DE19903126A1 - New sulphur substituted sulphonylaminocarboxylic acid N-arylamide derivatives used for treating e.g. cardiovascular diseases and atherosclerosis - Google Patents

Abstract

Sulphur substituted sulphonylaminocarboxylic acid N-arylamide derivatives (I) are new. Sulphur substituted sulphonylaminocarboxylic acid N-arylamide derivatives (I) and their salts are new. A<1> = phenylene, naphthylene or heteroarylene (all optionally substituted by halo, 1-5C alkyl, phenyl, tolyl, CF3, NO2, OH, 1-5C alkoxy, O-(2-4C alkyl)-O-(1-3C alkyl), 1-2C alkylenedioxy, NH2, NH(1-3C alkyl), N(1-3C alkyl)2, NHCHO, NHCO(1-5C alkyl), CN, CONH2, CONH(1-3C alkyl), CON(1-3C alkyl)2, COOH, COO(1-5C alkyl), heterocyclyl, CHO, CO(1-5C alkyl), SOn-(1-4C alkyl), SOn-phenyl or SOn-tolyl); A<2> = benzene, naphthalene, saturated or partially unsaturated 3- to 7-membered carbocyclyl, monocyclic 5- to 7-membered heterocyclyl containing one or more N, O or S atoms or bicyclic 8- to 10-membered heterocyclyl containing one or more N, O or S atoms; R<1> = aryl, heterocyclyl or 1-18C alkyl optionally substituted by R<4> or when n = 2, R<1> may also be NR<5>R<6> or when n = 0, R<1> may also be CN; R<2> = aryl, heterocyclyl, NR<5>R<6> or 1-10C alkyl optionally substituted by R<4>; R<3> = H, halo, CF3, OH, 1-7C alkoxy, O-(2-4C alkyl)-O-(1-7C alkyl), aryloxy, 1-2C alkylenedioxy, NO2, CN, NR<7>R<8>, CONR<7>R<8>, COOH, COO(1-5C alkyl), heterocyclyl, SOn-(1-5C alkyl) or 1-5C alkyl optionally substituted by R<4>; R<4> = F, OH, 1-10C alkoxy, O-(2-4C alkyl)-O-(1-7 alkyl), aryloxy, CN, NR<7>R<8>, CONH2, CONH(1-3C alkyl), CON(1-3C alkyl)2, COOH, COO(1-5C alkyl), heterocyclyl or oxo; R<5> = H, 1-10C alkyl (optionally substituted by R<4> and/or aryl), aryl, heterocyclyl, CONR<7>R<8>, CO-aryl or CO-(1-10C alkyl) (optionally substituted by R<4>); R<6> = a group R<5> or NR<5>R<6> = 5- to 8-membered saturated or partially unsaturated ring also containing N, O or S and optionally substituted by one or more F, 1-5C alkyl, 1-3C hydroxyalkyl, (1-3C alkyl)-O-(1-4C alkyl), aryl, CF3, OH, 1-7C alkoxy, aryloxy, O-(2-4C alkyl)-O-(1-7C alkyl), 2-3C alkylenedioxy, NR<7>R<8>, CN, CONH2, CONH(1-3C alkyl), CON(1-3C alkyl)2, COOH, COO(1-5C alkyl), CHO, CO(1-5C alkyl), SOn-(1-4C alkyl), SOn-NH2, SOn-NH(1-3C alkyl), SOn-N(1-3C alkyl)2, oxo, (CH2)mNH2, (CH2)m-NH(1-4C alkyl) or (CH2)m-N(1-4C alkyl)2 (in which N-(1-4C alkyl)2 optionally forms a 5- to 7-membered ring also containing O, S or NR<5>); R<7> = H or 1-7C alkyl optionally substituted by OH, 1-5C alkoxy, NH2, NH(1-4C alkyl) or N(1-4C alkyl)2 which optionally forms a 5- to 7-membered ring also containing O, S or NR<5>; R<8> = a group R<7> or CO-(1-4C alkyl); aryl = phenyl, naphthyl or heteroaryl (all optionally substituted by one or more halo, 1-5C alkyl, phenyl, tolyl, CF3, OCF3, NO2, OH, 1-5C alkoxy, O-(2-4C alkyl)-O-(1-3C alkyl), 1-2C alkylenedioxy, NH2, NH(1-3C alkyl), N(1-3C alkyl)2, NHCHO, NHCO(1-5C alkyl), CN, CONH2, CONH(1-3C alkyl), CON(1-3C alkyl)2, COOH, COO(1-5C alkyl), heterocyclyl, CHO, CO-(1-5C alkyl), SOn-(1-4C alkyl), SOn-phenyl or SOn-tolyl); heteroaryl, heteroarylene = monocyclic 5- or 6-membered aromatic heterocyclyl or bicyclic 8- to 10-membered aromatic heterocyclyl each containing N, O or S; heterocyclyl = mono- or poly-cyclic 5- to 11-membered saturated or partially unsaturated heterocyclyl containing one or more N, O or S atoms and optionally substituted by one or more F, 1-5C alkyl, OH, 1-5C alkoxy, -O-(2-4C alkyl)-O-(1-3C alkyl), NH2, NH(1-3C alkyl), N(1-3C alkyl)2, CN, CONH2, CONH(1-3C alkyl), CON(1-3C alkyl)2, COOH or COO(1-5C alkyl); n = 0-2; m = 2-4 and X = O or NH or a N-atom forming an anellate imidazole ring; excluding (I) in which A<2> = 3,5-dichlorophenyl, R<2> = Me, X = O and R<1>-SOn-A<1> = 5-chloro-2-(4-chlorophenylmercapto)phenyl. An Independent claim is included for the preparation of (I).

Description

The present invention relates to compounds of the formula I,

in which A ¹ , A ² , R ¹ , R ² , R ³ , X and n have the meanings given below, which are valuable pharmaceutical active ingredients for the therapy and prophylaxis of diseases, for example cardiovascular diseases such as hypertension, angina pectoris, Heart failure, thrombosis or arteriosclerosis. The compounds of formula I have the ability to modulate the body's production of cyclic guanosine monophosphate (cGMP) and are generally useful in the therapy and prophylaxis of disease states associated with a disturbed cGMP household. The invention further relates to processes for the preparation of compounds of the formula I, their use for the therapy and prophylaxis of the indicated disease states and for the production of medicaments therefor, as well as pharmaceutical preparations containing compounds of the formula I.

cGMP is an important intracellular messenger that transmits via cGMP modulation dependent protein kinases, phosphodiesterases and ion channels a number of pharmacological effects. Examples are the smooth muscle relaxation, the Inhibition of platelet activation and inhibition of Smooth Muscle Cell Proliferation and Leukocyte Adhesion. cGMP is made by particulate and soluble guanylate cyclases in response to a number of extracellular and produced intracellular stimuli. In the case of particulate guanylate cyclases occurs the stimulation essentially by peptidic signaling substances, such as the atrial natriuretic peptide or the cerebral natriuretic peptide. The soluble Guanylate cyclases (sGC), which are cytosolic, heterodimeric Hematoproteins are, however, are essentially by a family low molecular weight, enzymatically formed factors. Most important stimulant is the nitric oxide (NO) or a closely related species. The meaning other factors such as carbon monoxide or the hydroxyl radical is still largely present unexplained. The activation mechanism of activation by NO is the NO binding to the heme to form a pentacoordinated heme Nitrosyl complex discussed. The associated release of the State to the iron bound histidine converts the enzyme into the activated Conformation.

