EP1558583A1 - Novel phenylethanolamine derivatives and the use of the same as beta-3-agonists - Google Patents

Abstract

The invention relates to novel beta agonists of general formula (I) wherein the radicals R1 to R12 have the designations cited in the claims and in the description. The invention also relates to the isomers thereof, to methods for producing said compounds and to the use of the same as medicaments.

Description

 NEW PHENYLETHANOLAMINE DERIVATIVES AND THEIR USE AS BETA-3 AGONISTS

The present invention relates to new beta agonists of the general formula 1:

wherein the radicals R ¹ to R ^{12 have} the meanings given in the claims and the description, their isomers, processes for the preparation of these compounds and their use as medicaments.

Background of the Invention

Treatment of type II diabetes and obesity is primarily based on reducing calorie intake and increasing physical activity. This

Methods are rarely successful over long periods.

It is known that beta-3 receptor agonists have a marked effect on that

Lipolysis, thermogenesis and the serum glucose level in animal models of type II

Show diabetes (Arch JR. Beta (3) adrenoceptor agonists: potential, pitfalls and progress, Eur J Pharmacol. 2002 Apr 12; 440 (2-3): 99-107).

Structure-like compounds of the compounds according to the invention and their broncholytic, spasmolytic and antiallergic activity were disclosed, for example, in DE 2833140.

It is the object of the present invention to provide selective beta-3 agonists which are used in the manufacture of medicaments for the treatment of

Obesitas and type II diabetes.

Detailed description of the invention Surprisingly, it has been found that compounds of the general formula (I) in which the radicals R ¹ to R ^{12 have} the meanings given below act as selective beta-3 agonists. The compounds according to the invention can thus be used for the treatment of diseases which are associated with the stimulation of beta 3-receptors.

The present invention therefore relates to compounds of the general formula (I)

wherein

R ¹ , R ² , R ¹⁰ , R ¹¹ independently of one another are a radical selected from the group consisting of hydrogen, halogen, CN, NO _2l and -NHCXNH ₂ or a radical selected from the group consisting of optionally substituted

-COR ⁷ , -COOR ⁷ , -CONR ⁷ R ¹³ , -OR ¹⁴ , NR ¹³ R ¹⁵ , C Cιo-alkyl, C ₃ -C ₈ cycloalkyl,

-NR ¹⁶ CX-R ¹⁷ , -NR ¹⁸ CX-OR ¹⁹ , -NR ²⁰ SOmR ²¹ , -SO _p NR ²² R ²³ and -SO _q R ²⁴ , m, p, q independently of one another 0, 1 or 2, n 0, 1, 2 or 3,

R ^{3 is} hydrogen or a radical selected from the group consisting of optionally substituted CrCio-alkyl, C ₆ -Cιo-Ar l, heterocyclyl, C ₃ -C ₈ -

Cycloalkyl, -CX- C -C ₀ alkyl and -CX-C ₆ -C ₁₄ aryl,

R ⁴ , R ⁵ independently of one another hydrogen, halogen or optionally substituted C- _t -C- _t o-alkyl, or

R ⁴ and R ⁵ together form a C ₃ -C ₈ alkyl bridge,

R ^{6 is} a radical selected from the group consisting of the general formulas l, k independently of one another 1, 2 or 3, p ²⁵ _R ²⁶ p-, ²⁷ ^ _R ²⁸ independently of one another a residue selected from

Group consisting of hydrogen, OH, halogen, CN and NO ₂ , or a radical selected from the group consisting of optionally substituted d-do-alkyl, C ₆ -C ₁₈ aryl, heteroaryl, heterocyclyl, -CX-R ¹⁷ , - OR ¹⁴ , NR ¹³ R ¹⁵ , Cs-Cs cycloalkyl, -NR ²⁰ SOmR ²¹ , -SO _p NR ²² R ²³ , -SO _q R ²⁴ , -NR ¹⁸ CX-R ¹⁹ , -NR ¹⁸ CXOR ¹⁷ , where R ²⁵ and R ²⁶ cannot simultaneously mean hydrogen, R ^{8 is} hydrogen or a radical selected from the group consisting of optionally substituted CiC-io-alkyl, C ₆ -Cι ₈ aryl, -SO _q - CiC-io-alkyl, -SOq -Cβ-Cu-aryl, -CX- CrC ₁₀ alkyl, -CX-C ₆ -C ₁₄ aryl, C ₆ -C ₁₀ aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl R ⁹ hydrogen or a radical selected from the group consisting of optionally substituted CiC-io-alkyl, C ₆ -C aryl, heteroaryl, C ₃ -C ₈ cycloalkyl and heterocycloalkyl,

R ^{12 is} hydrogen or a radical selected from the group consisting of optionally substituted benzyl, C ₁ -C ₂ -alkyl and C ₆ -C- | Aryl, R ⁷ , R ¹³ , R ¹⁵ , R ¹⁶ , R ¹⁸ , R ²⁰ , R ²² , R ²³ independently of one another hydrogen, or a radical selected from the group consisting of optionally substituted. -C-Cιo-alkyl, C ₆ -C ₄ aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl R ¹⁴ , R ¹⁹ , R ²⁹ independently of one another are hydrogen or a radical selected from the group

Group consisting of optionally substituted CrCio alkyl, C ₆ -C ₄ aryl, C ₃ -

Cs-cycloalkyl, heteroaryl, heterocyclyl, -CXNR ₁₃ Rι ₅ , -CXR ₇

R ^{17 is} a radical selected from the group consisting of CrCio-alkyl, C ₆ -C ₄ aryl, heterocyclyl, heteroaryl and C ₃ -C ₈ cycloalkyl

R ²¹ , R ^{24 are} independently hydrogen or OH, or a radical selected from the group consisting of optionally substituted

N (C _r C ₁₀ alkyl) ₂ , N (C ₃ -C ₈ cycloalkyl), CrCio-alkyl, C _β -Cι ₄ aryl, heterocyclyl,

Heteroaryl and C ₃ -C ₈ cycloalkyl and

XO, S or NR ²⁹ , optionally in the form of their tautomers, their racemates, their enantiomers, their

Diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.

Compounds are preferred

R ¹⁰ , R ¹¹ independently of one another are hydrogen or halogen, m, p, q 0, 1 or 2 n 0, 1, 2 or 3 R ^{3 are} hydrogen or CC ₅ alkyl

R ⁴ , R ⁵ independently of one another are hydrogen or CrC ₅ alkyl,

R ^{8 is} a radical selected from the group consisting of hydrogen, CrC ₅ alkyl,

-SO _q - CrC ₅ alkyl, -SO _q -C ₆ -Cι aryl, phenyl and C ₃ -C ₆ cycloalkyl

R ^{9 is} hydrogen or d-Cio-alkyl ^' R ^{12 is} hydrogen or benzyl

R ¹³ , R ¹⁵ , R ¹⁶ , R ¹⁸ independently of one another are selected from the group consisting of hydrogen, .CrC ₅ alkyl, C ₃ -C ₆ cycloalkyl and phenyl

R ¹⁴ , R ¹⁹ independently of one another are hydrogen or d-Cs-alkyl, and

R ^{17 is} optionally substituted CrC ₅ alkyl or Cβ-Cio-aryl.

Also preferred are compounds in which

R ¹⁰ , R ^{11 are} hydrogen m, p, q 0, 1 or 2 n 0, 1, 2 or 3 R ^{3 is} hydrogen

R ⁴ , R ⁵ independently of one another are hydrogen or methyl,

R ^{8 is} hydrogen, -SO _q -C ₆ -C ₁₄ aryl or -SO ₂ -CC ₅ alkyl

R ⁹ hydrogen R ¹² hydrogen or benzyl,

R ¹³ , R ¹⁵ , R ¹⁶ , R ¹⁸ independently of one another are selected from the group consisting of hydrogen, .CrCι ₅ alkyl and phenyl,

R ¹⁴ , R ¹⁹ independently of one another are hydrogen or CrC ₅ alkyl, and R ^{17 is} C _r C ₅ alkyl or C ₆ -C ₄ aryl.

