WO2008132162A1

WO2008132162A1 - 3- (sulphonylamino) -phenyl-2 -hydroxy-ethylamino derivatives useful as beta-agonists, processes for preparing them and their use as medicaments

Info

Publication number: WO2008132162A1
Application number: PCT/EP2008/055067
Authority: WO
Inventors: Thomas Trieselmann; Matthew R. Netherton; Ingo Konetzki
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2007-04-26
Filing date: 2008-04-25
Publication date: 2008-11-06

Abstract

The present invention relates to compounds of general formula (I), wherein the groups A, L, R1 and R2 have the meanings given in the claims and specification, the tautomers, racemates, enantiomers, diastereomers, mixtures thereof, solvates thereof, hydrates thereof, the prodrugs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, processes for preparing these compounds and their use as medicaments.

Description

97825fft

3- (SULPHONYLAMINO) -PHENYL-2-HYDROXY-ETHYLAMINO DERIVATIVES USEFUL AS BETA-AGONISTS, PROCESSES FOR PREPARING THEM AND THEIR USE AS MEDICAMENTS

The present invention relates to new beta-agonists of general formula (I)

wherein the groups A, L, R¹ and R² have the meanings given in the claims and specification, the tautomers, racemates, enantiomers, diastereomers, solvates, hydrates thereof, mixtures thereof, the prodrungs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, processes for preparing these compounds and their use as medicaments.

Background to the invention

The treatment of type Il diabetes and obesity is based primarily on reducing calorie intake and increasing physical activity. These methods are seldom successful in the long term.

It is known that beta-3 receptor agonists exhibit a significant effect on lipolysis, thermogenesis and the serum glucose level in animal models of type Il diabetes (Arch JR. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress, Eur J Pharmacol. 2002 Apr 12; 440(2-3):99-107). Compounds that are structurally similar to the compounds according to the invention and their broncholytic, spasmolytic and antiallergic activity were disclosed for example in DE 2833140.

The aim of the present invention is to provide selective beta-3-agonists which are suitable for preparing medicaments for the treatment of obesity and type Il diabetes.

Detailed description of the invention

Surprisingly it has been found that compounds of general formula (I) wherein the groups A, L, R¹ and R² have the meanings given below act as selective beta-3-agonists. Thus the compounds according to the invention may be used for the treatment of ailments connected with the stimulation of beta-3- receptors.

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

wherein

R¹ denotes a phenyl group, which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl, methoxy, trifluoromethoxy or difluoromethoxy groups, wherein the substituents may be identical or different, or

a heteroaryl group selected from among pyridinyl and thienyl,

A denotes a group of formula

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂),,- , wherein the alkylene group may be substituted in each case by a Ci-3-alkyl group,

n denotes the number 0, 1 , 2 or 3 and

R² denotes a 5- to 10-membered saturated, aromatic or partly unsaturated heterocyclic group, which is optionally substituted by one or two halogen atoms or one or two Ci-3-alkyl, amino, nitro or hydroxy groups, wherein the substituents may be identical or different,

and the prodrugs, tautomers, racemates, enantiomers, diastereomers, solvates, hydrates, mixtures thereof and the salts thereof. Preferred compounds of general formula (I) are those wherein

R¹ denotes a phenyl group, which may be substituted by a fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethoxy or difluoromethoxy groups,

A denotes a group of formula

(A3) (A4)

(A5) (A6)

wherein in each case the nitrogen atom is linked to the alkylene group and the benzo or phenyl ring is linked to the group L,

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂)_n- , while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci_-3-alkyl group,

n denotes the number 0, 1 , 2 or 3 and R² denotes a group of formula

which is optionally substituted by one or two halogen atoms or one or two Ci-3-alkyl, amino, nitro or hydroxy groups,

or a 5-membered saturated, aromatic or partly unsaturated heterocyclic group, which is optionally substituted by one or two Ci-3-alkyl, amino, nitro or hydroxy groups, wherein the substituents may be identical or different,

the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof,

but particularly those compounds of general formula (I) wherein

R¹ denotes a phenyl group,

A denotes a group of formula

(A3) (A-4)

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n- or -NH-(CO)-(CH₂),,- , while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci_-3-alkyl group,

n denotes the number 0, 1 , 2 or 3 and

R² , if L denotes a -(CO)- group, denotes a group of formula

which is optionally substituted by a halogen atom or a Ci-3-alkyl, amino, nitro or hydroxy group,

or, if L denotes a-(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂)_n- group optionally substituted as stated above, R² denotes a 5-membered saturated or aromatic heterocyclic group, which contains a nitrogen atom and additionally one to three a further nitrogen atoms, or a nitrogen atom and additionally an oxygen or sulphur atom, or an NH group and additionally a nitrogen, oxygen or sulphur atom and a carbonyl group or a sulphonyl group, while the heterocyclic group is optionally substituted in each case by one or two C 1.3- alkyl, amino, nitro or hydroxy groups, wherein the substituents may be identical or different,

the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof. Particularly preferred compounds of general formula (I) are those wherein

R¹ denotes a phenyl group,

A denotes a group of formula

(A3) (A4)

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂),,- , while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂),,- may each be substituted in the alkylene moiety by a Ci_-3-alkyl group,

n denotes the number O, 1 or 2 and R² , if L denotes a -(CO)- group, denotes a group of formula

which may be substituted by a hydroxy group-,

or, if L denotes a -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂)_n- group optionally substituted as stated above, R² denotes a group of formula

which may be substituted by a Ci-3-alkyl, amino, nitro or hydroxy group and is optionally additionally substituted by a further methyl group,

but particularly those compounds of general formula (I) wherein

R¹ denotes a phenyl group,

A denotes a group of formula

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂),,- , while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci_-3-alkyl group,

n denotes the number 0, 1 or 2 and

R² , if L denotes a -(CO)- group, denotes a group of formula

which may be substituted by a hydroxy group,

which may be substituted by a fluorine, chlorine or bromine atom or a methyl, amino, nitro or hydroxy group,

the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

Most particularly preferred are those compounds of general formula (I) wherein A is a group of formula A1 , A3 or A5, wherein the nitrogen atom is linked to the alkylene group and the benzo ring is linked to the group L, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof,

but particularly those compounds of general formula (I) wherein A denotes a group of formula

(A1 ) (A3^') (A5^')

wherein the nitrogen atom is linked to the alkylene group and the benzo ring is linked to the group L, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof. A preferred sub-group relates to those compounds as described above which are the (R)-enantiomer of formula

A second preferred sub-group relates to the compounds as described above which are in the form of their (S)-enantiomer of formula

Particular mention should be made of the following compounds of general formula (I):

(1 ) N-(1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-indol-5-yl)-2-(2-amino-thiazol-4-yl)-acetamide, (2) N-(1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-indol-5-yl)-2-(3-hydroxy-isoxazol-5-yl)- carboxamide, (3) N-(1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-indol-5-yl)-2-(3-hydroxy-isoxazol-5-yl)- propionamide,

(4) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]- 3-methyl-butyl}-1 H-indole-5-carboxylic acid-thiazol-2-ylamide- hydrotrifluoroacetate,

(5) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(2H-tetrazol-5-ylmethyl)-amide, (6) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(1 H-tetrazol-5-yl)-amide,

(7) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(2-amino-thiazol-4-ylnnethyl)-annide, (8) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(thiazol-2-ylmethyl)-amide,

(9) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(5-nitro-thiazol-2-yl)-amide,

(10) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(1 ,1-dioxo-tetrahydro-1 -thiophen-3- yl)-amide,

(11 ) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(thiazol-5-ylmethyl)-amide,

(12) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(oxazol-2-ylmethyl)-amide,

(13) N-[3-((R)-1 -hydroxy-2-{3-[5-(3-hydroxy-4,7-dihydro-5H-isoxazolo[5,4- clpyridin-θ-ylcarbonylj-indol-i-yll-i .i -dinnethyl-propylanninoϊ-ethylj-phenyl]- benzenesulphonamide,