Active soluble guanylate cyclases are composed of one α- and one β-subunit. Subunits described several subtypes that differ in sequence, tissue-specific distribution, and expression at different stages of development. The subtypes α ₁ and β ₁ are mainly expressed in brain and lung, while β _{2 is} found mainly in liver and kidney. In human fetal brain, the subtype α ₂ could be detected. The subunits designated α ₃ and β ₃ were isolated from human brain and are homologous to α ₁ and β ₁ . Recent work indicates an α _2i subunit containing an insert in the catalytic domain. All subunits show large homologies in the domain of the catalytic domain. The enzymes presumably contain one heme per heterodimer bound via β ₁ -Cys-78 and / or β ₁ -His-105, which is part of the regulatory center.

Under pathological conditions, the formation of guanylate cyclase-activating Factors may be reduced or it may be freer due to the increased occurrence Radical an increased degradation of the same take place. The resulting diminished activation of sGC results in the attenuation of the respective cGMP mediated cell response, for example, to increase blood pressure, Platelet activation or increased cell proliferation and cell adhesion. When This leads to the formation of endothelial dysfunction, arteriosclerosis, Hypertension, stable and unstable angina, thrombosis, myocardial infarction, Strokes or erectile dysfunction. The pharmacological stimulation of sGC provides a way to normalize cGMP production and allowed thus the treatment or prevention of such diseases.

For pharmacological stimulation of sGC have been almost exclusively Used compounds whose action on an intermediate NO release based, for example, organic nitrates. The disadvantage of this treatment lies in the development of tolerance and impact mitigation and therefore required higher dosage.

Various non-NO-releasing sGC stimulators were used described by Vesely in a larger number of works. The connections, at which are mostly hormones, plant hormones, vitamins or for example Natural substances such as the venom toxins are, however, show only weak effects throughout on cGMP formation in cell lysates (D.L. Vesely, Eur. J. Clin. Invest., 15 (1985) 258; D.L. Vesely, Biochem. Biophys. Res. Comm. 88 (1979) 1244). A stimulation Heme-free guanylate cyclase by protoporphyrin IX has been described by Ignarro et al. (Adv. Pharmacol. 26 (1994) 35). Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307) for diphenyliodonium hexafluorophosphate  hypotensive effect and attributed it to stimulation of the sGC. Isoliquiritiginin, which has a relaxing effect on isolated rat aorta activated according to Yu et al. (Brit. J. Pharmacol., 114 (1995) 1587) also the sGC. Ko et al. (Blood 84 (1994) 4226), Yu et al. (Biochem J. 306 (1995) 787) and Wu et al. (Brit. J. Pharmacol 116 (1995) 1973) showed sGC-stimulating activity of 1- Benzyl-3- (5-hydroxymethyl-2-furyl) -indazole and demonstrated a antiproliferative and antiplatelet effect.

Various 2-sulfonylaminobenzoic acid N-aryl amides whose aryl group carries a thio substituent are mentioned in the literature. These compounds, in which the aryl group generally carries as further substituents easily oxidizable groups such as two hydroxy groups which are in para-position and which are then to be regarded as hydroquinone derivatives, are excipients for the preparation of photographic materials (see Examples Chemical Abstracts 119, 105 757, 120, 41 858, 123, 70 224 or 126, 257 007). If one considers isolated structural elements, then the aryl group contained in these known compounds corresponds to the group R ¹ -A ¹ in the formula I, when A ^{1 is} a 1,4-phenylene radical which is in the positions 2 and 5 hydroxy groups (or oxy- Substituents), and n is 0. British Patent 876,526 (Chemical Abstracts 56, 15 432e) describes 3,5-dichloro-2-methylsulfonylaminobenzoic acid N- (5-chloro-2- (4-chlorophenylthio) -phenyl) -amide, which can be used to protect wool against moth infestation. Pharmacological effects are not known for these known 2-sulfonylamino benzoic acid N-aryl amides.

Surprisingly, it has now been found that the compounds of the invention Formula I cause a strong guanylate cyclase activation, due to which they lead to Therapy and prophylaxis of diseases that are associated with a low cGMP levels are linked.