Compounds in which

R ^{1 is} a radical selected from the group consisting of hydrogen, NO ₂ , NH ₂ ,

-NHCX-R ¹⁷ and -NHSO ₂ R ²¹ . R ² , hydrogen or halogen n 2,

R ^{3 is} hydrogen

R ⁴ , R ^{5 are} hydrogen or methyl

R ^{6 is} a radical selected from the group consisting of the general formulas

ι, k 1

R ²⁶ R ²⁷ hydrogen, R ^{8 is} hydrogen or -SO ₂ CH ₃ ,

R ^{9 is} hydrogen,

R ¹⁰ , R ^{11 are} hydrogen, and

R ^{12 is} hydrogen or benzyl

Compounds in which

R ^{6 is} a radical selected from the group consisting of the general formulas

is.

Particularly preferred are compounds in which R ^{6 is} an optionally substituted radical of the formula (j)

means.

The invention further relates to compounds of the formula (I) for

Use as a medicine. The invention further relates to compounds of the formula (I) for use as medicaments with selective beta-3-agonistic activity. Another object of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment and / or prevention of diseases which are associated with the stimulation of beta-3 receptors.

Another object of the invention is a method for the treatment and / or prevention of diseases associated with the stimulation of beta-3 receptors in Are related, wherein an effective amount of a compound of formula I is administered to a patient.

Of particular importance according to the invention is a pharmaceutical composition containing as active ingredient one or more compounds of the general formula (I) or their physiologically tolerable salts, optionally in combination with customary auxiliaries and / or carriers.

Also of particular importance is a pharmaceutical composition containing as active ingredient one or more compounds of the general formula (I) according to one of Claims 1 to 6 or their physiologically tolerable salts and one or more active ingredients selected from the group consisting of antidiabetic agents, inhibitors of protein tyrosine phosphatase 1 , Substances that influence deregulated glucose production in the liver, lipid-lowering agents, cholesterol absorption inhibitors, HDL-increasing compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.

The invention further provides a process for the preparation of a compound of the general formula (I)

wherein

R ¹ -R ²⁸ and X can have the meaning given above, where a compound of the general formula (II)

(II) where R ⁴ and R ^{5 can have} the meaning given above, by means of a chlorinating agent into a compound of the formula (III)

(III), the compound of the formula (III), optionally provided with an amino protecting group, with an optionally substituted compound selected from the group consisting of the general formulas (IVa) to (IVi)

(IV)

wherein k, I, R 5≥7 _l u _m n _f d _i o R28 have the meaning given above, and the product of the formula (V)

(V) wherein n, R ⁴ , R ⁵ , R ⁶ and R ^{8 have} the meaning given above, with a compound of the formula (Via) to (Vlc)

(Vlc)

wherein R ¹ , R ² , R ⁹ and R ¹⁰ to R ^{12 have} the meaning given above, is reacted.

As alkyl groups and alkyl groups which are part of other radicals, branched and unbranched alkyl groups with 1 to 10 carbon atoms are preferably 1-6, particularly preferably 1-4 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, Heptyl, octyl, nonyl and decyl. Unless otherwise stated, all of the possible isomeric forms are included in the abovementioned designations propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. For example, the term propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert-butyl, the term pentyl, iso-pentyl, neopentyl etc. In the alkyl groups mentioned above, one or more hydrogen atoms can optionally be replaced by other radicals. For example, these alkyl groups can be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine or chlorine are preferred. The substituent chlorine is particularly preferred. Optionally, all hydrogen atoms of the alkyl group can also be replaced.

Unless otherwise described, one or more hydrogen atoms in the abovementioned alkyl groups may also be selected, for example, by an optionally substituted radical selected from the group consisting of OH, NO ₂ , CN, -O-CrC ₅ -alkyl, preferably -O -Methyl or -O- ethyl, O-Cβ-C-aryl, preferably O-phenyl, O-heteroaryl, preferably O-thienyl, O-thiazolyl, O-imidazolyl, O-pyridyl, O-pyrimidyl or O-pyrazinyl, saturated or unsaturated O-heterocycloalkyl, preferably O-pyrazolyl, O-pyrrolidinyl, O-piperidinyl, O-piperazinyl or O-tetrahydro-oxazinyl, Cβ-C-aryl, preferably phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, Pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine residue, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyc ring systems, preferably benzimidazolyl and C ₃ -C ₈ -cycloalkyl, preferably cyclohexyl or cyclopropyl, can be replaced.

The term aryl stands for an aromatic ring system with 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, particularly preferably phenyl, which, unless otherwise described, can carry, for example, one or more of the following substituents: OH, NO ₂ , CN, -OCHF ₂ , -OCF ₃ , -NH ₂ , halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, particularly preferably fluorine, d-Cio-alkyl, preferably CrC ₅ alkyl, preferred Cr C ₃ alkyl, particularly preferably methyl or ethyl, -O-CrC ₃ alkyl, preferably -O- methyl or -O-ethyl, -COOH or -CONH ₂ .

Heteroaryl radicals are 5-10-membered mono- or bicyclic heteroaryl rings in which up to three C atoms can be replaced by one or more heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, for example furan, thiophene, pyrrole, pyrazole, Imidazole, triazole, tetrazole, pyridine, Pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, where each of the heterocycles mentioned above may optionally also be fused to a benzene ring, preferably benzimidazole, and these heterocycles, unless otherwise described, for example one or can carry several of the substituents mentioned below: OH, NO ₂ , CN, -NH ₂ , halogen, preferably fluorine or chlorine, C -C ₀ alkyl, preferably dC _δ alkyl, preferably CrC ₃ alkyl, particularly preferably methyl or ethyl, -OC C ₃ alkyl, preferably -O-methyl or -O-ethyl, -COOH, -COOCH ₃ , -CONH ₂ , -SO-alkyl, -SO ₂ -alkyl, -SO ₂ H, -SO ₃ -alkyl or optionally substituted phenyl. .

Cycloalkyl radicals are saturated or unsaturated cycloalkyl radicals having 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyxclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, each of the above-mentioned cycloalkyl radicals optionally also bearing one or more cycloalkyl radicals or fused to a benzene ring.

Unless otherwise described in the definitions, the heterocycloalkyl radicals are 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulfur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranone, γ-butylrolactone, pyran, γ- pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazinoline, triazine, triazine, triazine, triazine Oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, and the heterocycle may be substituted.

Halogen is generally referred to as fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine, particularly preferably fluorine.

The compounds according to the invention can be in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids - such as, for example, acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, for example oxalic, fumaric, diglycolic, formic, apple, benzoic, benzenesulfonic, camphor sulfonic, vinegar , Ethanesulfonic, glutamic, maleic, almond, milk, phosphoric, nitric, sulfuric, succinic, para-toluenesulfonic, trifluoroacetic, wine, lemon or methanesulfonic acid are present.

The substituent R ¹ can be a radical selected from the group consisting of hydrogen, halogen, preferably fluorine or chlorine, CN, NO ₂ , and -NHCXNH ₂ , preferably NHCONH _2, or a radical selected from the group consisting of optionally substituted

-GOR ^7, -COOR ^7, -CONR ⁷ R ^13, -OR ^14, preferably OH, NR ¹³ R ^15, C Cι ₀ alkyl, C ₃ -C ₈ -

Cycloalkyl, -NR ¹⁶ CX-R ¹⁷ , -NR ¹⁸ CX-OR ¹⁹ , -NR ²⁰ SO _m R ²¹ , -SO _p NR ²² R ²³ , preferably -SO ₂ NHR ²³ , and -SO _q R ² ,

The substituent R1 particularly preferably denotes —NR ²⁰ SO _m R ²¹ , preferably

-NHSOmR ²¹ .