(14) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(3-hydroxy-isoxazol-5-ylmethyl)- amide,

(15) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (5-hydroxy-2H-pyrazol-3-ylmethyl)- amide, (16) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid[(S)-1 -(5-hydroxy-isoxazol-2-yl)-2- methyl-propyl]-amide,

(17) 1 -{3-[(R)-2-(3-phenyllsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-pyrrolo[2,3-b]pyhdine-5-carboxylic acid (3-hydroxy-isoxazol- 5-ylmethyl)-amide,

(18) 4-(1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-imidazol-4-yl)-N-(3-hydroxy-isoxazol-5-ylmethyl)-benzamide,

(19) 4-(1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-imidazol-4-yl)-N-[(S)-1 -(5-hydroxy-isoxazol-2-yl)-2-nnethyl- propyl]-benzamide, or

(20) 4-(1-{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylannino]-3- nnethyl-butyl}-1 H-innidazol-4-yl)-N-(5-hydroxy-2H-pyrazol-3-ylnnethyl)- benzamide,

21 ) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (5-hydroxy-1 -methyl -1 H-pyrazol-3- ylmethyl)-annide,

(22) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (2H-[1 ,2,4]triazol-3-ylmethyl)-annide,

(23) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (5-amino-2H-[1 ,2,4]triazol-3- ylmethyl)-amide or (24) 4-(1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]- 3-methyl-butyl}-1 H-imidazol-4-yl)-N-(5-hydroxy-1 -methyl-1 H-pyrazol-3- ylmethyl)-benzamide,

and the enantiomers and salts thereof.

The invention further relates to the compound 1 -{3-[(R)-2-(3-phenylsulphonyl- amino-phenyl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1 H-pyrrolo[2,3- b]pyridine-5-carboxylic acid, the enantiomers and salts thereof, methods of preparing this compound and the use thereof as pharmaceutical compositions. The compound 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2- hydroxy-ethylaminol-S-methyl-butylJ-I H-pyrrolo^.S-blpyridine-δ-carboxylic acid like the compounds of Examples (iii) and (iv) also has a beta-3-agonistic activity.

The invention further relates to compounds of general formula (I) for use as pharmaceutical compositions.

The invention further relates to compounds of general formula (I) for use as pharmaceutical compositions with a selective beta-3-agonistic activity.

The invention further relates to compounds of general formula (I) for preparing a pharmaceutical composition for the treatment and/or prevention of diseases which are associated with the stimulation of beta-3-receptors.

The invention further relates to a method for the treatment and/or prevention of diseases which are associated with the stimulation of beta-3-receptors, by administering to a patient an effective amount of a compound of general formula I.

The invention further relates to a pharmaceutical composition, containing as active substance one or more compounds of general formula (I) optionally in combination with conventional excipients and/or carriers.

The invention further relates to a pharmaceutical composition containing as active substance one or more compounds of general formula (I) or the physiologically acceptable salts thereof and one or more active substances selected from among the antidiabetic agents, inhibitors of protein tyrosine phosphatase 1 , substances that influence deregulated glucose production in the liver, lipid lowering agents, cholesterol absorption inhibitors, HDL-raising compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic system through alpha 1 and alpha 2 as well as beta 1 , beta 2 and beta 3 receptors.

The invention further relates to a process for preparing a compound of general formula (I)

(l)> wherein

R¹, A, L and R² have the meanings given above, wherein

a) in order to prepare a compound of general formula (I) according to claim 1 wherein L denotes a group of formula -(CO) or -(CO)-NH-(CH₂)_n-, while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci_-3-alkyl group,

a compound of general formula (Na)

wherein A is defined as in claim 1 ,

is reacted with an amine of general formula (III)

wherein n and R² are defined as in claim 1 , optionally using protective groups, or

b) in order to prepare a compound of general formula (I) according to claim 1 , wherein L denotes a group of formula -NH-(CO)-(CH₂)_n-, while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci-3-alkyl group,

a compound of general formula (lib)

(Hb)

wherein A is defined as in claim 1 ,

is reacted with a carboxylic acid of general formula (IV)

HOOC-(CH₂)_n-R² (IV)

wherein n and R² are defined as in claim 1 , optionally using protective groups,

and if necessary any protective group used during the reactions to protect reactive groups is cleaved and/or

if desired a compound of general formula I thus obtained is then resolved into its stereoisomers and/or

a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.

The starting compounds of general formulae (Ma) and (Mb) may be prepared as follows:

A compound of formula (V)

(V), after the introduction of a suitable protective group SG¹ at the amino function, is converted by cyclisation with thionyl chloride into a compound of formula (Vl)

and then by oxidation into a compound of formula (VII)

The compound of formula (VII) is reacted with a compound of formula (Villa) or (VIIIb),

(Villa) (VIIIb)

wherein A may have one of the meanings stated above, the protective group SG¹ at the amino function is cleaved and the product of formula (IXa) or (IXb)

(IXa) (IXb)

is reacted with a compound of formula (X)

(X)

wherein R¹ has the meaning given hereinbefore,

and then after desulphonation and deprotection of the ester it is reacted to form a compound (Ma) or after desulphonation and reduction of the nitro group it is reacted to form a compound of formula (lib),

(Ha) (Hb).

The reaction with the compound (X) leads to the respective (R)-enantiomer. An analogous reaction with the enantiomer to yield (X), which leads to the respective (S)-enantiomer, is of course also possible. The racemate may be obtained by using a compound of formula

instead of (X). The compound of general formula (VII) wherein SG¹ denotes a tert- butyloxacarbonyl group may for example be prepared according to the process described in this application or as described in International Application WO 03/037327, pp. 82-83.

aIO₄, H₂O, CH₂CI_;

(Va) (Vila)

Compounds of general formula Vl are obtained for example by reacting a compound of general formula V with thionyl chloride. The reaction may be carried out e.g. in acetonitrile in the presence of a base, e.g. pyridine, and a catalyst, e.g. dimethylaminopyridine (DMAP), at temperatures between -78°C and 10O⁰C, but preferably between -45°C and 0⁰C. Alternatively, dichloromethane, dimethoxyethane, N,N-dimethylformamide (DMF), N- methylpyrrolidone or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone

(DMPU) may also be used as solvent instead of acetonitrile, for example. The use of acetonitrile is preferred. As an alternative to pyridine other aromatic bases may be used, such as imidazole or N-methyl imidazole or a combination of these bases with aliphatic bases, for example pyhdine/thethylamine (TEA) or N,N-diisopropyl-N-ethyl-amine. The addition of dimethylaminopyridine (DMAP) is optional; the reaction may also be carried out without the addition of DMAP.

Compounds of general formula VII are obtained for example by oxidation of a compound of general formula Vl with ruthenium(lll)chloride hydrate/sodium - metaperiodate. The reaction may be carried out e.g. in acetonitrile/water in the presence of a buffer, e.g. disodium hydrogen phosphate, at temperatures between -30⁰C and 150°C, but preferably between 0°C and 50⁰C. The use of a buffered (disodium hydrogen phosphate) environment is optional, but is preferred. Possible alternatives to disodium hydrogen phosphate might be, for example, sodium phosphate, sodium and/or potassium bicarbonate, sodium and/or potassium carbonate or sodium and/or potassium hydroxide. Possible alternative ruthenium sources include for example ruthenium(VIII)tetroxide, ruthenium(IV)oxide, ruthenium(lll)bromide, ruthenium(lll)iodide (anhydrous or hydrates) and perruthenates (Ru(VII)). Instead of sodium metapehodate, potassium permanganate or oxone for example may also be used as an alternative.