The present invention thus relates to compounds of the formula I,

in the
A ^{1 is} a bivalent radical selected from the group consisting of phenylene, naphthylene and heteroarylene, all of which are substituted by one or more identical or different substituents selected from halogen, (C ₁ -C ₅ ) -alkyl, phenyl, tolyl, CF ₃ , NO ₂ , OH, OC ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₂ ) -alkylenedioxy, NH ₂ , NH- (C ₁ -C ₃ ) -alkyl, N ((C ₁ -C ₃ ) -alkyl) ₂ , NH-CHO, NH-CO- (C ₁ -C ₅ ) -alkyl, CN, CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl , CHO, CO- (C ₁ -C ₅ ) -alkyl, S (O) _n - (C ₁ -C ₄ ) -alkyl, S (O) _n -phenyl and S (O) _n -tolyl;
the ring A ² , which comprises the carbon atoms carrying the groups C (= X) -NH- and NH-SO ₂ R ² , for a benzene ring, a naphthalene ring, a saturated or partially unsaturated 3-membered to 7-membered carbocycle , a saturated, partially unsaturated or aromatic monocyclic 5-membered to 7-membered heterocycle containing one or more ring heteroatoms from the series N, O and S, or a saturated, partially unsaturated or aromatic bicyclic 8-membered to 10- a membered heterocycle containing one or more ring heteroatoms from the series N, O and S;
R ^{1 is} aryl, heterocyclyl or (C ₁ -C ₁₈ ) -alkyl, which may be substituted by one or more identical ones of the different radicals R ⁴ , or when n in the group R ¹ -S (O) _n - for the number 2 also stands for NR ⁵ R ⁶ , or if n in the group R ¹ -S (O) _n - stands for the number 0, then also stands for CN;
R ^{2 is} aryl, heterocyclyl, NR ⁵ R ⁶ or (C ₁ -C ₁₀ ) -alkyl which may be substituted by one or more identical or different radicals R ⁴ ;
R ^{3 represents} one or more identical or different substituents from the group consisting of hydrogen, halogen, CF ₃ , OH, -O- (C ₁ -C ₇ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O-, (C ₁ -C ₇ ) -alkyl, O-aryl, (C ₁ -C ₂ ) -alkylenedioxy, NO ₂ , CN, NR ⁷ R ⁸ , CO-NR ⁷ R ⁸ , CO-OH, CO-O- ( C ₁ -C ₅ ) -alkyl, heterocyclyl, S (O) _n - (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkyl which may be substituted by one or more identical or different radicals R ⁴ can, stands;
R ^{4 is} fluorine, OH, -O- (C ₁ -C ₁₀ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₇ ) -alkyl, -O-aryl, CN, NR ⁷ R ⁸ , CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl or oxo;
R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) -alkyl which may be substituted by one or more identical or different substituents R ⁴ and / or by aryl, aryl, heterocyclyl, CO-NR ⁷ R ⁸ , CO-aryl or CO- (C ₁ -C ₁₀ ) -alkyl, wherein the alkyl radical may be substituted by one or more identical or different radicals R ⁴ ;
R ⁶ independently of R ^{5 has} one of the meanings given for R ⁵ , or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 5-membered to 8-membered saturated or partially unsaturated ring which in addition to in which the nitrogen atom bearing the groups R ⁵ and R ⁶ may contain one or more further ring heteroatoms from the series N, O and S and which may be substituted by one or more identical or different substituents from the series fluorine, (C ₁ -C ₅ ) Alkyl, (C ₁ -C ₃ ) -hydroxyalkyl, - (C ₁ -C ₃ ) -alkyl-O- (C ₁ -C ₄ ) -alkyl, aryl, CF ₃ , OH, -O- (C ₁ -) C ₇ ) -alkyl, -O-aryl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₇ ) -alkyl, (C ₂ -C ₃ ) -alkylenedioxy, NR ⁷ R ⁸ , CN, CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -) C ₅ ) -alkyl, CHO, CO- (C ₁ -C ₅ ) -alkyl, S (O) _n (C ₁ -C ₄ ) -alkyl, S (O) _n -NH ₂ , S (O) _n - NH- (C ₁ -C ₃ ) -alkyl, S (O) _n -N ((C ₁ -C ₃ ) -alkyl) ₂ , oxo, - (CH ₂ ) _m -NH ₂ , - (CH ₂ ) _m -NH- (C ₁ -C ₄ ) -alkyl and - (CH ₂ ) _m -N ((C ₁ -C ₄ ) alkyl) ₂ may be substituted, wherein in the substituent - (CH ₂ ) _m -N ((C ₁ -C ₄ ) alkyl) _2, the two alkyl groups by a Single bond can be linked and then form together with the nitrogen atom carrying them a 5-membered to 7-membered ring, which may contain in addition to the nitrogen atom and the carbon atoms additionally also an oxygen atom, a sulfur atom or a group NR ⁵ as a ring member;
R ^{7 is} hydrogen or (C ₁ -C ₇ ) -alkyl which is substituted by one or more identical or different substituents from the group OH, -O- (C ₁ -C ₅ ) -alkyl, NH ₂ , -NH- (C ₁ -C ₄ ) - alkyl and -N ((C ₁ -C ₄ ) -alkyl) ₂ may be substituted, wherein in the substituent N ((C ₁ -C ₄ ) alkyl) _2, the two alkyl groups by a Single bond can be linked and then form together with the nitrogen atom carrying them a 5-membered to 7-membered ring, which in addition to the nitrogen atom and the carbon atoms may additionally contain an oxygen atom, a sulfur atom or a group NR ⁵ as a ring member;
R ⁸ independently of R ^{7 has} one of the meanings of R ⁷ or is CO- (C ₁ -C ₄ ) -alkyl;
Aryl is phenyl, naphthyl or heteroaryl, all of which are substituted by one or more identical or different substituents selected from halogen, (C ₁ -C ₅ ) -alkyl, phenyl, tolyl, CF ₃ , NO ₂ , OH, -O- ( C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₂ ) -alkylenedioxy, NH ₂ , -NH- (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , NH-CHO, -NH-CO- (C ₁ -C ₅ ) -alkyl, CN, CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl , CHO, CO- (C ₁ -C ₅₎ alkyl, S (O) _n - _n tolyl may be substituted phenyl and S (O) - (C ₁ -C ₄₎ alkyl, S (O) _n;
Heteroaryl and heteroarylene is the radical of a monocyclic 5-membered or 6-membered aromatic heterocycle or a bicyclic 8-membered to 10-membered aromatic heterocycle, each containing one or more ring heteroatoms from the series N, O and S;
Heterocyclyl is the radical of a monocyclic or polycyclic, 5-membered to 11-membered saturated or partially unsaturated heterocycle containing one or more ring heteroatoms from the series N, O and S, and by one or more identical or different substituents fluorine, (C ₁ -C ₅ ) -alkyl, OH, -O- (C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -Alkyl, NH ₂ , -NH- (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , CN, CO-NH ₂ , CO-NH- (C ₁ -) C ₃ ) alkyl, CO-N ((C ₁ -C ₃ ) alkyl) ₂ , CO-OH and CO-O- (C ₁ -C ₅ ) alkyl may be substituted;
n is 0, 1 or 2;
m is 2, 3 or 4;
X is O or NH, or X represents a nitrogen atom that is bonded via a single bond to a ring carbon atom in the group A ^1, where the group -NH-C (= X) - adjacent carbon atom carrying in A ¹ directly is such that the group -NH-C (= X) - together with the carbon atoms carrying them in A ¹ forms a fused imidazole ring;
in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts;
wherein the compound of the formula I is excluded, in which at the same time the ring A ² , which comprises the carbon atoms carrying the groups C (= X) -NH- and NH-SO ₂ R ² , is a benzene ring which in the Positions 3 and 5 is substituted by chlorine, R ^{2 is} methyl, X is oxygen and R ¹ -S (O) _n -A ¹ - is a 2- (4-chlorophenylmercapto) -5-chlorophenyl radical.

Can groups or substituents multiply in the compounds of formula I occur, they can all independently of each other the specified Meanings have and can be the same or different.

Alkyl radicals can be straight-chain or branched. This also applies if they are contained in other groups, for example in alkoxy groups, alkoxycarbonyl groups or in amino groups, or if they are substituted. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, the n-isomers of these radicals, isopropyl, isobutyl , Isopentyl, sec-butyl, tert -butyl, neopentyl, 3,3-dimethylbutyl. The term alkyl is to be understood as meaning here also unsaturated alkyl radicals, ie alkyl radicals which contain one or more double bonds and / or one or more triple bonds, ie alkenyl radicals and alkynyl radicals. Examples of such radicals are the vinyl radical, the 2-propenyl radical (allyl radical), the 2-butenyl radical, the 2-methyl-2-propenyl radical, the ethynyl radical, the 2-propynyl radical (propargyl radical) or the 3-butynyl radical. Furthermore, the term alkyl is to be understood here expressly also radicals in which a cyclic system is formed by an internal ring closure, the term alkyl thus also includes saturated and partially unsaturated cycloalkyl and cycloalkylalkyl (substituted by cycloalkyl) alkyl). Examples of such cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloctyl, all of which may also be substituted, for example, by one or more identical or different (C ₁ -C ₄ ) -alkyl radicals, in particular by methyl. Examples of such substituted cycloalkyl radicals are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl. Furthermore, unless otherwise stated, the term alkyl also expressly includes both unsubstituted alkyl radicals and also alkyl radicals which are substituted by one or more, for example one, two, three or four, identical or different aryl radicals. Thus, the term alkyl is also to be understood as meaning arylalkyl radicals, for example benzyl radicals, phenylethyl radicals or indanyl radicals.

A standing for the ring A ² saturated or partially unsaturated 3-membered to 7-membered carbocycle can be derived from monocyclic bodies cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane. If the carbocycle is unsaturated, it may contain, for example, a double bond or, in the case of the 5-ring, 6-ring or 7-ring, also contain two double bonds, which may be isolated or conjugated. Double bonds may be in any position relative to the groups C (= X) -NH- and NH-SO ₂ -R ² , so there may also be, for example, a double bond between the two ring carbon atoms bearing these two groups ,

Phenyl radicals, naphthyl radicals and heterocyclic radicals, for example heteroaryl radicals, may, unless stated otherwise, be unsubstituted or carry one or more, for example one, two, three or four, identical or different substituents, which may be in any positions. Unless otherwise indicated, these substituents may include, for example, the substituents specified in the definition of the aryl group. If nitro groups are present as substituents in compounds of the formula I, in total only up to two nitro groups may be present in the molecule. If, for example, phenyl radicals, phenoxy radicals, benzyl radicals or benzyloxy radicals are present as substituents in aryl radicals, for example phenyl radicals and / or in heterocyclic radicals, the benzene ring may again be unsubstituted or may be substituted by one or more, for example one, two, three or more four, identical or different radicals may be substituted, for example by radicals from the series (C ₁ -C ₄ ) -alkyl, halogen, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, ((C ₁ -C ₄₎ -alkoxy) carbonyl, aminocarbonyl, nitro, amino, (C ₁ - C ₄₎ alkylamino, di - ((C ₁ -C ₄₎ -alkyl) amino and ((C ₁ -C ₄₎ -alkyl ) carbonylamino.

In monosubstituted phenyl radicals, the substituent in the 2-position, the 3-position or the 4-position, in disubstituted phenyl radicals may be located the substituents in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4- Position or 3.5-position. In trisubstituted phenyl radicals, the Substituents in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6- Position or 3,4,5-position. Tolyl (= methylphenyl) is 2-tolyl, 3-tolyl or 4-tolyl. Naphthyl can be 1-naphthyl or 2-naphthyl. In monosubstituted 1- Naphthyl radicals may be the substituent in the 2-position, the 3-position, the 4- Position, 5-position, 6-position, 7-position or 8-position, in monosubstituted 2-naphthyl radicals in the 1-position, the 3-position, the 4- Position, 5-position, 6-position, 7-position or 8-position.