The substituent R ² can be a radical selected from the group consisting of hydrogen, halogen, preferably fluorine or chlorine, CN, NO ₂ , and -NHCXNH ₂ , preferably NHCONH ₂ or a radical selected from the group consisting of optionally substituted -COR ⁷ , -COOR ^7, -CONR ⁷ R ^13, -OR ^14, preferably OH, NR ¹³ R ^15, C Cι ₀ alkyl, C ₃ -C ₈ - cycloalkyl, -NR ¹⁶ CX-R ^17, -NR ¹⁸ CX-OR ¹⁹ , -NR ²⁰ SO _m R ²¹ , -SO _p NR ²² R ²³ , preferably -SO ₂ NHR ²³ and -SO _q R ²³ . The substituent R2 particularly preferably denotes hydrogen or fluorine.

The substituents R ¹⁰ and R ¹¹ may be the same or different and a radical selected from the group consisting of hydrogen, halogen, preferably fluorine or chlorine, CN, NO ₂ , and -NHCXNH ₂ , preferably NHCONH ₂ or a radical selected from the group consisting of optionally substituted -COR ⁷ , -COOR ⁷ , -CONR ⁷ R ¹³ , -OR ¹⁴ , preferably OH, NR ¹³ R ¹⁵ , C Cι ₀ alkyl, C ₃ -C ₈ cycloalkyl, -NR ¹⁶ CX-R ¹⁷ , -NR ¹⁸ CX-OR ¹⁹ , -NR ²⁰ SO _m R ²¹ , -SO _p NR ²² R ²³ preferably -SO ₂ NHR ²³ and -SO _q R ² . The substituents R ¹⁰ and R ¹¹ particularly preferably signified hydrogen. The variables m, p and q can mean 0.1 or 2, preferably 2. The variable n can mean 0, 1, 2 or 3, preferably 2.

The substituent R ³ can be hydrogen or a radical selected from the group consisting of optionally substituted C 1 -C ₈ alkyl, C ₆ -C ₈ aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl, -CX- d-Cι ₀ alkyl, CX-C ₆ -C aryl mean. The substituent R ^{3 is} preferably hydrogen.

The substituents R ⁴ and R ⁵ can be identical or different and can be hydrogen, halogen or optionally substituted CrCio-alkyl, preferably hydrogen or Crdo-alkyl, particularly preferably hydrogen or methyl, or R ⁴ and R ⁵ can together be a C ₃ -C ₈ alkyl bridge, preferably a cyclohexyl, cyclopentyl or cyclopropyl bridge, form.

The substituent R ⁶ can be a radical selected from the group consisting of the general formulas

where the variables I and k independently of one another are 1, 2 or 3, preferably 1. R particularly preferably denotes ⁶

R particularly preferably denotes ⁶

The substituents R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ can be the same or different and a radical selected from the group consisting of hydrogen, OH, halogen, CN and NO ₂ , or a radical selected from the group consisting of optionally substituted CrCio -Alkyl, C ₆ -C ₈ -aryl, preferably phenyl, heteroaryl, preferably pyridyl, heterocyclyl, -CX-R ¹⁷ , -OR ¹⁴ , NR ¹³ R ¹⁵ , C ₂ -C ₈ cycloalkyl, -NR ²⁰ SO _m R ²¹ , -SO _p NR ²² R ²³ , -SO _q R ²⁴ , -NR ¹⁸ CX-R ¹⁹ , -NR ¹⁸ CXOR ¹⁷ , where R ²⁵ and R ²⁶ cannot simultaneously denote hydrogen,

The substituent R ⁸ can be hydrogen or a radical selected from the group consisting of optionally substituted CrCio-alkyl, C ₆ -C ₈ aryl, -SO _q - C1-C10 alkyl, -SO _q -C ₆ -C ₄ aryl , -CX- C -C ₀ alkyl, -CX-C ₆ -Cι ₄ aryl, C ₆ -Cι ₀ aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl, preferably hydrogen or -SO ₂ CH ₃ mean.

The substituent R ⁹ is selected hydrogen or a radical from the group consisting of optionally substituted d-Cι ₀ alkyl, C ₆ D ₄ aryl, heteroaryl, C ₃ -C ₈ cycloalkyl, and heterocycloalkyl, are preferably hydrogen. The substituent R ¹² can be hydrogen or a radical selected from the group consisting of optionally substituted benzyl, CrCι ₂ alkyl and C ₆ -Cι ₄ aryl, CX-d-Ci2-alkyl and CX-C ₆ -Cι ₄ aryl, preferably hydrogen.

The substituents R ⁷ , R ¹³ , R ¹⁵ R ¹⁶ , R ¹⁸ , R ²⁰ , R ²² , R ²³ and R ²⁴ can be the same or different and hydrogen, or a radical selected from the group consisting of optionally substituted. CrCio-alkyl, C ₆ -C aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl mean. The substituent R ²⁰ particularly preferably denotes methyl, ethyl or isopropyl.

The substituents R ¹⁴ , R ¹⁹ and R ²⁹ can be the same or different and hydrogen or a radical selected from the group consisting of optionally substituted d-Cio-alkyl, preferably methyl or difluoromethyl, Cβ-Cu-aryl, C ₃ -C ₈ -Cycloalkyl, heteroaryl, heterocyclyl, -CXNRι ₃ Rι ₅ ,

The substituent R ¹⁴ particularly preferably denotes methyl or difluoromethyl.

The substituent R ¹⁷ can be a radical selected from the group consisting of CrCio-alkyl, preferably methyl or ethyl, C ₆ -d ₄ -aryl, heterocyclyl, heteroaryl and C ₃ -C ₈ -cycloalkyl.

The substituent R ²¹ can be hydrogen or OH, or a radical selected from the group consisting of optionally substituted N (CrCιo-alkyl) ₂ - N (C ₃ -C ₈ cycloalkyl), d-Cio-alkyl, C ₆ -d ₄ -Ary !, heterocyclyl, heteroaryl and C ₃ -C ₈ cycloalkyl.

X can be O, S or NR ²⁹ , preferably O.

The compounds according to the invention can be prepared by the synthesis processes described below, the formulas (I) to (IV) and the substituents of the general formulas R ¹ to R ¹² having the meanings mentioned above. These methods are to be understood as an explanation of the invention without restricting it to the subject matter thereof. ("0 (III)

(purple)

SG = protective group

Synthesis of 3-chloro-propylamine hydrochloride (compound III):

A compound of formula (II) is converted into a by means of a chlorinating agent

Transfer compound of formula (III).

Compound (II) can be prepared according to regulations known from the literature, for example DE 2200108 (Pander, Hans J. 3-amino-3-methyl-1-butanol, Ger. Offen. (1973), 6 pp.).

About 0.5 mol of compound (II) is dissolved or suspended in about 100 to 300 ml of a solvent, preferably in methylene chloride / dimethylformamide (50: 1), pyridine, carbon tetrachloride, chloroform or dichloromethane. The mixture is at about -3 to 5 ° C, preferably at 0 ° C with stirring 0.4 to 0.9 mol, preferably 0.6 mol of a chlorinating agent, preferably thionyl chloride, N-chlorosuccinimide, para-toluosulfonic acid chloride, methanesulfonic acid chloride / lithium chloride or, zinc (II) chloride / triphenylphosphine / diethyldiazodicarboxylate, particularly preferably thionyl chloride, added dropwise. The Solvent is removed, the residue is washed with acetonitrile, for example, and dried.

Synthesis of dichlorobenzylidene amine of compound (III):

The base is released from about 80-90, preferably 84.0 mmol of 3-chloro-1, 1-dimethylpropylamine hydrochloride by known methods. The free base is dissolved in about 50 ml of a solvent, preferably toluene, diethyl ethyl ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or methylene chloride, and about 60 to 100 mmol, preferably 80.0 mmol, of 2,6-dichlorobenzaldehyde are added at room temperature with stirring. The reaction mixture is stirred for 5 to 20 h, preferably 15 h at room temperature, dried again and the solvent is removed. The corresponding dichlorobenzylidene amine of the compound (III) is obtained.