Compounds of general formula IXa and IXb are obtained e.g. by reacting a compound of general formula VII with a compound of general formula Villa or VIIIb and subsequently cleaving the protective group SG¹ at the amino function. The reaction may be carried out e.g. in N,N-dimethylformamide (DMF) in the presence of a base, e.g. potassium tert-butoxide, at temperatures between -20⁰C and 200⁰C, but preferably between 0°C and 50⁰C. Alternatively, instead of N,N-dimethylformamide (DMF), the solvent used may be for example acetonitrile, tetrahydrofuran, dimethylsulphoxide (DMSO), dioxane, dimethoxyethane, acetone, methylethyl ketone, ethyl acetate, N-methylpyrrolidone or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (DMPU). The use of N,N-dimethylformamide (DMF) is preferred. As an alternative to potassium tert-butoxide, other bases may be used such as e.g. potassium carbonate, sodium hydride, thethylamine or N- ethyl-diisopropylamine.

Compounds of general formula Ma and Mb are obtained e.g. by reacting a compound of general formula X with a compound of general formula IXa or IXb with subsequent desulphonation. The reaction may be carried out for example at temperatures between 20°C and 300°C, but preferably between 80⁰C and 200°C. Alternatively, an aliphatic alcohol, for example methanol, ethanol, isopropanol, butanol or pentanol, may also be used as solvent. Instead of an aliphatic alcohol it is also possible to use N₁N- dimethylformamide (DMF), acetonitrile, tetrahydrofuran, dimethylsulphoxide (DMSO), dioxane, dimethoxyethane, ethyl acetate, N-methylpyrrolidone or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyhmidinone (DMPU), for example, as solvent. It is preferable to carry out the reaction without a solvent or to use an aliphatic alcohol as solvent. The desulphonation may be carried out hydrolytically, for example, in an aqueous solvent, e.g. water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water in the presence of an alkali metal base such as sodium hydroxide, lithium hydroxide or potassium hydroxide at temperatures between 0⁰C and 200⁰C, but preferably between 10⁰C and 100°C.

Compounds of general formula Mb are obtained e.g. by reacting the desulpho- nated product of the reaction of a compound of general formula IXb with a compound of general formula X with a reducing agent. Alternatively compounds of general formula Mb may also be obtained e.g. by reacting the product of the reaction of a compound of general formula IXb with a compound of general formula X with a reducing agent and subsequent desulphonation. A suitable reducing agent is for example hydrogen in the presence of a catalyst, such as palladium on charcoal, palladium hydroxide on charcoal or Raney nickel, of which palladium on charcoal is particularly preferred. The hydrogenation is carried out in a suitable solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane or ethyl acetate, but preferably methanol, ethanol or tetrahydrofuran, at a pressure of between 0.5 and 7 bar, but preferably at a pressure of between 0.5 and 3 bar, and at a temperature between 0⁰C and 60⁰C, but preferably at a temperature between 15°C and 40°C. Also suitable for the reduction is tin dichlohde hydrate in lower alcoholic solvents such as methanol or ethanol at a temperature between ambient temperature and 80⁰C. Alternatively, titanium trichloride may be used as the reducing agent. A suitable solvent might be a mixture of acetone and water. The reaction is carried out at between 0°C and 60°C, but preferably between 15°C and 40⁰C and in the presence of ammonium acetate.

Compounds of general formula I are obtained e.g. by reacting a compound of general formula Ma with amine. The transformation may be carried out by first converting the acid into an acid chloride. For this, a compound of general formula Ma is mixed with thionyl chloride, optionally in the presence of a solvent such as toluene or benzene and heated to temperatures between 50⁰C and 150⁰C, but preferably between 80°C and 120⁰C. After elimination of the volatile constituents the acid chloride thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran, at temperatures between -30°C and 150°C, but preferably between 0⁰C and 80⁰C and optionally in the presence of a base such as thethylamine, N₁N- diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine. Alternatively, the acid may be converted into an acid imidazolide. For this, a compound of general formula Ma is reacted with carbonyldiimidazole in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 20°C and 100°C. The acid imidazolide thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, preferably tetrahydrofuran, at temperatures between - 30⁰C and 150°C, but preferably between 0°C and 80⁰C, and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyhdine. Moreover, compounds of general formula I may be prepared by in situ activation of the carboxylic acid of general formula Ma. For this, the acid is activated by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-i-yl)- N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), O-(benzotriazol-1 -yl)- N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzothazol-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoro- phosphate (BOP) or (benzothazol-i -yloxy)-thpyrrolidinophosphonium- hexafluorophosphate (PyBOP) and reacted in a dipolar aprotic solvent such as for example dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, but preferably in dimethylformamide or N-methylpyrrolidone, with an alcohol or an amine in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally a catalyst such as 4-N,N-dimethylaminopyridine at temperatures between -20⁰C and 80⁰C, but preferably between 0°C and 50⁰C.

Alternatively, compounds of general formula I may be obtained e.g. by reacting a compound of general formula Mb with an acylating reagent. Acyl groups may be introduced by reacting a compound of general formula Mb with an acylating reagent such as for example an acid chloride or acid anhydride. The reaction may be carried out in the presence of a base such as sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, caesium carbonate, thethylamine or N,N-diisopropyl-N-ethyl-amine as well as in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, at temperatures between -30°C and 200°C, but preferably between 0⁰C and 160⁰C place. Alternatively the reaction may be carried out by acylation with an acid. For this, the acid is activated in situ by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'- tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)- N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzotriazol-1 - yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP) or (benzotriazol-1 -yloxy)-tripyrrolidinophosphonium-hexafluorophosphate (PyBOP) and reacted in a dipolar aprotic solvent such as for example N₁N- dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in N₁N- dimethylformamide or N-methylpyrrolidone, with a compound of general formula V in the presence of a base such as triethylamine, N,N-diisopropyl-N- ethyl-amine and optionally a catalyst such as 4-N,N-dimethylaminopyridine, at temperatures between -20°C and 80°C, but preferably between 0⁰C and 50⁰C.

In the reactions described hereinbefore, any reactive groups present such as carboxy, hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert. butyl, benzyl or tetrahydropyranyl group and protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleaving, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100⁰C, preferably at temperatures between 10 and 50⁰C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50⁰C, but preferably at ambient temperature.

A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol. A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50⁰C.

An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1 ,3-dimedone at temperatures between 0 and 100⁰C, preferably at ambient temperature and under inert gas, or by treating with a catalytic amount of tris-(thphenylphosphine)-rhodium(l)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1 ,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70°C.

The compounds of general formulae Il to X used as starting materials, which are not known from the literature or commercially obtainable, are obtained by methods known from the literature and moreover their preparation is described in the Examples.

The compounds of the above general formula (I) which contain a group that can be cleaved in-vivo are so-called prodrugs, and compounds of general formula I which contain two groups that can be cleaved in-vivo are so-called double prodrugs.

By a group that can be converted in-vivo into a carboxy group is meant for example an ester of formula -CO2R¹¹, wherein

R¹¹ denotes hydroxymethyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkenyl, heterocycloalkyl, Ci-C₃-alkoxycarbonyl, 1 ,3-dihydro-3-oxo-1 -isobenzofuranol, -C(-alkyl)(-alkyl)-OC(O)-alkyl, -CHC(O)NH(-alkyl), -CHC(O)N(-alkyl)(-alkyl), alkyl, preferably Ci-Cβ-alkyl, particularly preferably methyl, ethyl, n-propyl, iso- propyl, n-butyl, n-pentyl or n-hexyl, cycloalkyl, preferably Ci-C₆-cycloalkyl, particularly preferably cyclohexyl, -(Ci-C₃-alkyl)-aryl, preferably (Ci-C₃-alkyl)-phenyl, particularly preferably benzyl,

-CHC(O)N(-alkyl)(-alkyl), preferably -CHC(O)N(-Ci-C₃-alkyl)(-Ci-C₃-alkyl), particularly preferably -CHC(O)N(CH₃^,

-CH(-alkyl)OC(O)-alkyl, preferably -CH(-CH₃)OC(O)(-Ci-C6-alkyl), particularly preferably -CH(-CH₃)OC(O)-methyl, -CH(-CH₃)OC(O)-ethyl, -CH(-CH₃)OC(O)- n-propyl, -CH(-CH₃)OC(O)-n-butyl or -CH(-CH₃)OC(O)-t-butyl, or

-CH₂OC(O)-alkyl, preferably -CH₂OC(O)(-Ci-C₆-alkyl), particularly preferably

-CH₂OC(O)-methyl, -CH₂OC(O)-ethyl, -CH₂OC(O)-n-propyl, -CH₂OC(O)-n- butyl or -CH₂OC(O)-t-butyl.