The above explanations as well as the following explanations to the monovalent radicals apply correspondingly to the divalent radicals phenylene, Naphthylene and heteroarylene. The free bonds through which the divalent radical bound to the neighboring groups, can be attached to any ring Carbon atoms are located. For a phenylene radical, they can be in 1,2-position (ortho-phenylene), 1,3-position (meta-phenylene) or 1,4-position (para-phenylene) are located. In the case of a naphthylene radical, the free bonds in 1,2- Position (= 1,2-naphthylene or 1,2-naphthalenediyl) or in the 1,3-position, 1,4-position, 1,5-position, 1,6-position, 1,7-position, 1,8-position, 2,3-position, 2,6- Position or 2,7-position. In the case of 5-membered heteroaromatic ring with a Heteroatom such as thiophene or furan can become the two free ones Bindings are located in 2,3-position, 2,4-position, 2,5-position or 3,4-position. On derived from the pyridine divalent radical may be a 2 3, 2,4, 2,5, 2,6, 3,4 or Be 3,5-Pyridindiylrest. In the case of unsymmetrical divalent radicals the present invention all positional isomers, for example in the case of a 2,3- Pyridinediylrestes thus the compound in which a first neighboring group in the 2- Position is located and a second neighbor group in the 3-position, as well as the Connection in which the first neighbor group is in the 3-position and the second neighbor group in the 2-position.  

Heteroaryl radicals, heteroarylene radicals, heterocyclyl radicals, heterocycles standing for the ring A ² and rings which are formed from two groups bonded to a nitrogen atom together with this nitrogen atom are preferably derived from heterocycles which have one, two, three or four identical or different rings - Contain heteroatoms, more preferably of heterocycles containing one or two or three, especially one or two, identical or different heteroatoms. Unless otherwise indicated, the heterocycles may be monocyclic or polycyclic, for example monocyclic, bicyclic or tricyclic. They are preferably monocyclic or bicyclic. The rings are preferably 5-rings, 6-rings or 7-rings. Examples of monocyclic and bicyclic heterocyclic systems, of which radicals which can be found in the compounds of the formula I, are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1 , 3-dioxole, 1,3-oxazole, 1,2-oxazole, 9,3-thiazole, 1,2-thiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1,4-dioxin, 1 , 2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine , 1,3,5-triazine, 1,2,4,5-tetrazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine, 1,3-thiazepine , Indole, benzothiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, thienothiophene, 1,8-naphthyridine and other naphthyridines, pteridine, or phenothiazine, all in each case in saturated form (perhydro form) or in partially unsaturated form (for example dihydro form and tetrahydro form) or in maximum unsaturated form, insofar as the b meeting forms are known and stable. Thus, for example, the saturated heterocycles pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine also belong to the suitable heterocycles. The degree of saturation of heterocyclic groups is given in the individual definitions. Unsaturated heterocycles may contain, for example, one, two or three double bonds in the ring system. In particular, 5-rings and 6-membered rings in monocyclic and polycyclic heterocycles may also be aromatic.

The radicals derived from these heterocycles may be any suitable Be bound carbon atom. Nitrogen heterocycles attached to a ring Nitrogen atom carry a hydrogen atom or a substituent, for example Pyrrole, imidazole, pyrrolidine, morpholine, piperazine etc. can also be synthesized via a ring Nitrogen atom be bound, in particular, if the concerned Nitrogen heterocycle is bonded to a carbon atom. For example, a Thienyl as 2-thienyl or 3-thienyl, a furan as 2- Furyl radical or 3-furyl radical, a pyridyl radical as 2-pyridyl radical, 3-pyridyl radical or 4- Pyridylrest, a Piperidinrest as 1-Piperidylrest, 2-Piperidylrest, 3-Piperidylrest or 4-piperidyl radical, a thiomorpholine radical as 2-thiomorpholinyl radical, 3 Thiomorpholinylrest or 4-Thiomorpholinylrest (= Thiomorpholinorest). One over one Carbon atom-bound radical derived from the 1,3-thiazole or imidazole can be bound via the 2-position, the 4-position or the 5-position.

Unless otherwise indicated, the heterocyclic groups may be unsubstituted or may carry one or more, for example one, two, three or four, identical or different substituents. The substituents in heterocycles may be in any positions, for example in a 2-thienyl radical or 2-furyl radical in the 3-position and / or in the 4-position and / or in the 5-position, in a 3-thienyl radical or 3 -Furylrest in the 2-position and / or in the 4-position and / or in the 5-position, in a 2-pyridyl radical in the 3-position and / or in the 4-position and / or in the 5-position and / or in the 6-position, in a 3-pyridyl radical in the 2-position and / or in the 4-position and / or in the 5-position and / or in the 6-position, in a 4-pyridyl radical in 2 position and / or 3 position and / or 5 position and / or 6 position. Unless stated otherwise, substituents may be, for example, the substituents specified in the definition of the group aryl, in the case of saturated or partially unsaturated heterocycles further substituents also include the oxo group and the thioxo group. Substituents on a heterocycle as well as substituents on a carbocycle can also form a ring, so it can be fused to a ring system more rings, so that, for example cyclopenta-fused, cyclohexa-fused or benzo-fused rings can be present. Suitable substituents on a substitutable nitrogen atom of a heterocycle especially, for example, unsubstituted (C ₁ -C ₅₎ come - alkyl and aryl-substituted alkyl radicals, aryl radicals, acyl radicals such as CO- (C ₁ -C ₅₎ alkyl, or sulfonyl groups such as SO ₂ - (C ₁ -C ₅ ) -alkyl. Suitable nitrogen heterocycles may also be present as N-oxides or as quaternary salts with an anion derived from a physiologically acceptable acid as the counterion. Pyridyl radicals may be present, for example, as pyridine N-oxides.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Without restricting the present invention, in the formulas Ia, Ib, Ic, Id, Ie, If, Ig and Ih examples of groups of compounds according to the invention are shown in which A ² in the formula I has specific meanings. In the formulas Ia, Ib, Ic, Id, Ie, If, Ig and Ih, A ¹ , R ¹ , R ² , R ³ , X and n have the meanings given above for the formula I, the number k in the formula Ib stands for 1, 2, 3, 4 or 5.

The compounds of the formula I in which X is a nitrogen atom which is bonded via a single bond to a ring carbon atom in the group A ¹ , directly to the carbon atom bearing the group -NH-C (XX) in A ¹ is adjacent, so that the group -NH-C (= X) - together with the carbon atoms carrying them in A ¹ forms a fused imidazole ring, are represented by the formula Ii.

In formula II, A ² , R ¹ , R ² , R ³ and n have the meanings given for the formula I. The ring A ³ , which has arisen from the group A ¹ by forming a bond to the X-standing nitrogen atom and which comprises the two indicated in the formula Ii carbon atoms which carry the nitrogen atoms of the fused imidazole ring, stands for a benzene ring, a naphthalene ring or a heteroaromatic ring, in which case the explanations given above for A ¹ apply correspondingly to these rings.