Synthesis of dichlorobenzylidenamine of compound (V):

To a solution of 25 to 40 mmol, preferably 33.0 mmol, of one of the compounds (IVa) to (IVi) in about 25 to 100 ml, preferably 50 ml of a solvent, for example tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidine, preferably 1, 3-Dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidone are at 5 to 15 ° C, preferably about 10 ° C with stirring 30 to 45 mmol, preferably 39.0 mmol of a base , for example sodium hydride. When the addition is complete, the reaction mixture is stirred at room temperature for 1 h and then 35 to 45 mmol, preferably 39.0 mmol, of the dichlorobenzylidenamine of the compound (III), dissolved in a solvent, preferably about 50 ml of 1,3-dimethyl-3,4, 5,6-tetrahydro-2 (1 H) -pyrimidone, and 2 to 4 mmol, preferably about 3.3 mmol, of tetrabutylammonium iodide were added. The reaction mixture is stirred for about 5 to 20 hours, preferably 18 hours at room temperature, stirred for about 4 hours at 80 ° and then poured into about 200 ml of ice water / ethyl acetate (1: 1). The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and the solvent is removed. Hydrochloric acid was added to the residue and the mixture was stirred at about 100 ° C. for about 1 h. The reaction mixture is cooled to about 0 ° C, mixed with ethyl acetate and the pH value, for example with sodium hydroxide solution set to 10. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and the solvent is removed on a rotary evaporator. The residue is purified, for example, by chromatography. This gives about 430 mmol of compound (V).

Synthesis of compound (I):

The base is released from about 3 mmol of the compound (V) by known methods. The free base is dissolved in methylene chloride and about 2.6 mmol of a compound of the formula (VI a-c) and about 2.6 mmol of ytterbium (III) trifluoromethanesulfonate are added at room temperature with stirring. The reaction mixture is stirred for about 3 days at room temperature and then water is added. The phases are separated and the aqueous phase is extracted, for example with methylene chloride. The combined organic phases are dried and the solvent is removed. The residue is purified, for example, by chromatography.

About 0.1 mmol of platinum (IV) oxide are added to a solution of about 0.3 mmol of the purified residue in, for example, about 10 mL of tetrahydrofuran / toluene (1: 1). The reaction mixture is shaken in an autoclave under a hydrogen pressure of a little O psi at room temperature for about 5 to 20 h, preferably 16 h. The platinum (IV) oxide is filtered off and the filtrate is freed from the solvent. The compound I is obtained.

The new compounds of the general formula (I) can be synthesized in analogy to the following synthesis examples. However, these examples are only to be understood as an exemplary procedure for further explaining the invention, without restricting it to the subject matter thereof.

example 1

a) Synthesis of 3-chloro-1, 1-dimethylpropylamine hydrochloride:

A solution of 53.0 g (514 mmol) of 3-amino-3-methylbutanol in 255 ml of methylene chloride / dimethylformamide (50: 1) was added at 0 ° C. with vigorous stirring 48.7 mL (668 mmol) thionyl chloride slowly added dropwise. After the addition was complete, the reaction mixture was boiled under reflux for 1 h and then stirred at room temperature for 16 h. The solvent was removed and the residue was mixed with 50 ml of acetonitrile with stirring. The solid was filtered off and dried at 45 ° C. for 18 h. 67.9 g (430 mmol, 84%) of 3-chloro-1,1-dimethylpropylamine hydrochloride were obtained as a colorless solid.

MS: (M + H) = 122/124 (CI)

b) Synthesis of the (3-chloro-1, 1-dimethylpropyl) - (2,6-dichlorobenzylidene) amine:

13.3 g (84.0 mmol) of 3-chloro-1, 1-dimethyl-propylamine hydrochloride were added to 84.0 ml of sodium hydroxide solution (1 M) at 0 ° C. with vigorous stirring. The reaction mixture was stirred at 0 ° C. for 30 min and then 50 ml of methylene chloride were added. The phases were separated and the aqueous phase extracted twice with 35 mL methylene chloride. The combined organic phases were dried over magnesium sulfate and 14.2 g (81.0 mmol) of 2,6-dichlorobenzaldehyde were added at room temperature while stirring. The reaction mixture was stirred at room temperature for 18 h, dried again with magnesium sulfate and the solvent was removed. 22.3 g (80.0 mmol, 99%) (3-chloro-1, 1-dimethylpropyl) - (2,6-dichlorobenzylidene) amine were obtained as a yellowish oil.

MS: (M + H) = 278/280/282 (CI3)

c) Synthesis of 1, 1-dimethyl-3- (4-phenyl-imidazol-1-yl) propylamine:

To a solution of 4.80 g (33.0 mmol) of 4-phenylimidazole in 50 ml of 1, 3-dimethyl-3,4,5, 6-tetrahydro-2 (1 H) -pyrimidone were violently at 10 ° C. Stir slowly 1.60 g (50% in oil, 39.0 mmol) sodium hydride. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h and then 10.9 g (39.0 mmol) (3-chloro-1, 1-dimethylpropyl) - (2,6-dichlorobenzylidene) amine dissolved in 50 mL 1, 3-Dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidone, and 1, 20 g (3.33 mmol) of tetrabutylammonium iodide were added. The reaction mixture was stirred at room temperature for 18 h, stirred at 80 ° for 4 h and then poured into 200 ml of ice water / ethyl acetate (1: 1). The phases were separated and the aqueous phase extracted three times with 50 mL ethyl acetate each. The combined organic phases were dried over magnesium sulfate and the solvent was removed. The residue was mixed with 11 ml of hydrochloric acid (3.5 M) and stirred at 100 ° C. for 1 h. The reaction mixture was cooled to 0 ° C., 50 ml of ethyl acetate were added and the pH was adjusted to 10 using sodium hydroxide solution (1 M). The phases were separated and the aqueous phase extracted three times with 50 mL ethyl acetate each. The combined organic phases were dried over magnesium sulfate and the solvent was removed. The residue was purified by flash column chromatography [methylene chloride / methanol / ammonia (90: 10: 1)]. 67.9 g (430 mmol, 83%) of 3-chloro-1, 1-dimethylpropylamine hydrochloride were obtained as a colorless solid.

MS: (M + H) = 230

R _f : 0.30 [methylene chloride / methanol / ammonia (90: 10: 1)]

d) Synthesis of the (R) -1- (4-benzyloxy-3-nitrophenyl) -2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] ethanol:

0.90 g (3.1 mmol) of 3-chloro-1, 1-dimethylpropylamine hydrochloride were added to 10 ml of sodium hydroxide solution (1 M) at 0 ° C. with vigorous stirring. The reaction mixture was stirred at 0 ° C for 30 min and then 20 mL methylene chloride was added. The phases were separated and the aqueous phase extracted twice with 20 mL methylene chloride. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was dissolved in 5.0 mL methylene chloride and at

0.70 g (2.6 mmol) of (R) -2- (4-benzyloxy-3-nitrophenyl) oxirane and 0.20 g (0.26 mmol) of ytterbium (III) trifluoromethanesulfonate were added to the room temperature with vigorous stirring. The reaction mixture was stirred for 3 d at room temperature and then 30 mL water / methylene chloride (1: 1) was added. The phases were separated and the aqueous phase extracted twice with 20 mL methylene chloride. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol / ammonia (90: 10: 1)]. 0.40 g (0.86 mmol, 33%) of (R) -1 - (4-benzyloxy-3-nitrophenyl) - 2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] ethanol was obtained as a yellowish solid.