By a group that can be converted in-vivo into a sulphonamide or amino group is meant for example one of the following groups:

-OH, -formyl, -C(O)-alkyl, -C(O)-aryl, -C(O)-heteroaryl, -CH₂OC(O)-alkyl,

-CH(-alkyl)OC(O)-alkyl, -C(-alkyl)(-alkyl)OC(O)-alkyl, -CO₂-alkyl, preferably Ci-C₉-alkoxy-carbonyl, particularly preferably methoxy- carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl,n-butyl- oxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycar- bonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl,

-CO₂(-Ci-C₃-alkyl)-aryl, preferably -CO₂(-Ci-C₃-alkyl)-phenyl, particularly preferably benzyloxycarbonyl,

-C(O)-aryl, preferably benzoyl,

-C(O)-heteroaryl, preferably pyhdinoyl or nicotinoyl or

-C(O)-alkyl, preferably -C(O)(-Ci-C₆-alkyl), particularly preferably 2-methyl- sulphonylethoxycarbonyl, 2-(2-ethoxy)-ethoxycarbonyl.

The halogen used is generally fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine, particularly preferably fluorine. The compounds according to the invention may be in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, prodrugs, double prodrugs and in the form of the tautomers, salts, solvates and hydrates thereof as well as in the form of the free bases or the 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, such as for example oxalic acid, fumaric acid, diglycolic acid, formic acid, malic acid, benzoic acid, benzenesulphonic acid, camphorsulphonic acid, acetic acid, ethanesulphonic acid, glutamic acid, maleic acid, mandelic acid, lactic acid, phosphoric acid, nitric acid, sulphuric acid, succinic acid, para-toluene- sulphonic acid, thfluoroacetic acid, tartaric acid, citric acid or methanesulphonic acid.

Moreover, if the new compounds of formula I thus obtained contain a carboxy group or another acid group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Moreover the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. And ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomehc mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be, for example, (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl .

As has been found, the compounds of general formula (I) are characterised by their great versatility in the therapeutic field. Particular mention should be made of those applications in which the effects of beta-3-agonists, particularly selective beta-3-agonists play a part.

Such diseases include for example: atherosclerosis, cholangitis, gall bladder disease, chronic cystitis, chronic bladder inflammation; chronic prostatitis, cystospasm, depression, duodenal ulcer, duodenitis, dysmenorrhoea, increased intraocular pressure and glaucoma, enteritis, oesophagitis, gastric ulcer, gastritis, gastrointestinal disorders caused by contraction(s) of the smooth muscle, gastrointestinal disorders incl. gastric ulcer, gastrointestinal ulceration, gastrointestinal ulcers, glaucoma, glucosuria, hyperanakinesia, hypercholesterolaemia, hyperglycaemia, hyperlipaemia, arterial hypertension, hypertriglycehdaemia, insulin resistance, intestinal ulceration or small bowel ulcers (incl. inflammatory bowel diseases, ulcerative colitis, Crohn's disease and proctitis = inflammation of the rectum), irritable colon and other diseases with decreased intestinal motility, depression, melancholy, pollacisuria, frequent urinary urgency, nervous neurogenic inflammation, neurogenic bladder dysfunction, neurogenic inflammation of the respiratory tract, neuropathic bladder dysfunction, nycturia, non-specific diarrhoea, dumping syndrome, obesity, fatness, pancreatitis, inflammation of the pancreas, stomach ulcers, prostate diseases such as benign prostatic hyperplasia, enlarged prostate, spasm, cramp, type 2 diabetes mellitus, irritable bladder or concrement of the lower urinary tract.

The following may also be mentioned: urge incontinence, stress incontinence, mixed incontinence, overactive bladder (OAB) in the forms of wet OAB or dry OAB, OAB with imperative need to urinate, with or without urge incontinence, with or without increased frequency of urination, with or without nocturnal urination, dysuria, nycturia, pollacisuria, build-up of residual urine. Of these indications, OAB with increased frequency of urination, with or without urge incontinence, with or without nocturnal urination, is preferred.

The compounds may also be used in cases of pain in the prostate or of the lower urogenital tract. The diseases in question include benign prostatic hyperplasiam (BPH), prostatitis, particularly chronic abacterial prostatitis, of neurogenic, muscular or bacterial origin, chronic pain syndrome of the pelvis, pelvic myoneuropathy, prostatodynia, LUTS (lower urinary tract symptoms), obstructive bladder emptying disorders (BOO) and/or prostatopathy.

The use according to the invention is directed not only to causative treatment of the above indications, but also to the treatment of the accompanying symptoms, particularly any related pain or problems of urine release, pain and discomfort in the region of the prostate or the lower urinary tract including the penis, pain during erection or ejaculation, pain on defecation, erectile disorders. The compounds according to the invention are also suitable for the treatment of neurodegenerative diseases such as e.g. Alzheimer's-type dementia (Alzheimer's disease), vascular dementia, Parkinson's dementia (Parkinson's disease), Huntington's disease, dystonia, degenerative ataxia, AIDS-related dementia, Creutzfeld-Jakob's syndrome, Bovine Spongiform Encephalopathy, infections associated with prions, diseases associated with mitochondrial disorders, Down's syndrome, hepatic encephalopathy, amyotrophic lateral sclerosis, multiple sclerosis, olivopontocerebellar atrophy, postoperative cognitive deficit, mild cognitive impairment, hypoxia, ischaemia caused by stoppage of the heart, stroke, glioma and other tumours, attention deficit/hyperactivity disorder, autism, convulsions, epilepsy, Korsakoff's syndrome, depression or schizophrenia.

The beta-3 agonists according to the invention are particularly suitable for the treatment of obesity, insulin resistance, type 2 diabetes mellitus, urinary incontinence, irritable colon and other diseases with decreased intestinal motility or depression, particularly 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 procedure may be carried out as follows:

Adipocytes were isolated from fatty tissue ex vivo by modifying a method according to Rodbell (Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 239: 375-380. 1964). The excised fatty tissue was cut into small pieces and mixed with 1 mg/ml collagenase in Krebs Ringer Buffer (KRB) containing 6 mM glucose and 2% albumin by gently shaking for 30-40 min at 37°C. The cells were filtered through a gauze, washed twice with KRB and in each case 50-150 g were centhfuged for 5 min. 10 μl of the centhfuged adipocytes were incubated with 90 μl of a compound according to the invention (agonist) at concentrations of between 10^~15 to 10^~4 M. The agonists were incubated over 40 min at 37°C. A varying release of glycerol into the medium indicated that the fat cell lipolysis had altered as a result of the addition of the agonist. Released glycerol was detected enzymatically with a Sigma kit (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 oxidised by glycerophosphate oxidase to form dihydroxyacetone phosphate and hydrogen peroxide. Then a quinonimine dye is produced by the peroxidase-catalysed coupling of sodium- N-ethyl-N- (3-sulphopropyl)m-ansidine and 4-aminoantipyrine. The dye has an absorption peak at 540 nm. The absorption is directly proportional to the glycerol concentration in the samples.

The new compounds may be used for the prevention or short-term or long- term treatment of the above-mentioned diseases, and may also be used in conjunction with other active substances used for the same indications. These include, for example, antidiabetics, such as metformin, sulphonylureas (e.g. glibenclamid, tolbutamide, glimepihde), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. Gl 262570), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), alpha2 antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. Also, inhibitors of protein tyrosine phosphatase 1 , substances which influence deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1 ,6- bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA- reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, cholesterol absorption inhibitors such as for example ezetimibe, bile acid-binding substances such as for example cholestyramine, HDL-raising compounds such as for example inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin.