The present invention includes all stereoisomeric forms of the compounds of formula I. In the compounds of formula I contained Asymmetriezentren can all independently of each other the S configuration or the R configuration respectively. The invention includes all possible enantiomers and  Diastereomers, as well as mixtures of two or more stereoisomeric forms, for example, mixtures of enantiomers and / or diastereomers, in all Conditions. Enantiomers are therefore in enantiomerically pure form, both as levorotatory as well as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios Subject of the invention. In the presence of a cis / trans isomerism, both the cis form as well as the trans form and mixtures of these forms in all Conditions of the invention. The production of individual If desired, stereoisomers can be obtained by separation of a mixture conventional methods, for example by chromatography or crystallization, by Use of stereochemically uniform starting materials in the Synthesis or by stereoselective synthesis. If necessary, before a separation of stereoisomers carried out a derivatization. The separation of a stereoisomeric mixture can be at the stage of the compounds of formula I. or at the stage of an intermediate in the course of the synthesis. at Presence of mobile hydrogens embraces the present invention also all tautomeric forms of the compounds of the formula I.

Contain the compounds of formula I one or more acidic or basic Groups, so are the corresponding physiological or toxicological compatible salts of the invention, in particular the pharmaceutical usable salts. Thus, the compounds of formula I, the acidic groups contained in these groups, for example as alkali metal salts, Alkaline earth metal salts or as ammonium salts and according to the invention be used. Examples of such salts are sodium salts, potassium salts, Calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula I which have one or more basic, that is Protonatable groups may be in the form of their acid addition salts physiologically compatible inorganic or organic acids are present and be used according to the terminal, for example as salts with hydrogen chloride,  Hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, Methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, Acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, Propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, Pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, Phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid, etc. Contain the compounds of formula I simultaneously acidic and basic groups in the molecule, so belong in addition to the described salt forms also internal salts or betaines (zwitterions) to the invention. Salts may be out the compounds of the formula I according to customary methods known to the person skilled in the art obtained, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or also by anion exchange or cation exchange from other salts. The The present invention also encompasses all salts of the compounds of the formula I which because of low physiological compatibility not directly for use in pharmaceuticals, but for example as intermediates for chemical Reactions or for the preparation of physiologically acceptable salts into consideration come.

The present invention further includes all solvates of compounds of the Formula I, for example, hydrates or adducts with alcohols, and derivatives of Compounds of formula I such as esters, and prodrugs and active Metabolites.

A ¹ is preferably phenylene or a 5-membered or 6-membered heteroaryl radical, particularly preferably phenylene, where all these radicals may be unsubstituted or substituted as indicated. When the group A ^{1 is} substituted, that is, when it bears one or more further substituents in addition to the group R ¹ -S (O) _n , it is preferably substituted by one or two identical or different substituents given above. The group R ¹ -S (O) _n is preferably bonded to a carbon atom in A ¹ which is not directly adjacent to the carbon atom bearing the group C (= X) -NH. When A ^{1 is} phenylene, the group R ¹ -S (O) _{n is more} preferably in the meta position or in the para position, most preferably in the para position, relative to the carbon atom which is the group Carries C (= X) -NH.

A ² preferably together with the two atoms carrying the group R ² -SO ₂ -NH and the group C (= X) -NH forms an aromatic ring, especially a benzene ring or a thiophene ring.

R ¹ is preferably (C ₁ -C ₇ ) -alkyl, NR ⁵ R ⁶ or aryl, particularly preferably NR ⁵ R ⁶ , phenyl or 5-membered or 6-membered heteroaryl, where all these radicals are unsubstituted or substituted as indicated could be.

R ² is preferably for. Aryl, particularly preferably phenyl or 5-membered or 6-membered heteroaryl, where all these radicals may be unsubstituted or substituted as indicated.

The rings standing for A ² can be unsubstituted, that is to say bear hydrogen R ³ only, or be substituted as indicated, that is to say carry one or more radicals R ³ other than hydrogen. The other substituent positions on the ring A ² , which do not bear any hydrogen other than R ³ carry hydrogen atoms. If the ring A ² carries one or more radicals R ³ which are different from hydrogen, it preferably carries one or two such radicals R ³ , in particular such a radical R ³ . Such radicals R ³ are preferably in those positions of the ring A ² , which are not directly adjacent to the groups C (= X) NH and R ² -SO ₂ -NH. When A ^{2 is} a saturated or partially unsaturated carbocycle, such R ^{3 is} preferably (C ₁ -C ₄ ) -alkyl, especially methyl. When A ^{2 is} an aromatic ring, especially when A ^{2 is} a benzene ring, such R ^{3 is} preferably (C ₁ -C ₃ ) -alkyl, halogen, (C ₁ -C ₃ ) -alkoxy or CF ₃ , especially preferably methyl, chloro or methoxy. When A ^{2 is} an aromatic ring, in particular a benzene ring, it is most particularly preferred if it bears a chlorine atom or two methoxy groups as substituents, that is, if one radical R ^{3 is} chlorine or two radicals R ^{3 are} methoxy are present and the other substituent positions carry hydrogen atoms. When A ^{2 is} a benzene ring, radicals R ³ other than hydrogen are preferably in positions 4 and / or 5 (relative to the group C (= X) NH in the 1-position).

If a group is substituted by one or more radicals R ⁴ , it is preferably substituted by one, two or three, in particular one or two, identical or different radicals R ⁴ . R ⁴ is preferably hydroxy, (C ₁ -C ₄ ) -alkyloxy, di- ((C ₁ -C ₄ ) -alkyl) amino or heteroaryl.

R ⁵ and R ⁶ are preferably each independently hydrogen, (C ₁ -C ₉ ) -alkyl, - (C ₁ -C ₃ ) -alkyl-O- (C ₁ -C ₄ ) -alkyl or 5-membered or 6 or, together with the nitrogen atom carrying R ⁵ and R ^{6, form} a 5-membered to 7-membered heterocycle which, in addition to the nitrogen atom carrying the groups R ⁵ and R ^{6, contains} another ring heteroatom from the series N, O and S may contain one or more, for example one, two, three or four, identical or different radicals from the series (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₃ ) -hydroxyalkyl, may be substituted by lower or 6-membered aryl, carbamoyl, hydroxy and oxo. R ⁵ and R ⁶ together with the nitrogen atom carrying them form particularly preferably a 5-membered to 7-membered heterocycle which, in addition to the nitrogen atom carrying the groups R ⁵ and R ^6, also contains a further nitrogen atom from the series N, O and S. may be substituted by one or more, for example one, two, three or four identical or different radicals from the series (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₃ ) -hydroxyalkyl, 5-membered or 6-membered may be substituted by lower aryl, carbamoyl, hydroxy and oxo. Very particular preference is given to such a ring which is formed by R ⁵ and R ⁶ together with the nitrogen atom carrying it; from morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, 1-oxo-thiomorpholine, 3,5-dimethylmorpholine, cis-3,5-dimethylmorpholine, 1- (pyrimidin-2-yl) -piperazine, piperidine-4 carboxamide, 1- (2-hydroxyethyl) piperazine, 1-methylpiperazine, 1-ethylpiperazine, of 1-arylpiperazines, of piperazine-1-carboxylic acid ethyl ester, piperidine, 2-methylpiperidine, 4-hydroxypiperidine, 4-oxopiperidine or a ketal thereof such as 1,4-dioxa-8-aza spiro [4.5] decane, from tetrahydropyridine, tetrahydropyrimidine, 1-methylhomopiperazine, thiazolidine, pyrroline, 3-hydroxypyrrolidine, 1,2,3,4-tetrahydraisoquinoline or 2,3-dihydro-1H -isoindole, wherein the ring is bonded via the ring nitrogen atom or in the case of piperazine derivatives via the unsubstituted ring nitrogen atom. Especially preferred, such a ring, which is formed by R ⁵ and R ⁶ together with the nitrogen atom carrying it, is derived from morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, 1-oxo-thiomorpholine, 3,5-dimethylmorpholine, cis-3,5-dimethylmorpholine, 1- (pyrimidin-2-yl) piperazine, piperidine-4-carboxylic acid amide, 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydro-1H-isoindole.