MS: (M + H) = 501, (M-H) = 499

R _f : 0.27 [methylene chloride / methanol / ammonia (90: 10: 1)]

e) Synthesis of (R) -1- (3-amino-4-benzyloxyphenyl) -2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] ethanoIs:

To a solution of 0.15 g (0.28 mmol) of (R) -1- (4-benzyloxy-3-nitrophenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) -propylamino] ethanol in 10 mL tetrahydrofuran / toluene (1: 1) were added 0.025 g (0.11 mmol) of platinum (IV) oxide. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 10 psi at room temperature for 16 hours. The hydrogen pressure was released, the platinum (IV) oxide was filtered off and the filtrate was freed from the solvent. 0.14 g (0.28 mmol, 99%) of (R) -1- (3-amino-4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl ) -propylamino] -ethanol obtained as a brown oil. MS: (M + H) = 471, (MH) = 469 R _f : 0.26 [ethyl acetate / methanol / ammonia (90: 10: 1)]

f) Synthesis of (R) -N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl} phenyl) - benzenesulfonamide:

To a solution of 0.20 g (41 mmol) of (R) -1 - (3-amino-4-benzyloxyphenyl) -2- [1, 1-dimethyl-3- (4-phenylimidazoI-1-yl) propylamino ] -ethanol in 5 mL pyridine was slowly added 0.10 mL (41 mmol) benzenesulfonic acid chloride at 0 ° C with vigorous stirring. After the addition was complete, the reaction mixture was stirred at 0 ° C. for 4 h and then poured into 40 ml of ice water / ethyl acetate (1: 1). The phases were separated and the aqueous phase was extracted three times with 20 mL ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. 0.14 g (0.28 mmol, 99%) of (R) -N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) - propylamino] -1-hydroxyethyl} -phenyl) -benzenesulfonamide obtained as a white solid. MS: (M + H) = 611, (MH) = 609

R _f : 0.36 [methylene chloride / methanol / ammonia (90: 10: 1)]

g) Synthesis of (R) -N- (5- {2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl} -2-hydroxy-phenyl) - benzenesulfonamide:

To a solution of 0.30 g (0.41 mmol) of (R) -N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino ] -1-hydroxyethyl} -phenyl) -benzenesulfonamide in 15 mL ethanol were added 0.10 g palladium (5% on activated carbon). The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at room temperature for 3 hours. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol / ammonia (90: 10: 1)]. 0.20 g (0.31 mmol, 75%) of (R) -N- (5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) -propylamino] -1 -hydroxyethyl} -2-hydroxy-phenyl) -benzenesulfonamide obtained as a colorless solid. MS: (M + H) = 521, (MH) = 519 R _f : 0.33 [methylene chloride / methanol / ammonia (90: 10: 1)

Example 5 a) Enantiomerically pure synthesis of (R) -1 - (4-benzyloxy-3-nitrophenyl) -2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] ethanol:

0.90 g (3.1 mmol) of 3-chloro-1, 1-dimethylpropylamine hydrochloride were added to 0 ml of sodium hydroxide solution (1 M) at 0 ° C. with vigorous stirring. The reaction mixture was stirred at 0 ° C for 30 min and then 20 mL methylene chloride was added. The phases were separated and the aqueous phase extracted twice with 20 mL methylene chloride. The combined organic phases were dried over magnesium sulfate and the solvent was removed. The residue was dissolved in 5.0 mL methylene chloride and at room temperature with stirring with 0.70 g (2.6 mmol) of (R) -2- (4-benzyloxy-3-nitrophenyl) oxirane and 0.20 g (0 , 26 mmol) of ytterbium (III) trifluoromethanesulfonate. The reaction mixture was stirred for 3 d at room temperature and then 30 mL water / methylene chloride (1: 1) was added. The phases were separated and the aqueous phase extracted twice with 20 mL methylene chloride. The combined organic phases were over Magnesium sulfate dried and the solvent removed on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol / ammonia (90: 10: 1)]. 0.40 g (0.86 mmol, 33%) of (R) -1 - (4-benzyloxy-3-nitrophenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl ) - Propylamino] ethanol obtained as a yellowish solid.

MS: (M + H) = 501, (M-H) = 499

R _f : 0.27 [methylene chloride / methanol / ammonia (90: 10: 1)]

b) Enantiomerically pure synthesis of (R) -1- (3-amino-4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] ethanol:

To a solution of 0.15 g (0.28 mmol) of (R) -1- (4-benzyloxy-3-nitrophenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) -propylamino] ethanol in 10 mL tetrahydrofuran / toluene (1: 1) were added 0.025 g (0.11 mmol) of platinum (IV) oxide. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 10 psi at room temperature for 16 hours. The hydrogen pressure was released, the platinum (IV) oxide was filtered off and the filtrate was freed from the solvent on a rotary evaporator. 0.14 g (0.28 mmol, 99%) of (R) -1- (3-amino-4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl ) -propylamino] -ethanol obtained as a brown oil.

MS: (M + H) = 471, (M-H) = 469

R _f : 0.26 [ethyl acetate / methanol / ammonia (90: 10: 1)]

c) (R) -N- (2-benzyloxy-5- {2- [1,1-dimethyl-3- (4-phenylimidazol-1-yI) propylamino] -1-hydroxyethyl} phenyl) benzenesulfonamide:

To a solution of 0.20 g (41 mmol) of (R) -1- (3-amino-4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino ] -ethanol in 5 mL pyridine was slowly added 0.10 mL (41 mmol) benzenesulfonic acid chloride at 0 ° C with vigorous stirring. After the addition was complete, the reaction mixture was stirred at 0 ° C. for 4 h and then poured into 40 ml of ice water / ethyl acetate (1: 1). The phases were separated and the aqueous phase was extracted three times with 20 mL ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Thereby 0.14 g (0.28 mmol, 99%) (R) -N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl } -phenyl) -benzenesulfonamide obtained as a white solid.

MS: (M + H) = 611, (MH) = 609 R _f : 0.36 [methylene chloride / methanol / ammonia (90: 10: 1)]

d) Enantiomerically pure synthesis of

(R) -N- (5- {2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) -propylamino] -1-hydroxyethyl} -2-hydroxy-phenyl) -benzenesulfonamide: To one Solution of 0.30 g (0.41 mmol) of (R) -N- (2-benzyloxy-5- {2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] - 1-Hydroxyethyl} -phenyl) -benzenesulfonamide in 15 mL ethanol were added 0.10 g palladium (5% on activated carbon). The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at room temperature for 3 hours. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol / ammonia (90: 10: 1)]. 0.20 g (0.31 mmol, 75%) of (R) -1 - (4-benzyloxy-3-nitrophenyl) -2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl ) - Propylamino] ethanol obtained as a colorless solid. MS: (M + H) = 521, (M-H) = 519

R _f : 0.33 [methylene chloride / methanol / ammonia (90: 10: 1)]

e) Synthesis of (R) -1, 2,3,4-tetrahydroquinoline-8-sulfonic acid (5- {2- [1, 1-dimethyl-3- (4-phenyl-imidazol-1-yl) - propylamino] -1-hydroxy-ethyl} -2-hydroxy-phenyl) -amide

To a solution of 0.20 g (0.41 mmol) of (R) -1, 2,3,4-tetrahydroquinoline-8-sulfonic acid (2-benzyloxy-5- {2- [1, 1-dimethyl- 3- (4-phenyl-imidazol-1-yl) -propylamino] - 1-hydroxyethyl} phenyl) -amide in 20 ml of ethanol, 0.10 g of palladium (5% on activated carbon) was added. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at room temperature for 6 hours. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol / ammonia (90: 10: 1)]. 0.20 g (0.31 mmol, 75%) (R) -1, 2,3,4-tetrahydro-quinoline-8- sulfonic acid (5- {2- [1, 1-dimethyl-3- (4-phenyl-imidazol-1-yl) propylamino] -1-hydroxyethyl} -2-hydroxy-phenyl) -amide was obtained as a colorless solid ,