In particular, they may also be combined with drugs for treating high blood pressure such as e.g. all antagonists or ACE inhibitors, diuretics, β-blockers, and other modulators of the adrenergic system or combinations thereof. In addition, combinations with stimulators of the adrenergic system via alpha 1 and alpha 2 and also beta 1 , beta 2 and beta 3 receptors are particularly suitable.

The compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.α, i.v., i.m.) and infusion, elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The specified doses may be taken several times a day, if necessary.

Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. A flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, optionally organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). The preparations are administered by the usual methods, preferably by oral or transdermal route, preferably oral. For oral administration the tablets may, of course contain, apart from the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various added substances such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

For parenteral use, solutions of the active substances with suitable liquid carriers may be used.

The dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.

The formulation Examples which follow illustrate the present invention without restricting its scope: Examples of pharmaceutical formulations

A) Tablets per tablet

active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg =

500 mg

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet

active substance 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg

400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution

active substance 50 mg sodium chloride 50 mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

The following Examples illustrate the present invention without restricting its scope:

HPLC method:

Retention times were determined on an Agilent type 1100 apparatus (quarternary pump, diode array detector, LC-MSD) fitted with a Merck Cromolith Speed ROD column (RP18e, 50 x 4.6 mm). Elution was carried out using mixtures of acetonitrile and water, in each case modified with 0.1 % formic acid, at a flow rate of 1.5 ml/min with the following gradient pattern:

Preparation of the starting compounds:

Component i

N-[(R)-3-Oxiranyl-phenyl]-dibenzenesulphonamide

a. N-(3-acetyl-phenyl)-dibenzenesulphonannide 2.8 g (10 mmol) N-(3-acetyl-phenyl)-benzenesulphonamide are dissolved in 50 ml acetonitrile dissolved and combined with 3.3 ml (24 mmol) triethylamine. 3.9 g (22 mmol) benzenesulphonic acid chloride are added dropwise with vigorous stirring over a period of 10 minutes at ambient temperature. The reaction mixture is then stirred for 20 hours at ambient temperature and the solvent is eliminated in vacuo. The residue is poured into ice water, whereupon a beige solid is precipitated. This precipitate is filtered off and reprecipitated from ethyl acetate. Yield: 3.6 g (87 % of theory) C₂₀Hi₇NO₅S₂ (415.49) Mass spectrum: (M+NH₄)⁺ = 433

Rf = 0.44 (silica gel; toluene/ethyl acetate = 9:1 )

b. N-[3-(2-chloro-acetyl)-phenyl1-dibenzenesulphonamide

2.1 ml (26 mmol) sulphuryl chloride are added dropwise to 3.6 g (8.7 mmol) N-(3-acetyl-phenyl)-dibenzenesulphonamide in 70 ml DCM and 2.11 ml (52 mmol) methanol at 0⁰C with vigorous stirring over a period of 20 min. The reaction mixture is refluxed for 2.5 hours and then stirred for 18 hours at ambient temperature. Then the reaction solution is washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is precipitated from toluene to form a colourless solid. Yield: 2.55 g (65 % of theory) C₂₀Hi₆CINO₅S₂ (449.93)

Mass spectrum: (M+NH₄)⁺ = 459, 457

Rf = 0.56 (silica gel; toluene/ethyl acetate = 9:1 )

c. N-[(R)-3-Oxiranyl-phenyl1-dibenzenesulphonamide 7.84 g (24.4 mmol) (-)-B-chloro-diisopinocampheylborane (dissolved in 15 ml of tetrahydrofuran) are added dropwise to a solution of 5.00 g (11.1 mmol) N- [3-(2-chloro-acetyl)-phenyl]-dibenzenesulphonamide in 70 ml of tetrahydrofuran at -30⁰C over a period of 60 minutes. After one hour another 2.00 g (6.24 mmol) (-)-B-chloro-diisopinocampheylborane (dissolved in 5 ml of tetrahydrofuran) are added dropwise at -30⁰C. The mixture is stirred for 14 hours at this temperature and the reaction solution is then poured into a mixture of ice water and saturated, aqueous sodium hydrogen carbonate solution. It is extracted with ethyl acetate, the combined organic phases are washed with water and dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on silica gel (toluene/ethyl acetate = 97.5:2.5 ->90:10). The intermediate product is triturated with diisopropylether, suction filtered and dried. The solid is dissolved in 30 ml N,N-dimethylformamide and combined with 8.33 ml of 4 N lithium hydroxide solution, 3 ml N,N-dimethylformamide and 2 ml of water at - 5°C with stirring within 15 minutes. After 25 minutes the reaction mixture is acidified at -5°C with glacial acetic acid and diluted with water. The precipitated solid is suction filtered, washed several times with ice water and dried. (The product may also be obtained in racemic form by reacting N-[3-(2-chloro- acetyl)-phenyl]-dibenzenesulphonamide with borane-tetrahydrofuran complex (1 M in tetrahydrofuran) and then with 4 M lithium hydroxide.) Yield: 3.65 g (79 % of theory) C₂₀Hi₇NO₅S₂ (415.49) Mass spectrum: (M+NH₄)⁺ = 433

Rf value: 0.47 (silica gel; toluene/ethyl acetate = 9:1 )

Component ii

N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinan-2,2-dioxide

a. Tert-butyl (3-hvdroxy-1 ,1-dimethylpropyl)-carbamidate

200 g (1.94 mol) 3-amino-3-methylbutan-1 -ol in 0.75 I ethyl acetate are combined with a solution of 435.0 g (1.99 mol) di-tert-butyl-dicarbonate in 0.75 I ethyl acetate within one hour. The reaction mixture is stirred for 30 min and the solvent is eliminated in vacuo. The residue obtained is used in the next step without further purification. Yield: 412.5 g

¹H-NMR (DMSO, 400 MHz): 1.19 (s, 9H); 1.36 (s, 6H); 1.68-1.74 (m, 2H); 3.42-3.50 (m, 2H); 4.39 (t, J = 4.8, 1 H); 6.36 (br s, 1 H).

Alternatively, tert-butyl (3-hydroxy-1 ,1-dimethylpropyl)-carbamidate may also be prepared by the methods described for example in J. of Labell. Compounds & Radioph. 2001 , 44(4), 265-275 or WO 03/037327, p. 82/83.

b. N-tert-butoxycarbonyl-4,4-dimethyl-[1 ,2,31oxathiazinan-2-oxide 171 ml (2.23 mol) thionyl chloride in 0.6 I acetonitrile are combined at -45°C within 20 min with a solution of 200 g (930 mmol) tert-butyl (3-hydroxy-1 ,1- dimethylpropyl)-carbamidate (from Step a) in 0.7 I acetonitrile, while the internal temperature is kept below -40⁰C. Then 11.0 g (900 mmol) dimethylaminopyridine are added and 378 ml (4.70 mol) pyridine are added dropwise at -45°C over 2 hours. The mixture is stirred for one hour at this temperature and 2.5 I of ethyl acetate are added thereto. The suspension is stirred for 30 min, during which time the temperature rises to -15°C. The precipitate is filtered off and washed with ethyl acetate. The combined filtrates are added to saturated aqueous sodium hydrogen phosphate solution and the two-phase mixture is stirred for one hour. The organic phase is washed with 1.0 I hydrochloric acid (1 M), then with saturated aqueous sodium chloride solution and dried on sodium sulphate. After elimination of the solvent 204.3 g crude product (contents approx. 60 wt.-%) are obtained. This crude product is used in the next step without any further purification.

c. N-tert-butoxycarbonyl-4,4-dimethyl-π ,2,31oxathiazinane-2,2-dioxide A solution of 0.440 g (2.12 mmol) ruthenium trichloride hydrate and 132 g sodium periodate (620 mmol) in 1.5 I water is stirred for 45 min and added to a suspension of 140 g N-tert-butoxycarbonyl-4,4-dimethyl-[1 ,2,3]oxathiazinan- 2-oxide (crude product from Step b) in a mixture of 0.6 I of acetonitrile and 0.3 I of saturated, aqueous sodium hydrogen phosphate solution at a temperature of 20-25⁰C over a period of 35 min. During the addition the pH of the suspension is maintained between 6.9 and 7.3 by the continuous addition of saturated aqueous sodium hydrogen phosphate solution. After the addition has ended the reaction mixture is stirred for one hour at 20⁰C, the pH is adjusted to 6.4 with hydrochloric acid (1 M) and stirred for another hour. The solid is collected by filtration, washed with water and stirred for 2 hours with 1.5 I of water. The solid is isolated by filtration, washed with water and dried at 50°C. Yield: 87.4 g (51.3 %, over two steps)

¹H-NMR (DMSO, 400 MHz): 1.45 (s, 9H); 1.52 (s, 6H); 2.27 (t, J = 6.60 Hz, 2H); 4.68 (t, J = 6.60 Hz, 2H).