R ⁷ preferably represents hydrogen, (C ₁ -C ₃₎ alkyl, di - ((C ₁ -C ₄₎ alkyl) amino, or - (C ₁ - C ₃₎ alkyl-O- (C ₁ -C ₄ ) -alkyl.

R ⁸ is preferably hydrogen, (C ₁ -C ₃ ) alkyl or acetyl.

Aryl is preferably phenyl or heteroaryl, in particular phenyl or 5-membered or 6-membered heteroaryl. Preferred substituents in aryl radicals are halogen, CF ₃ , (C ₁ -C ₃ ) -alkyl, cyano, nitro and (C ₁ -C ₃ ) -alkyloxy, particularly preferred substituents are CF ₃ , chlorine, methyl and methoxy.

Heteroaryl preferably represents radicals which differ from the heteroaromatics thiophene, Derive pyrazole, thiazole, oxazole, pyridine, pyrimidine, pyridazine and tetrazole.

Heterocyclyl is preferably radicals derived from saturated heterocycles especially for radicals derived from pyrrolidine, piperidine, N- Alkylpiperazines, from morpholine, from dialkylmorpholines, from thiomorpholine or Derive tetrahydrofuran.  

When a group S (O) _n is bonded to a nitrogen atom, the number n therein is preferably 1 or 2, more preferably 2. The number n in the group R ¹ -S (O) _n is preferably 0 and 2 , more preferably for 2.

X is preferably O or a nitrogen atom bonded via a single bond to a ring carbon atom in the group A ¹ which is directly adjacent to the carbon atom in the group -NH-C (= X) in A ^1, US Pat that the group -NH-C (= X) - together with their carrying carbon atoms in A ¹ forms a fused imidazole ring. Most preferably, X is O.

Preferred compounds of the formula I are those in which one or more of the groups contained therein have preferred meanings, all combinations of preferred substituent definitions is the subject of the present invention are. Also of all the preferred compounds of formula I includes the present Invention all their stereoisomeric forms and mixtures thereof in all Conditions, and their physiologically acceptable salts.

The present invention also provides processes for the preparation of the compounds of the formula I, which are explained below and according to which the compounds according to the invention are obtainable. According to Scheme 1, compounds according to the invention can be prepared, for example, by first reacting an aminocarboxylic acid of the formula II in a solvent such as water, pyridine or an ether in the presence of a base with a sulfonyl chloride of the formula R ² -SO ₂ -Cl or a sulfonic anhydride. Suitable bases are inorganic bases such as, for example, sodium carbonate or organic bases such as, for example, pyridine or triethylamine. The resulting sulfonylaminocarboxylic acid of formula III can then be activated, for example by reaction with a chlorinating agent such as phosphorus pentachloride, phosphorus oxychloride or thionyl chloride in an inert solvent to form an acid chloride of formula IV and then reacted with an arylamine. become. However, the activation of the carboxylic acid group in the compound of formula III can also take place in other ways, for example by one of the numerous methods known to those skilled in the art, which are used in peptide chemistry for the formation of amide bonds, for example by conversion into a mixed anhydride or an activated ester or using a carbodiimide such as dicyclohexylcarbodiimide.

Scheme 1

The reaction of the activated sulfonylaminocarboxylic acid with an arylamine is advantageously carried out in an inert solvent such as, for example, pyridine, tetrahydrofuran or toluene with without without addition of an inert auxiliary base, for example a tertiary amine or pyridine. If the arylamine used in the reaction with the activated carboxylic acid already contains the desired substituent R ¹ -S (O) _n , the reaction leads directly to the end product of the formula I. Compounds of the formula I in which n in the group R ¹ -S (O) _{n is} 1 or 2 can also be obtained by reacting the activated carboxylic acid with a mercapto-substituted arylamine of the formula R ¹ -SA ¹ -NH ₂ and then oxidizing the mercapto group in the compound of formula V under standard conditions, for Example with a peroxide such as hydrogen peroxide or a peracid such as 3-chloroperbenzoic acid or monoperoxyphthalic acid in a solvent such as methylene chloride or acetone. The activated carboxylic acids can also be first reacted with an arylamine of the formula A ¹ -NH ₂ . The resulting reaction product of formula VI may then be chlorosulfonated under standard conditions and the chlorosulfonyl group then also converted under standard conditions into the group R ¹ -SO ₂ , for example by reaction with suitable amines in bulk or in a solvent such as N-methylpyrrolidone, dimethylformamide , Toluene or an ether, optionally in the presence of an auxiliary base. In a similar manner, the activated carboxylic acids can be reacted with fluorosulfonylarylamines of the formula F-SO ₂ -A ¹ -NH ₂ and the resulting fluorosulfonyl intermediates of the formula VII can be converted into compounds of the formula I according to the invention by standard methods.

A further access to compounds of the formula I according to the invention provides the reaction of the activated sulfonylaminocarboxylic acids, that is, for example, the acid chlorides of the formula IV indicated in Scheme 1 with a mercaptoarylamine unsubstituted on the sulfur of the formula H ₂ NA ¹ -SH. The resulting product of formula VIII may then subsequently be alkylated or arylated under standard conditions in a nucleophilic substitution reaction on sulfur with an alkyl halide or aryl halide or other reactive compound and then, if desired, as explained for the compounds of formula V, on the sulfur to the sulfoxide or sulfone oxidized (see Scheme 2).

Scheme 2

Compounds of formula I can also be obtained, for example, by first activating an appropriately substituted nitrocarboxylic acid of formula IX, for example by conversion to the corresponding acid chloride of formula X or otherwise, and then, for example, with a substituted arylamine of the formula R ¹ -S (O) _n -A ¹ -NH ₂ is reacted analogously to the methods described above (see Scheme 3). As arylamine it is also possible in turn to use a fluorosulfonylarylamine of the formula F-SO ₂ -A ¹ -NH ₂ and in the obtained N- (fluorosulfonylaryl) -carboxamide of the formula XI the fluorosulfonyl group then in a further step under standard conditions into a group R ¹ according to the invention -SO ₂ , for example with an amine of the formula HNR ⁵ R ⁶ . Then, before the nitro group is reduced to the amino group in the resulting nitro intermediates of formula XII, the activating effect of the nitro group on the ring A ² can be exploited and a suitable radical R ³ , for example a halogen atom, by reaction with a nucleophile, for Example, an amine to be replaced by another radical R ³ . The reduction of the nitro group to the amino group can be effected for example by catalytic hydrogenation in the presence of a noble metal catalyst or preferably in the presence of Raney nickel in a solvent such as ethanol, glacial acetic acid or ethanolic hydrochloric acid, or by reduction with a base metal such as tin, zinc or iron in the presence of acid. The reduction can also be carried out, for example, with tin (II) chloride or by reaction with sodium dithionite, advantageously for example in a mixture of methanol, tetrahydrofuran and water as solvent. The sulfonylation of the amino group in the reduction product of formula XIII with an activated sulfonic acid derivative analogous to the reactions described above, for example with a sulfonic acid chloride in the presence of pyridine, finally gives the compounds of formula I.

Scheme 3

Scheme 4

The compounds of the formula I in which X is a nitrogen atom which is bonded via a single bond to a ring carbon atom in the group A ¹ , directly to the carbon atom bearing the group -NH-C (XX) in A ¹ adjacent, so the benzimidazole derivatives of the formula Ii can be obtained, for example, by a as obtained above according to Scheme 1 activated Sulfonylaminocarbonsäurederivat, for example a carboxylic acid chloride of formula IV, (or analogous to Scheme 3, a nitrocarboxylic acid derivative) with a 1,2-diaminoaromatic in the presence of a dehydrating agent, such as thionyl chloride or phosphorus pentachloride (see Scheme 4). The reaction is usually carried out in an inert solvent, for example in a hydrocarbon such as toluene or xylene. The 1,2-diaminoaromatic compound may already contain the end group R ¹ -S (O) _n or a precursor thereof, for example the group R ¹ -S. contain. Subsequent steps, for example reactions on the sulfur atom, can then in turn be carried out as explained above. For example, the products of formula XIV resulting from unsubstituted 1,2-diaminoaromatics may be chlorosulfonated with chlorosulfonic acid and the resulting sulfonyl chlorides converted to the final compounds having the group R ¹ -SO ₂ , for example by reaction with a suitable amine.