MS: (M + H) = 576, (MH) = 574 R _f : 0.32 [methylene chloride / methanol / ammonia (90: 10: 1)]

^' Example 12 a) Racemic synthesis of N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxy-ethyl} phenyl) methanesulfonamide

21.1 g (33.0 mmol) N- [2-benzyloxy-5- (2-ethoxy-2-hydroxyacetyl) phenyl] methanesulfonamide and 7.00 g (30.0 mmol) 1.1 Dimethyl-3- (4-phenyl-imidazol-1-yl) propylamine in 150 mL ethanol were heated under reflux for 18 h. The reaction mixture was cooled to 0 ° C. and 3 g (77.0 mmol) of sodium borohydride were then added. The mixture was stirred for a further 3 h at room temperature and glacial acetic acid was then added. The solvent was removed on a rotary evaporator and the residue was dissolved in 300 ml of ethyl acetate / water (1: 2). The aqueous phase was concentrated. Ammonia made alkaline and separated from the organic phase. The organic phase was washed twice with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue was dissolved in 70 ml of warm ethanol, 5.4 g of oxalic acid were added and the resulting oxalate was recrystallized from ethanol. 16.0 g (22.0 mmol, 73%) of N- (2-benzyloxy-5- {2- [1,1-dimethyl-3- (4-phenyl-imidazol-1-yl) propylamino] Obtained -1 - hydroxy-ethyl} -phenyl) methanesulfonamide as oxalate. M.p .: 183-184 ° C b) Racemic synthesis of N- (5- {2- [1, 1-dimethyl-3- (4-phenyl-imidazol-1-yl) - propylamino] -1-hydroxy-ethyl } -2-hydroxy-phenyl) methanesulfonamide

From 16.0 g of oxalate of N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenyl-imidazol-1-yl) - propylamino] -1-hydroxy-ethyl} - phenyl) methanesulfonamide the base was released by known methods.

1.5 g of palladium (5% on activated carbon) were added to a solution of the free base in 150 ml of methanol. The reaction mixture was placed in an autoclave a hydrogen pressure of 20 psi shaken at room temperature for 6 h. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue was recrystallized from acetonitrile. 3.9 g (93%) of N- (5- {2- [1,1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl} -2 -hydroxy-phenyl) methanesulfonamide obtained as a colorless solid. M.p .: 133-136 ° C

Example 27

a) Racemic synthesis of N- (2-benzyloxy-5- {1-hydroxy-2- [3- (4-iodimidazol-1-yl) -1,1-dimethylpropylamino] ethyl} phenyl) phenylsulfonamide :

2.1 g (7.7 mmol) of 3- (4-iodimidazol-1-yl) -1, 1-dimethyl-propylamine and 3.4 g (7.7 mmol) of N- [2-benzyloxy-5- ( 2-ethoxy-1,2-dihydroxy-ethyl) -phenyl] -phenylsulfonamide in 25 ml of ethanol were heated under reflux for 18 h. The reaction mixture was cooled to 0 ° C. and 0.3 g (7.7 mmol) of sodium borohydride were then added. The mixture was stirred for a further 3 h at room temperature and glacial acetic acid was then added. The solvent was removed on a rotary evaporator and the residue was dissolved in 300 ml of ethyl acetate / water (1: 2). The aqueous phase was concentrated. Ammonia made alkaline and separated from the organic phase. The organic phase was washed twice with 100 ml of water and once with 100 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by flash column chromatography

[Methylene chloride / methanol / ammonia (90: 10: 1)]. 3.5 g (5.0 mmol, 69%) of N- (2-benzyloxy-5- {1-hydroxy-2- [3- (4-iodo-imidazol-1-yl) -1, 1- Dimethyl-propylamino] -ethyl} -phenyl) -phenylsulfonamide obtained as a yellowish solid.

MS: (M + H) = 661, (M-H) = 659

R _f : 0.51 [methylene chloride / methanol / ammonia (90: 10: 1)]

b) Racemic synthesis of N- (2-benzyloxy-5- {2- [1,1, dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl} phenyl) -phenylsuIfonamid: 0.500 g (0.757 mmol) of N- (2-benzyloxy-5- {1-hydroxy-2- [3- (4-iodo-imidazol-1-yl) -1, 1-dimethyl-propylamino] ethyl} phenyl ) -phenylsulfonamide, 0.211 g (1.51 mmol) 4-fluorophenylboronic acid, 0.012 g (0.010 mmol) tetrakis (triphenylphosphino) palladium, 0.010 g (0.010 mmol) tetrabutylammonium bromide in 20 mL saturated, aqueous sodium hydrogen carbonate solution / toluene (1: 1 ) were boiled under reflux for 3 d. The reaction mixture was mixed with 100 ml of toluene water (1: 1) at room temperature, the phases were separated and the organic phase was washed three times with 50 ml of water. The organic phase was dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol (90:10)]. 0.420 g (0.668 mmol, 88%) of N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl } -phenyl) -phenylsulfonamide obtained as a colorless oil.

MS: (M + H) = 629, (M-H) = 627

R _f : 0.36 [methylene chloride / methanol (90:10)]

Example 25 a) Racemic synthesis of 1- (4-benzyloxy-2-fluoro-phenyl) -2- [3- (4,5-diphenylimidazol-1-yl) -1, 1-dimethyl-propylamino] ethanol :

12.2 g (40.0 mmol) 1- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-2-hydroxyethanone and 9.2 g (30.0 mmol) 3- (4.5 -Diphenyl-imidazol-1-yl) -1, 1 -dimethyl-propylamine in 200 ml of ethanol were boiled under reflux for 18 h. The reaction mixture was cooled to 0 ° C. and 3 g (77.0 mmol) of sodium borohydride were then added. The mixture was stirred for a further 3 h at room temperature and glacial acetic acid was then added. The solvent was removed on a rotary evaporator and the residue was dissolved in 300 ml of ethyl acetate / water (1: 2). The aqueous phase was concentrated. Ammonia made alkaline and separated from the organic phase. The organic phase was washed twice with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue was dissolved in 70 ml of warm ethanol, 3.5 g of fumaric acid were added and the fumarate formed was recrystallized from ethanol. 11.0 g (20.0 mmol, 50%) of 1- (4-benzyloxy-2-fluoro-ρhenyl) -2- [3- (4,5-diphenyl-imidazol-1-yl) -1, Obtained 1-dimethyl-proρylamino] ethanol as fumarate.

M.p .: 182-183 ° C

b) Racemic synthesis of 4- {2- [3- (4,5-diphenylimidazol-1-yl) -1, 1-dimethylpropylamino] -1-hydroxyethyl!} - 3-fluoro-phenol:

From 7.0 g of fumarate of 1 - (4-benzyloxy-2-fluoro-phenyl) -2- [3- (4,5-diphenyl-imidazol-1-yl) -1, 1-dimethyl-propylamino] ethanol the base was released by known methods. 1.0 g of palladium (5% on activated carbon) was added to a solution of the free base in 100 ml of methanol. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at room temperature for 6 h. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue was recrystallized from acetonitrile. 3.9 g (93%) of 4- {2- [3- (4,5-diphenylimidazol-1-yl) -1, 1-dimethylpropylamino] -1-hydroxyethyl} -3- Fluoro-phenol obtained as a colorless solid.

M.p .: 163-165 ° C

Analogously to the procedure described above, the compounds of the formulas (IA), (IB) and (IC) listed in Tables 1, 2 and 3 are obtained. The abbreviations Xj, X ₂ , X, X ₅ , Xe, X ₈ and Xι ₂ used in the tables each represent a link to a position in the general formula listed in Table 1 instead of the corresponding radicals R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ¹² . Table 2.

(IC)

As has been found, the compounds of the general formula (1) are distinguished by a wide range of possible uses in the therapeutic field. Emphasis should be given to those applications for which the action of beta-3 agonists, in particular selective beta-3 agonists, play a role.

