) a reactive derivative of a compound of the general formula Era. N-B-SO, H (XIII) wherein Ar, A, E and B have the meanings given above, with an amine of the general formula HNR ⁶ R ⁷ (XIV) reacts, taking a compound of the general forms
or Formula I wherein D is SO-NR R; 1) acidifying a compound of general formula I to form the acid addition salt or neutralizing an acid addition salt to form the free base: or m) a compound of the above defined general formula II with a sulton of the general my formula implements, wherein B has the meanings given above, wherein a compound of general formula I, wherein D ^ is SO3H, or: a salt thereof. A pharmaceutical composition / containing a compound according to claim 1 of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.