All reactions for the synthesis of the compounds of formula I are those skilled in the art per se well known and can under standard conditions after or analogous to Literature regulations are carried out, as for example in Houben-Weyl, Methods of Organic Chemistry, Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York. Depending on the Particular circumstances of the case may be in the synthesis of the compounds of Formula (to avoid side reactions also be beneficial or necessary, certain functional groups temporarily through the introduction of To block protective groups and later release them again or functional Groups initially in the form of precursors, from which in a later Step then the desired functional group is generated. Such Synthesis strategies and suitable for the individual case protecting groups or Precursors are known in the art. The obtained compounds of formula I may, where appropriate, by customary cleaning methods, for example by Recrystallization or chromatography, be purified. The Starting compounds for the preparation of the compounds of formula I are are commercially available or can be prepared according to or analogously to literature specifications become.

The compounds of the formula I according to the invention act via the activation of soluble guanylate cyclase (sGC) an increase in cGMP concentration and are therefore valuable agents for the therapy and prophylaxis of diseases that associated with a low or decreased cGMP level or by such or for their therapy or prophylaxis  The aim is to increase the existing cGMP level. Activation of the sGC through the compounds of formula I can be found, for example, in the below activity assay described.

Diseases and pathological conditions with a low cGMP level connected or where an increase in the cGMP level is sought and for their therapy and prophylaxis compounds of the formula I used For example, cardiovascular diseases such as endothelial Dysfunction, diastolic dysfunction, arteriosclerosis, high blood pressure, stable and unstable angina, thrombosis, restenosis, myocardial infarction, strokes, Heart failure or pulmonary hypertension, or, for example, erectile dysfunction, Bronchial asthma, chronic renal insufficiency and diabetes. Compounds of Formula I can also be used in the therapy of Liver cirrhosis as well as to improve a limited learning ability or Memory.

The compounds of the formula I and their physiologically tolerable salts can thus be used on the animal, preferably on the mammal, and in particular on humans, as medicines on their own, in mixtures with one another or in the form of pharmaceutical preparations. The present invention therefore also provides the compounds of the formula I and their physiologically tolerated salts for use as medicaments, their use for normalizing a disturbed cGMP household and, in particular, their use in the therapy and prophylaxis of the above-mentioned clinical pictures, and their use for the preparation of medication for it. Furthermore, the present invention relates to pharmaceutical preparations containing an effective dose of at least one compound of formula I and / or a physiologically acceptable salt thereof as an active ingredient in addition to conventional pharmaceutically acceptable excipients and / or additives. The present invention also provides the already known as such compound of formula I in which at the same time the ring A ² , which comprises the carbon atoms which carry the groups C (= X) -NH- and NH-SO ₂ R ² , for a benzene ring which is substituted in the positions 3 and 5 by chlorine, R ^{2 is} methyl, X is oxygen and R ^{1 is} -S (O) _n -A ¹ - for a 2- (4-chlorophenylmercapto) -5 - Chlorphenylrest, and their physiologically acceptable salts as activators of soluble guanylate cyclase. All the above and subsequent statements on the pharmacological action and the use of the compounds of the formula I apply correspondingly to this compound. The invention therefore also provides, for example, this compound and its physiologically tolerable salts for use as pharmaceuticals, pharmaceutical preparations which are an effective dose of this compound and / or a physiologically acceptable salt thereof as an active ingredient in addition to conventional pharmaceutically acceptable excipients and / or additives, and the use of this compound and / or its physiologically acceptable salts in the therapy or prophylaxis of the above-mentioned diseases and the use for the preparation of medicaments for this.

The medicaments according to the invention can be administered orally, for example in the form of pills, Tablets, coated tablets, dragees, granules, hard and soft gelatine capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or Suspensions, or rectally, for example in the form of suppositories administered become. The administration can also be parenteral, for example subcutaneously, intramuscularly or intravenously in the form of injection solutions or Infusion solutions. Other possible forms of application are for Example, the percutaneous or topical application, for example in the form of ointments, Tinctures, sprays or transdermal therapeutic systems, or the inhalation application in the form of nasal sprays or aerosol mixtures, or for Example microcapsules, implants or rods. The preferred form of application depends for example, the disease to be treated and its strength.

The pharmaceutical preparations usually contain 0.5 to 90 Weight percent of the compounds of formula I and / or their physiological  compatible salts. The preparation of the pharmaceutical preparations can in in be done in a known manner. These are one or more compounds of Formula I and / or their physiologically acceptable salts together with one or several solid or liquid galenic carriers and / or excipients and, if desired, in combination with other active pharmaceutical ingredients therapeutic or prophylactic effect in a suitable Administration form or dosage form, which is then used as a drug in the Human medicine or veterinary medicine can be used.

For example, for the production of pills, tablets, dragees and Hard gelatin capsules may be lactose, starch, for example corn starch, or Starch derivatives, talc, stearic acid or its salts, etc. use. excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. As carriers for the preparation of solutions, for example injection solutions, or of Emulsions or syrups are, for example, water, physiological Saline, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, Glucose, mannitol, vegetable oils etc. The compounds of formula I and their physiologically acceptable salts can also be lyophilized and the obtained lyophilisates, for example for the preparation of injection preparations or Infusion preparations are used. As carriers for microcapsules, Implants or rods are, for example, copolymers of glycolic acid and lactic acid.

The pharmaceutical preparations can in addition to the active ingredients and carriers nor conventional additives contain, for example, fillers, blasting, binding, sliding, Wetting, stabilizing, emulsifying, dispersing, preserving, sweetening, coloring, Flavoring or flavoring, thickening, diluting, Buffer substances, also solvents or solubilizers or agents for Achieving a depot effect, salts for changing the osmotic pressure, Coating agents or antioxidants.  

The dosage of the active ingredient of the formula I to be administered and / or a Physiologically acceptable salts thereof depends on the individual case and is as usual to adapt to individual circumstances for optimum effect. So hangs depending on the nature and strength of the disease to be treated as well as gender, Age, weight and individual responsiveness of the person to be treated or animal, on the potency and duration of action of the compounds used, whether it is acute or chronic treatment or prophylaxis, or of whether, in addition to compounds of formula I, further active ingredients are administered. In general, a daily dose of about 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, in particular 0.3 to 5 mg / kg (in each case mg per kg of body weight) Administration to an approximately 75 kg adult to achieve the appropriate effect. The daily dose may be in a single dose be administered or, in particular in the application of larger quantities, in several, for example two, three or four individual doses. If necessary, depending on individual behavior, it may become necessary to deviate upwards or downwards from the given daily dose. Pharmaceutical preparations usually contain 0.2 to 500 mg, preferably 1 to 200 mg of active ingredient of the formula I and / or its physiologically tolerable Salts.

The compounds of the formula I activate the soluble guanylate cyclase, primarily by binding in the heme binding pocket of the enzyme. Based on these They can be except as active pharmaceutical ingredients in human medicine and property Veterinary medicine also as a scientific tool or as an aid to biochemical studies are used in which such Influencing guanylate cyclase is intended, as well as for diagnostic purposes, for example, in the in vitro diagnosis of cell or tissue samples. Furthermore, can the compounds of the formula I and their salts, as already mentioned above, as Intermediates for the preparation of other active pharmaceutical ingredients serve.  

The following examples illustrate the invention without limiting it.