Such diseases include, for example: atherosclerosis, cholangitis ;, gallbladder disease, chronic cystitis, chronic cystitis; chronic prostatitis, cystospasm, depression, duodenal ulcer, duodenitis, dysmenorrhea; increased intraocular pressure and glaucoma, enteritis, esophagitis, gastric ulcer, gastritis, gastrointestinal tract

Disorders caused by smooth muscle contraction (s), gastrointestinal disorders including gastric ulcer; gastrointestinal ulcers, gastrointestinal ulcers, glaucoma, glucosuria, hyperanakinesia, hypercholesterolaemia, hypercholesterolaemia, hyperglycaemia, hyperlipemia, arterial hypertension, hypertriglyceridaemia, insulin resistance, intestinal ulceration or small bowel ulcers, inflammatory ulcers, mastitis, inflammatory ulcers, inflammatory bowel ulcers, inflammatory bowel ulcers, and inflammatory bowel ulcers (pro Colon and other diseases with decreased intestinal motility Depression, melancholy, pollakiuria, frequent urge to urinate, neurogenic inflammation due to nerves, neurogenic bladder dysfunction, neurogenic inflammation of the respiratory tract, neuropathic bladder dysfunction, nocturia, unspecified diarrhea, abdominal inflammation, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, pancreatitis , Gastric ulcers, prostate diseases such as benign prostatic hyperplasia, prostate enlargement, spasm, cramp, diabetes mellitus type 2, irritable bladder or concretion of the dissipative n urinary tract.

The beta-3 agonists according to the invention are particularly suitable for the treatment of obesity, insulin resistance; Diabetes ^mellitus' type 2; urinary incontinence; Irritable colon and other diseases with decreased intestinal motility or depression, especially for the treatment of diabetes and obesity. The activity of the beta-3 agonists can be determined, for example, in a lipolysis test. The test method can be carried out as described below:

Adipocytes were isolated from ex vivo adipose tissue by modifying a Rodbell method (Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 239: 375-380, 1964). Cut out adipose tissue was cut into small pieces and mixed with 1 mg / ml collagenase in Krebs Ringer buffer (KBR) containing 6 mM glucose and 2% albumin by gentle shaking at 37 ° C. for 30-40 min. The cells were filtered through a gauze, washed twice with KRB and centrifuged 50-150 g each for 5 min. 10 / I of the centrifuged adipocytes were incubated with 90 μl of a compound (agonists) according to the invention at concentrations between 10 ^"15 to 10 ^{" 4} M. The agonists were incubated at 37 ° C for 40 min. Varying glycerol release into the medium indicated a change in fat cell lipolysis due to the agonist added. Released glycerol was detected enzymatically using a kit from Sigma (Triglyceride (GPO Trinder) Reagent A; Cat. # 337-40A) as described below.

Glycerol is phosphorylated by ATP via glycerol kinase. The resulting glycerol-1-phosphate is oxidized to dihydroxyacetone phosphate and hydrogen peroxide by glycerol phosphate oxidase. A quinonimine dye is then formed by the peroxidase-catalyzed coupling of sodium N-ethyl-N- (3-sulfopropyl) m-ansidine and 4-aminoantipyrine. The dye shows an absorption maximum at 540 nm. The absorption is directly proportional to the glycerol concentration in the samples.

The new compounds can be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, also in combination with other active ingredients which are used for the same indications. These include, for example, anti-diabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. Gl 262570), alpha-glucosidose inhibitors (e.g. acglibosarbose inhibitors) ), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. Exendin-4) or amylin. In addition, inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as, for example, inhibitors of glucose-6-phosphatase, or of fructose-1, 6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol-pyruvate carboxy Glycogen synthase kinase or pyruvate dehydrokinase, lipid-lowering agents, such as HMG-CoA reductase inhibitors (eg simvastatin, atorvastatin), Fibrates (eg bezafibrate, fenofibrate), nicotinic acid and its derivatives, cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, colestyramine, HDL-increasing compounds such as, for example, inhibitors of CETP or regulators of ABC1 or active substances for treating obesity, such as such as sibutramine or tetrahydrolipstatin.

In particular, a combination with medications for influencing high blood pressure, e.g. All antagonists or ACE inhibitors, diuretics, β-blockers, and other modulators of the adrenergic system or combinations thereof are suitable. In addition, combinations with stimulators of the adrenergic system via alpha 1 and alpha 2 and beta 1, beta 2 and beta 3 receptors are particularly suitable.

The compounds of general formula (I) can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (SC, IV, IM) and infusion, juices, emulsions or dispersible powders. The proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the total composition, i.e. in amounts sufficient to reach the dosage range given below. If necessary, the doses mentioned can be given several times a day. Corresponding tablets can be mixed, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, and disintegrants, such as

Corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, wherein the auxiliaries mentioned above for the tablets can be used.

Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection and infusion solutions are used in the usual way, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally under

Use of emulsifiers and / or dispersants, where, for example when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents, produced and filled into injection bottles or ampoules or infusion bottles.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules. Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.

Examples of auxiliaries are water, pharmaceutically acceptable organic solvents, such as paraffins (for example petroleum fractions), oils of vegetable origin (for example peanut or sesame oil), mono- or polyfunctional alcohols (for example ethanol or glycerol), carriers such as natural rock meal (for example kaolins, Clays, talc, chalk) synthetic powdered stone (e.g. highly disperse silica and silicates), sugar (e.g. cane, milk and glucose) emulsifiers (e.g. lignin, sulfite liquor, methyl cellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate) mentioned.

The application is carried out in the usual way, preferably orally or transdermally, particularly preferably orally. In the case of oral use, the tablets can of course also contain additives, such as e.g. Contain sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active ingredients can be mixed with various flavor enhancers or colorants. In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials. The dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the drug, the type of its formulation and the time or interval at which the administration takes place , In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the above-mentioned upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute them in several single doses throughout the day.

The following formulation examples illustrate the present invention without, however, restricting its scope:

Pharmaceutical formulation examples

A) tablets per tablet

Active ingredient 100 mg Milk sugar 140 mg

Corn starch 240 mg

Polyvinyl pyrrolidone 15 mg

Magnesium stearate 5 mg

500 mg

The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of a suitable shape and size.

B) tablets per tablet

Active ingredient 80 mg

Milk sugar 55 mg

Corn starch 190 mg

Microcrystalline cellulose 35 mg

Polyvinyl pyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mg

400 mg

The finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate which is dried and sieved. Add the sodium carboxymethyl starch and the magnesium stearate, mix and compress the mixture into tablets of a suitable size. C) Amoullenolution α

Active ingredient 50 mg

Sodium chloride 50 mg

Aqua per inj. 5 ml

The active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5-6.5, and sodium chloride is added as an isotonic agent. The solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.