Component iii

N-(3-((R)-2-r3-(5-amino-indol-1-yl)-1,1-dimethyl-propylamino1-1 -hydroxy- ethvD-phenvD-benzenesulphonamide-hvdrotrifluoroacetate

a. 1 -(3-tert-butoxycarbonylamino-3-methyl-butyl)-5-nitroindole

5.81 g (35.8 mmol) 5-nitroindole in 60 ml N,N-dinnethylfornnannide are combined with 4.23 g (37.7 mmol) potassium tert-butoxide while cooling with ice and stirred for 10 minutes at 0⁰C. To this are added 10.0 g (37.7 mmol) N- tert-butoxycarbonyl-4,4-dimethyl-[1 ,2,3]oxathiazinan-2,2-dioxide (Component ii) and the mixture is stirred for two hours at ambient temperature. The reaction mixture is poured onto 800 ml of water and 13.2 ml (13.2 mmol) hydrochloric acid (1 M). The precipitate is filtered off and dried for 24 hours at 55°C in the vacuum dryer. Yield: 12.05 g crude product (92 % of theory) Ci₉H₂₈N₂O₂S (347.41 ) Mass spectrum: (M+H)⁺ = 365 Rf = 0.70 (silica gel; petroleum ether/ethyl acetate = 2:1 )

b. 1 -(3-amino-3-methyl-butyl)-5-nitroindole

12.0 g (34.5 mmol) 1 -(3-tert-butoxycarbonylamino-3-methyl-butyl)-5- nitroindole are dissolved in 150 ml of methanol at 0⁰C and combined with 15.4 ml (62.2 mmol) hydrochloric acid (4N solution in dioxane) with stirring. Then the reaction mixture is refluxed for 3 hours. The solvent is eliminated in vacuo and the residue is stirred with 200ml tert-butylmethylether. The solid obtained is dissolved in 150 ml of methanol and added to a mixture of 200 ml saturated, aqueous potassium carbonate solution and 500 ml of ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried on sodium sulphate and and the solvent is eliminated in vacuo. Yield: 8.2O g (96% of theory) Ci₄H₂₀N₂S x HCI (284.85) Mass spectrum: (M+H)⁺ = 248 retention time (method 1 ): 2.16 min

c. N-(3-{(R)-2-[1 ,1 -dimethyl-3-(5-nitro-indol-1 -vD-propylaminoH -hvdroxy- ethvD-phenvD-benzenesulphonannide A mixture of 1.68 g (4.05 mmol) N-[(R)-3-Oxiranyl-phenyl]- dibenzenesulphonamide (Component i) and 1.32 g (4.66 mmol) 1 -(3-amino-3- methyl-butyl)-5-nitroindole is heated to 120⁰C for two hours. The reaction mixture is dissolved in 10 ml of methanol, combined with 10 ml sodium hydroxide solution (4N), stirred for five hours at ambient temperature and then neutralised with trifluoroacetic acid. After elimination of the solvent in vacuo the residue is chromatographed on silica gel (dichloromethane/methanol/32% ammonia solution in water = 100:0:0 -> 90:10:0.1 ). Yield: 1.40 g (66 % of theory) C₃₄H₃₄N₄O₅S₂ (636.64) Mass spectrum: (M+H)⁺ = 523

R_f = 0.25 (silica gel; dichloromethane/methanol/32% ammonia solution in water = 95:5:0.1 )

d. N-(3-{(R)-2-[3-(5-amino-indol-1 -yl)-1 ,1 -dimethyl-propylaminoi-1 -hvdroxy- ethvD-phenvD-benzenesulphonamide-hydrotrifluoroacetate

40 mg Raney nickel are added to a solution of 200 mg (0.310 mmol) N-(3-

{(R)-2-[1 ,1-dimethyl-3-(5-nitro-indol-1-yl)-propylamino]-1-hydroxy-ethyl}- phenyl)-benzenesulphonamide in 5 ml of ethyl acetate and 5 ml of methanol.

The reaction mixture is stirred for 7 hours at ambient temperature under 3 bar hydrogen. The Raney nickel is filtered off, and the filtrate is freed from the solvent in vacuo. The residue is chromatographed on reversed phase

Microsorb C18 [acetonitrile (0.1 % trifluoroacetic acid)/water (0.13% trifluoroacetic acid) = 10:90 ^■* 100:0].

Yield: 155 mg (68 % of theory) C₂₇H₃₂N₄O₃S x 2C₂HF₃O₂ (726.81 )

Mass spectrum: (M+H)⁺ = 493

R_f = 0.33 (silica gel; dichloromethane/methanol/32% ammonia solution in water = 90:10:0.1 ) The free base (N-(3-{(R)-2-[3-(5-amino-indol-1-yl)-1 ,1-dimethyl-propylamino]- 1 -hydroxy-ethyl}-phenyl)-benzenesulphonamide) is prepared as follows: A mixture of N-(3-{(R)-2-[3-(5-amino-indol-1 -yl)-1 ,1-dimethyl-propylamino]-1 - hydroxy-ethylj-phenylj-benzenesulphonamide-hydrotrifluoroacetate) in chloroform and stirred for 10 minutes with saturated, aqueous sodium carbonate solution. The organic phase is separated off, dried on sodium sulphate and the solvent is eliminated in vacuo.

Component iv

1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-hydrotrifluoroacetate

a. Methyl 1 -(3-amino-3-methyl-butyl)-indole-5-carboxylate

Prepared analogously to Component iiia by alkylation of methyl indole-5- carboxylate with N-tert-butoxycarbonyl-4,4-dimethyl-[1 ,2,3]oxathiazinan-2,2- dioxide (Component ii), acid cleaving of the protective group analogously to

Component iiib and subsequent liberation of the base.

Yield: 98 % of theory

Ci₅H₂₀N₂O₂ (260.33)

Mass spectrum: (M+H)⁺ = 261 R_f = 0.47 (silica gel; dichloromethane/methanol/32% ammonia solution in water = 60:10:0.1 ) b. 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenvπ-2-hvdroxy-ethylamino1-3- methyl-butyl)-1 H-indole-5-carboxylic acid-hydrotrifluoroacetate Prepared analogously to Component iiic by reacting N-[(R)-3-oxiranyl-phenyl]- dibenzenesulphonamide (Component i) with methyl 1 -(3-amino-3-methyl- butyl)-indole-5-carboxylate, followed by reaction with sodium hydroxide solution and acidification with trifluoroacetic acid. Yield: 85 % of theory C₂₉H₃₃N₃O₅S x C₂HF₃O₂ (649.68) Mass spectrum: (M+H)⁺ = 536 R_f = 0.35 (silica gel; dichloromethane/methanol/32% ammonia solution in water = 90:10:0.1 ) retention time (method 1 ): 8.67 min

The free base (zwittehon; 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2- hydroxy-ethylamino]-3-methyl-butyl}-1 H-indole-5-carboxylic acid) is prepared from an aqueous solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2- hydroxy-ethylamino]-3-methyl-butyl}-1 H-indole-5-carboxylic acid- hydrotrifluoroacetate by adjusting the pH to pH 7.6 using sodium hydroxide solution. Then the precipitate is filtered off, washed with water and dried in the vacuum dryer.