Claims

claims 1. Compounds of the general formula (I), wherein R, R ² , R, R independently of one another are a radical selected from the group consisting of hydrogen, halogen, CN, NO ₂ , and -NHCXNH ₂ or a radical selected from the group consisting of optionally substituted -COR ⁷ , -COOR ⁷ , -CONR ⁷ R ¹³ , -OR ¹⁴ , NR ¹³ R ¹⁵ , CC ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, - NR ¹⁶ CX-R ¹⁷ , -NR ¹⁸ CX-OR ¹⁹ , -NR ²⁰ SOmR ²¹ , -SO _p NR ²² R ²³ and -SO _q R ²⁴ . m, p, q 0, 1 or 2 n 0, 1, 2 or 3 R ^{3 is} hydrogen or a radical selected from the group consisting of optionally substituted C ₀ -C alkyl, C ₆ -C ₀ aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl, -CX- CC ₁₀ alkyl, -CX-C ₆ -C ₁₄ aryl, R ⁴ , R ⁵ independently of one another are hydrogen, halogen or optionally substituted CrC-io-alkyl, or R ⁴ and R ⁵ together form a C ₃ -C ₈ alkyl bridge, R ^{6 is} a radical selected from the group consisting of the general formulas l, k independently of one another 1, 2 or 3, R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ independently of one another are selected from the group Group consisting of hydrogen, OH, halogen, CN and NO ₂ , or a radical selected from the group consisting of optionally substituted d-Cio-alkyl, Cβ-dβ-aryl, heteroaryl, heterocyclyl, -CX-R ¹⁷ , -OR ¹⁴ , NR ¹³ R ¹⁵ , C ₂ -C ₈ - cycloalkyl, -NR ²⁰ SO _m R ²¹ , -SO _p NR ²² R ²³ , -SO _q R ²⁴ , -NR ¹⁸ CX-R ¹⁹ , -NR ¹⁸ CXOR ¹⁷ , where R ²⁵ and R ²⁶ cannot simultaneously denote hydrogen, R ^{8 is} hydrogen or a radical selected from the group consisting of optionally substituted d -CC ₀ alkyl, C ₆ -C ₈ aryl, -SO _q - CrC ₁₀ alkyl, -SO _q -C ₆ -C ₁₄ aryl, -CX- CC ₁₀ alkyl, -CX-C ₆ -Cι ₄ aryl, C ₆ -C ₁₀ aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl R ^{9 is} hydrogen or a radical selected from the group consisting of optionally substituted d-Cio-alkyl, C ₆ -d ₄ -aryl, heteroaryl, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl, R ^{12 is} hydrogen or a radical selected from the group consisting of optionally substituted benzyl, C ₁ -C ₂ -alkyl and C ₆ -C ₄ aryl, R ⁷ , R ¹³ , R ¹⁵ , R ¹⁶ , R ¹⁸ , R ²⁰ , R ²² , R ²³ independently of one another are hydrogen, or a radical selected from the group consisting of optionally substituted. d-Cio-alkyl, C ₆ -C aryl, heterocyclyl and C ₃ -C ₈ cycloalkyl R ¹⁴ , R ¹⁹ , R ²⁹ independently of one another hydrogen or a radical selected from the group consisting of optionally substituted d-Cio-alkyl, C ₆ -C ₄ aryl, C ₃ - C ₈ cycloalkyl, heteroaryl, heterocyclyl, -CXNRι ₃ R ₁₅ and -CXR ₇ R ^{17 is} a radical selected from the group consisting of CrCio-alkyl, C ₆ -C ₄ aryl, heterocyclyl, heteroaryl and C ₃ -C ₈ cycloalkyl R ²¹ , R ^{24 are} independently hydrogen or OH, or a radical selected from the group consisting of optionally substituted N (-CC- ₀ alkyl) ₂ , N (C ₃ -C ₈ cycloalkyl), d-Cio-alkyl, C ₆ -C ₄ aryl, heterocyclyl, heteroaryl and C ₃ -C ₈ cycloalkyl and XO, S or NR ²⁹ , optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts. 2. Compounds according to claim 1, wherein R ¹⁰ , R ¹¹ independently of one another are hydrogen or halogen, m, p, q independently of one another 0, 1 or 2 n 0, 1, 2 or 3 R ^{3 is} hydrogen or CC ₅ alkyl R ⁴ , R ⁵ independently of one another are hydrogen or Ci-Cs-alkyl, R ^{8 is} a radical selected from the group consisting of hydrogen, dC ₅ alkyl, -SO _q - d-Cs alkyl, -SO _q -C ₆ -Cι ₄ aryl, phenyl and C ₃ -C ₆ cycloalkyl R ^{9 is} hydrogen or CC ₁₀ alkyl R ^{12 is} hydrogen or benzyl R ¹³ , R ¹⁵ , R ¹⁶ , R ¹⁸ independently of one another are selected from the group consisting of hydrogen. Ci-Cs-alkyl, C ₃ -C ₆ cycloalkyl and phenyl R ¹⁴ R ¹⁹ independently of one another are hydrogen or Ci-Cs-alkyl, and R ^{17 is} optionally substituted CrC ₅ alkyl or C ₆ -Cι ₀ aryl. 3. Compounds according to claim 1 or 2, wherein R ¹⁰ , R ^{11 are} hydrogen m, p, q 0, 1 or 2 n 0, 1, 2 or 3. R ^{3 is} hydrogen R ⁴ , R ⁵ independently of one another are hydrogen or methyl, R ^{8 is} hydrogen, -SO _q -C ₆ -Cι ₄ -aryl or -SO ₂ -Cι-C ₅ -Alky1 R ^{9 is} hydrogen R ^{12 is} hydrogen or benzyl, R ¹³ , R ¹⁵ , R ¹⁶ , R ¹⁸ independently of one another are selected from the group consisting of hydrogen. CrCι ₅ alkyl and phenyl, R ¹⁴ , R ¹⁹ independently of one another are hydrogen or CrC ₅ alkyl, and R ¹⁷ d-Cs-alkyl or C ₆ -C aryl 4. Compounds according to any one of claims 1 to 3, wherein R ^{1 is} a radical selected from the group consisting of hydrogen, NO ₂ , NH ₂ , -NHCX-R ¹⁷ and -NHSO ₂ R ²¹ . R ² , hydrogen or halogen n 2, R ^{3 is} hydrogen R ⁴ , R ^{5 are} hydrogen or methyl R ^{6 is} a radical selected from the group consisting of the general formulas l, k 1 R ²⁶ R ²⁷ hydrogen, R ^{8 is} hydrogen or -SO ₂ CH ₃ , R ^{9 is} hydrogen, R ¹⁰ , R ^{11 are} hydrogen, and R ^{12 is} hydrogen or benzyl, 5. Compounds according to any one of claims 1 to 4, wherein R ^{6 is} a radical selected from the group consisting of the general formulas is. 6. Compounds according to any one of claims 1 to 5, wherein R ^{6 is} an optionally substituted radical of the formula j) means. 7. Compounds of formula (I) according to any one of claims 1 to 6 for use as a medicament. 8. Compounds of formula (I) according to any one of claims 1 to 6 for use as a medicament with selective beta-3 agonistic activity. 9. Use of a compound of formula (I) according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of diseases which are associated with the stimulation of beta-3 receptors. 10. Method for the treatment and / or prevention of diseases associated with the stimulation of beta-3 receptors., Thereby characterized in that an effective amount of a compound of formula I according to claims 1 to 6 is administered to a patient. 11. Pharmaceutical composition containing one or more compounds of the general formula (I) according to one of the active ingredients Claims 1 to 6 or their physiologically compatible salts, if appropriate in combination with customary auxiliaries and / or carriers. 12. Pharmaceutical composition containing as active ingredient one or more compounds of general formula (I) according to one of the Claims 1 to 6 or their physiologically tolerated salts and one or more active substances selected from the group consisting of antidiabetic agents, antidiabetic agents, inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, lipid-lowering agents, cholesterol absorption inhibitors, HDL-increasing compounds, active substances for Treatment of obesity and modulators or stimulators of the adrenergic via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors. 13. Process for the preparation of a compound of the general formula (I), wherein R ¹ -R ²⁸ and X can have the meaning given in Claims 1 to 6, characterized in that a compound of the general formula (II) (II) where R -> 4. u, _ndJ r R * .5 can have the meaning given in claims 1 to 6, by means of a chlorinating agent in a compound of the formula (III) (Hl), the compound of formula (III), optionally provided with an amino protecting group, with an optionally substituted compound selected from the group consisting of the general formulas (IVa) to (IVi) (IV) wherein k, I, R ²⁷ and R ^{28 have} the meaning given in claims 1 to 6, implemented and the product of the formula (V) (V) where n, R ⁴ , R ⁵ , R ⁶ and R ^{8 have} the meaning given in claims 1 to 6, with a compound of the formula (VI) (VI) where R ¹ , R ² , R ⁹ and R ⁰ to R ^{12 have} the meaning given in claims 1 to 6, is implemented.