Component v

1-{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-pyrrolo[2,3-b]pyridine-5-carboxylic acid- hydrotrifluoroacetate

a. ethyl 1 -(3-amino-3-methyl-butyl)-1 H-pyrrolo[2,3-bipyhdine-5-carboxylate Prepared analogously to Component iiia by alkylation of ethyl 1 H-pyrrolo[2,3- b]pyridine-5-carboxylate [prepared by esterification of 1 H-pyrrolo[2,3- b]pyridine-5-carboxylic acid (WO0478757)] with N-tert-butoxycarbonyl-4,4- dimethyl-[1 ,2,3]oxathiazinan-2,2-dioxide (Component ii), acid cleaving of the protective group analogously to Component iiib and subsequent liberation of the base.

Yield: 84 % of theory

Mass spectrum: (M+H)⁺ = 276 retention time (method 1 ): 1.43 min

b. 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hvdroxy-ethylamino1-3- methyl-butyl)-1 H-pyrrolo[2,3-bipyridine-5-carboxylic acid-hvdrotrifluoroacetate Prepared analogously to Component iiic by reacting N-[(R)-3-oxiranyl-phenyl]- dibenzenesulphonamide (Component i) with ethyl 1 -(3-amino-3-methyl-butyl)- 1 H-pyrrolo[2,3-b]pyhdine-5-carboxylate, followed by reaction with sodium hydroxide solution and acidification with trifluoroacetic acid. Yield: 53 % of theory C₂₇H₃₀N₄O₅S x 2C₂HF₃O₂ (750.66) Mass spectrum: (M+H)⁺ = 523 retention time (method 1 ): 2.25 min

The free base (zwittehon; 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2- hydroxy-ethylaminol-S-methyl-butylJ-I H-pyrrolo^.S-blpyridine-δ-carboxylic acid) is prepared from an aqueous solution of 1 -{3-[(R)-2-[3-

(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1 H- pyrrolo[2,3-b]pyridine-5-carboxylic acid-hydrotrifluoroacetate by adjusting the pH to 7.6 using sodium hydroxide solution. Then the precipitate is filtered off, washed with water and dried in the vacuum dryer. Component vi

(S)-3-(1-amino-2-methyl-propyl)-isoxazol-5-ol-hydrotrifluoroacetate

a. Tert-butyl (S)-[I -(5-hvdroxy-isoxazol-3-yl)-2-methyl-propyπ-carbamate 5.03 ml_ (20.1 mol) sodium hydroxide solution (4N) are added at 0⁰C to a solution of 500 mg (1.83 mmol) ethyl (S )-4-[(tert-butoxycarbonyl)-amino]-5- methyl-3-oxo-caproate (J. Org. Chem., 1987, Vol. 52, No. 20, 4531-4536) and 1.27 g (18.3 mmol) hydroxylamine hydrochloride in 20 ml of methanol. The reaction mixture is and stirred for 18 hours at ambient temperature in vacuo freed from the solvent and the residue is chromatographed on reversed-phase Microsorb C18 [acetonitrile (0.1 % trifluoroacetic acid)/water (0.13% trifluoroacetic acid) = 10:90 -> 100:0]. Yield: 210 mg (45 % of theory) Ci₂H₂₀N₂O₄ (256.30) Mass spectrum: (M+H)⁺ = 257 retention time (method 1 ): 1.96 min

b. (S)-3-(1 -amino-2-methyl-propyl)-isoxazol-5-ol

2.0 ml_ trifluoroacetic acid are added to a solution of 180 mg (0.702 mmol) tert-butyl (S)-[I -(5-hydroxy-isoxazol-3-yl)-2-methyl-propyl]-carbamate in 20 ml dichloromethane and the mixture is stirred for 1.5 hours at ambient temperature. The reaction mixture is freed from the solvent in vacuo and the residue is chromatographed on reversed-phase Microsorb C18 [acetonitrile (0.1 % trifluoroacetic acid)/water (0.13% trifluoroacetic acid) = 10:90 ^■* 100:0]. Yield: 130 mg (69 % of theory) C₇Hi₂N₂O₂ x C₂HF₃O₂ (270.21 ) Mass spectrum: (M+H)⁺ = 157 retention time (method 1 ): 0.31 min

Component vii

5-aminomethyl-2-methyl-2H-pyrazol-3-ole

was prepared according to EP1847543A1 , page 32.

Preparation of the end products:

Example 1

N-(1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]- 3-methyl-butyl}-1 H-indol-5-yl)-2-(2-amino-thiazol-4-yl)-acetamide

40 mg (0.056 mmol) N-(3-{(R)-2-[3-(5-amino-indol-1 -yl)-1 ,1-dimethyl- propylamino]-1-hydroxy-ethyl}-phenyl)-benzenesulphonamide (free base of Component iii) are dissolved in 0.5 ml of water and 150 μl hydrochloric acid (1 M). Then 17.6 mg (0.11 mmol) (2-amino-thiazol-4-yl)-acetic acid and 21.3 mg (0.11 mmol) N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride are added. The reaction mixture is stirred for three hours at ambient temperature and then diluted with 5 ml of water. The pH is adjusted to 7.5. Then the precipitate formed is filtered off and washed with water. The solid obtained is dried in the vacuum dryer. Yield: 10 mg (29 % of theory) C₃₂H₃₆N₆O₄S₂ (632.80) Mass spectrum: (M+H)⁺ = 633

R_f = 0.38 (silica gel; dichloromethane/methanol/32% ammonia solution in water = 90:9:1 )

Examples 2 and 3

Prepared analogously to Example 1 by amide linking between Component and the corresponding substituted carboxylic acid (see the R group in the

Table).

Example 4

1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-thiazol-2-ylamide- hydrotrifluoroacetate

75 mg (0.39 mmol) N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 49 mg hydroxybenzotriazole-hydrate (0.36 mmol) are added to a solution of 100 mg (0.16 mmol) 1 -{3-[(R)-2-[3-(phenylsulphonyl- amino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1 H-indole-5-carboxylic acid-hydrotrifluoroacetate (Component iv) in 2 ml N,N-dimethylformamide. The reaction mixture is stirred for one hour at ambient temperature, combined with 66 μl (0.39 mmol) N-ethyl-diisopropylamine and stirred for a further 10 minutes at ambient temperature. 500 mg (5.0 mmol) 2-aminothiazole are added and the mixture is stirred for 22 hours at ambient temperature. The solvent is eliminated in vacuo and the residue is chromatographed on reversed-phase Microsorb C18 [acetonitrile (0.1 % trifluoroacetic acid)/water (0.13% trifluoroacetic acid) = 10:90 ^■* 100:0]. Yield: 85 mg (75 % of theory)

C₃IH₃₃N₅O₄S₂ x C₂HF₃O₂ (717.78) Mass spectrum: (M+H)⁺ = 604 retention time (method 1 ): 2.77 min

Examples 5-16, 21 , 22 and 23

Prepared analogously to Example 4 by amide linking between Component iv and the corresponding substituted amine (see R^' group in Table).

thin layer chromatography on silica gel eluant: dichloromethane / methanol / 32% ammonia solution in water

90/10/0.1

Examples 17

Prepared analogously to Example 4 by amide linking between Component iv and δ-aminomethyl-isoxazol-3-ole.

Yield: 87 % of theory C₃IH₃₄N₆O₆S (618.72) Mass spectrum: (M+H)⁺ = 619 retention time (method 1 ): 1.51 min

Examples 18-20 and 24

Prepared analogously to Example 4 by amide linking between 4-(1 -{3-[(R)-2- (3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1 H- imidazol-4-yl)-benzoic acid (WO05108373) and the corresponding substituted amine (see R^' group in Table).

The following compounds may be prepared analogously to the foregoing Examples:

Claims

Patent Claims

1. Compounds of general formula (I)

wherein

a heteroaryl group selected from among pyridinyl and thienyl,

A denotes a group of formula

(A3) (A-4)

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂)_n- , while the groups of formulae -(CO)-NH-(CH₂)_n and -NH-(CO)-(CH₂)_n- in the alkylene moiety may be substituted in each case by a Ci_-3-alkyl group,

n denotes the number 0, 1 , 2 or 3 and

and the prodrugs, tautomers, racemates, enantiomers, diastereomers, solvates, hydrates, mixtures thereof and the salts thereof.

2. Compounds of general formula (I) according to claim 1 , wherein

A denotes a group of formula

(A5) (A6)

n denotes the number 0, 1 , 2 or 3 and

R denotes a group of formula

which is optionally substituted by one or two h-alogen atoms or one or two Ci- 3-alkyl, amino, nitro or hydroxy groups,

or a 5-membered saturated, aromatic or partly unsaturated heterocyclic group, which is optionally substituted by one or two Ci-3-alkyl, amino, nitro or hydroxy groups, wherein the substituents may be identical or different, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

3. Compounds of general formula (I) according to claim 2, wherein

R¹ denotes a phenyl group,

A denotes a group of formula

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n- or -NH-(CO)-(CH₂),,- , wherein the alkylene group may be substituted in each case by a Ci-3-alkyl group, n denotes the number 0, 1 , 2 or 3 and

R² , if L denotes a -(CO)- group, denotes a group of formula

4. Compounds of general formula (I) according to claim 3, wherein

R¹ denotes a phenyl group,

A denotes a group of formula

(A5) (A6)

n denotes the number 0, 1 or 2 and

R² , if L denotes a -(CO)- group, denotes a group of formula

which may be substituted by a hydroxy group,

5. Compounds of general formula (I) according to claim 4, wherein

R¹ denotes a phenyl group,

A denotes a group of formula

(A3) (A4)

(A5) (A6)

L denotes a group of formula -(CO), -(CO)-NH-(CH₂)_n or -NH-(CO)-(CH₂),,- , while the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci-3-alkyl group,

n denotes the number 0, 1 or 2 and

R² , if L denotes a -(CO)- group, denotes a group of formula

which may be substituted by a hydroxy group,

which may be substituted by a fluorine, chlorine or bromine atom or a methyl, amino, nitro or hydroxy group, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

6. Compounds of general formula (I) according to one of claims 1 to 5, wherein A is a group of formula A1 , A3 or A5, wherein the nitrogen atom is linked to the alkylene group and the benzo ring is linked to the group L, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

7. Compounds of general formula (I) according to claim 6, wherein A denotes a group of formula

(A1 ) (A3^') (A5^')

wherein the nitrogen atom is linked to the alkylene group and the benzo ring is linked to the group L, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

8. Compounds according to one of claims 1 to 7, characterised in that they are the (R)-enantiomer of formula

9. Compounds according to one of claims 1 to 7, characterised in that they are the (S)-enantiomer of formula

10. The following compounds according to claim 1 :

(4) N-(1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-indol-5-yl)-2-(2-amino-thiazol-4-yl)-acetamide, (5) N-(1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-indol-5-yl)-2-(3-hydroxy-isoxazol-5-yl)- carboxamide, (6) N-(1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-indol-5-yl)-2-(3-hydroxy-isoxazol-5-yl)- propionamide,

(5) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(2H-tetrazol-5-ylmethyl)-amide,

(6) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(1 H-tetrazol-5-yl)-amide, (7) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(2-amino-thiazol-4-ylmethyl)-amide,

(8) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(thiazol-2-ylmethyl)-amide,

(11 ) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(thiazol-5-ylmethyl)-amide, (12) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(oxazol-2-ylnnethyl)-annide,

(14) 1 -{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid-(3-hydroxy-isoxazol-5-ylmethyl)- amide,

(15) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (5-hydroxy-2H-pyrazol-3-ylmethyl)- amide,

(16) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid[(S)-1 -(5-hydroxy-isoxazol-2-yl)-2- methyl-propyl]-annide, (17) 1 -{3-[(R)-2-(3-phenyllsulphonylamino-phenyl)-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3-hydroxy-isoxazol- 5-ylmethyl)-annide,

(18) 4-(1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylannino]-3- methyl-butyl}-1 H-imidazol-4-yl)-N-(3-hydroxy-isoxazol-5-ylnnethyl)-benzannide, (19) 4-(1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-innidazol-4-yl)-N-[(S)-1 -(5-hydroxy-isoxazol-2-yl)-2-nnethyl- propyl]-benzamide, or

(20) 4-(1-{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-imidazol-4-yl)-N-(5-hydroxy-2H-pyrazol-3-ylmethyl)- benzamide,

(21 ) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (5-hydroxy-1 -methyl -1 H-pyrazol-3- ylmethyl)-amide,

(23) 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3- methyl-butyl}-1 H-indole-5-carboxylic acid (5-amino-2H-[1 ,2,4]triazol-3- ylmethyl)-amide or

(24) 4-(1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylannino]- 3-methyl-butyl}-1 H-imidazol-4-yl)-N-(5-hydroxy-1 -methyl-1 H-pyrazol-3- ylmethyl)-benzannide,

and the enantiomers and salts thereof.

11. The compound 1 -{3-[(R)-2-(3-phenylsulphonylamino-phenyl)-2-hydroxy- ethylamino]-3-methyl-butyl}-1 H-pyrrolo[2,3-b]pyhdine-5-carboxylic acid and the enantiomers and salts thereof.

12. Physiologically acceptable salts of the compounds according to claims 1 to 11.

13. Compounds of formula (I) according to one of claims 1 to 12 for use as pharmaceutical compositions.

14. Compounds of formula (I) according to one of claims 1 to 12 for use as pharmaceutical compositions with a selective beta-3-agonistic activity.

15. Use of a compound of formula (I) according to one of claims 1 to 12 for preparing a pharmaceutical composition for the treatment and/or prevention of diseases which are associated with the stimulation of beta-3-receptors.

16. Use of a compound of formula (I) according to one of claims 1 to 12 for preparing a pharmaceutical composition for the treatment of obesity, insulin resistance, type 2 diabetes mellitus, urinary incontinence, irritable colon or depression.

17. Method for the treatment and/or prevention of diseases which are associated with the stimulation of beta-3-receptors, characterised in that a patient is given an effective amount of a compound of formula I according to one of claims 1 to 12.

18. Method for the treatment of obesity, insulin resistance, type 2 diabetes mellitus, urinary incontinence, irritable colon or depression characterised in that a patient is given an effective amount of a compound of formula I according to one of claims 1 to 12.

19. Pharmaceutical composition, containing as active substance one or more compounds of general formula (I) according to one of claims 1 to 12, optionally combined with conventional excipients and/or carriers.

20. Pharmaceutical composition containing as active substance one or more compounds of general formula (I) according to one of claims 1 to 11 or the physiologically acceptable salts thereof and one or more active substances selected from among antidiabetics, inhibitors of protein tyrosinephosphatase 1 , substances which influence deregulated glucose production in the liver, lipid lowering agents, cholesterol absorption inhibitors, HDL-raising compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic system via alpha 1 and alpha 2 as well as beta 1 , beta 2 and beta 3 receptors.

21. Process for preparing a compound of general formula (I) according to claim 1 , characterised in that

a) in order to prepare a compound of general formula (I) according to claim 1 , wherein L denotes a group of formula -(CO) or -(CO)-NH-(CH₂)_n-, wherein the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci_-3-alkyl group,

a compound of general formula (Na)

(Ha), wherein A is defined as in claim 1 ,

is reacted with an amine of general formula (III)

b) in order to prepare a compound of general formula (I) according to claim 1 , wherein L denotes a group of formula -NH-(CO)-(CH₂)_n-, wherein the groups of formulae -(CO)-NH-(CH₂)_n- and -NH-(CO)-(CH₂)_n- may each be substituted in the alkylene moiety by a Ci-3-alkyl group,

a compound of general formula (lib)

(Hb)

wherein A is defined as in claim 1 ,

is reacted with a carboxylic acid of general formula (IV) HOOC-(CH₂)_n-R² (IV)