Examples

1) 2- (4-Chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoic acid.

33.71 g (0.32 mol) of sodium carbonate were dissolved in 250 ml of water and heated to 60.degree heated. Into the solution was added 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxy benzoic acid added and to this solution in the period of 15 min 29.55 g (0.14 mol) of 4-chloro-benzenesulfonyl chloride added in portions. After cooling of the mixture was filtered off with suction, the residue in 1% Sodium bicarbonate solution, filtered and by addition of 1 N Hydrochloric acid like the product. 25.90 g (55%) of 2- (4-chloro) phenylsulfonylamino) -4,5-dimethoxy-benzoic acid of melting point 212-214 ° C.

In an analogous way were obtained:

2) 5-chloro-2- (4-chloro-phenylsulfonylamino) benzoic acid; M.p .: 210 ° C
3) 5-Chloro-2- (3,4-dichloro-phenylsulfonylamino) -benzoic acid
5) 2- (4-chloro-phenylsulfonylamino) -cyclopentanecarboxylic acid; M.p .: 147 ° C 3
6) 2- (4-chloro-phenylsulfonylamino) -5-methyl-benzoic acid; M.p .: 201 ° C
7) 3- (4-chloro-phenylsulfonylamino) -thiophene-2-carboxylic acid; M.p .: 180 ° C
8) 3- (4-chloro-phenylsulfonylamino) -pyrazole-4-carboxylic acid; oil
9) 2- (4-chloro-phenylsulfonylamino) -nicotinic acid; M .: Zers. <360 ° C
10) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoic acid chloride

25.90 g (0.07 mol) of 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoic acid were slurried in 75 ml of toluene, 17.30 g (0.08 mol) of phosphorus pentachloride added and the mixture was stirred at 40-45 ° C for 2.5 h. Subsequently was Concentrated in vacuo to half the volume, the precipitated product filtered off with suction and washed with a little toluene. 25.30 g (93%) of 2- (4-chloro) phenylsulfonylamino) -4,5-dimethoxy-benzoic acid chloride of melting point 175-177 ° C.

In an analogous way were obtained:

11) 5-chloro-2- (4-chloro-phenylsulfonylamino) -benzoic acid chloride; Mp .: 127 ° C.
12) 5-chloro-2- (3,4-dichloro-phenylsulfonylamino) -benzoic acid chloride; M.p .: 117 ° C
13) 2- (4-chloro-phenylsulfonylamino) -cyclopentanecarboxylic acid chloride; M.p .: 107 ° C
14) 2- (4-chloro-phenylsulfonylamino) -5-methyl-benzoic acid chloride; M.p .: 114 ° C
15) 3- (4-chloro-phenylsulfonylamino) -thiophene-2-carboxylic acid chloride; M .: 122 ° C
16) 3- (4-chloro-phenylsulfonylamino) -pyrazole-4-carboxylic acid chloride; M.p .: 260 ° C (decomp.)
17) 2- (4-chloro-phenylsulfonylamino) -nicotinic acid chloride
18) 4 - ((2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoyl) -amino) -benzenesulfonic acid fluoride

10.00 g (25.6 mmol) of 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy Benzoic acid chloride was slurried in 300 ml of toluene, 4.49 g (25.6 mmol) 4- Sulfanilsäurefluorid added and the mixture heated for 4 h under reflux. To After cooling, the precipitate was filtered off with suction and washed with toluene washed. 11.71 g (87%) of the title compound of melting point were obtained 216-219 ° C.

In an analogous way were obtained:

19) 4 - ((5-chloro-2- (4-chloro-phenylsulfonylamino) -benzoyl) -amino) -benzenesulfonic acid fluoride; Mp .: 242 ° C
20) N- (4-aminosulfonyl-phenyl) -5-chloro-2- (4-chloro-phenylsulfonylamino) -benzamide; M.p .: 260 ° C
21) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N - ((4- (4-nitro-phenyl) -mercapto) -phenyl) -benzamide; Mp .: 255 ° C
22) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (phenylmercapto) -phenyl) -benzamide; M .: 169 ° C
23) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-methylmercapto-phenyl) -benzamide; M .: 220 ° C
24) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-methyl-benzothiazol-5-yl) -benzamide; M.p .: 251 ° C
25) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (3-diethylamino-2-hydroxy-propyl-mercapto) -phenyl) -benzamide; M.p .: 102 ° C
26) 4 - ((5-chloro-2- (3,4-dichloro-phenylsulfonylamino) -benzoyl) -amino) -benzenesulfonic acid fluoride; Mp .: 232 ° C
27) 4- (2- (4-chloro-phenylsulfonylamino) -cyclopentylcarbonylamino) -benzenesulfonic acid fluoride; M.p .: 211 ° C
28) 4 - ((2- (4-chloro-phenylsulfonylamino) -5-methylbenzoyl) -amino) -benzenesulfonic acid fluoride; M .: 224 ° C
29) 4 - ((3- (4-chloro-phenylsulfonylamino) -thiophene-2-carbonyl) -amino) -benzenesulfonic acid fluoride; Mp .: 255 ° C
30) 5-Chloro-2- (4-chloro-phenylsulphonylamino) -N- (4-mercapto-phenyl) -benzamide; Mp .: 202 ° C
31) 4 - ((3- (4-chloro-phenylsulfonylamino) -pyrazole-4-carbonyl) -amino) -benzenesulfonic acid fluoride; M.p .: 251 ° C
32) 3 - ((5-chloro-2- (4-chloro-phenylsulfonylamino) -benzoyl) -amino) -benzenesulfonic acid fluoride; M .: 224 ° C
33) 4- (2- (4-chloro-phenylsulfonylamino) -pyridine-3-carbonyl) -amino) -benzenesulfonic acid fluoride; M .: 263-265 ° C
34) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-methyl-5- (thiomorpholine-4-sulfonyl) -thiazol-2-yl) -benzamide; M.p .: 265-267 ° C
35) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-methylmercapto-phenyl) -benzamide
36) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (3-methylmercapto-phenyl) -benzamide
37) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (5-methyl-isoxazol-3-ylsulfamoyl) -phenyl) -benzamide
38) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (4-nitro-phenylsulfonyl) -phenyl) -benzamide
39) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (5-ethylsulfonyl-2-hydroxy-phenyl) -benzamide
40) N- (3-butylsulfamoyl-phenyl) -5-chloro-2- (4-chloro-phenylsulfonylamino) -benzamide
41) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-nitro-5-propylmercapto-phenyl) -benzamide
42) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-thiocyanato-phenyl) -benzamide
43) N- (4-acetylsulfamoyl-phenyl) -5-chloro-2- (4-chloro-phenylsulfonylamino) -benzamide
44) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-phenylmercapto-phenyl) -benzamide
45) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-chloro-5- (2-cyano-ethylsulfamoyl) -phenyl) -benzamide
46) N- (5-butylsulfamoyl-2-methoxy-phenyl) -5-chloro-2- (4-chloro-phenylsulfonylamino) -benzamide
47) N- (4-benzoylsulfamoyl-phenyl) -5-chloro-2- (4-chloro-phenylsulfonylamino) -benzamide
48) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-chloro-4-methylsulfonyl-phenyl) -benzamide
49) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (hexadecylsulfonyl) -phenyl) -benzamide
50) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (butylaminocarbonylaminosulfonyl) -phenyl) -benzamide
51) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-sulfamoyl-phenyl) -benzamide
52) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (2-methylmercapto-5-trifluoromethylphenyl) -benzamide
53) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (3-methylsulfonyl-phenyl) -benzamide
54) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (3- (2-hydroxy-ethylsulfonyl) -phenyl) -benzamide
55) (4- (5-chloro-2- (4-chloro-phenylsulfonylamino) -benzoylamino) -phenylmercapto) -acetic acid
56) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (3,4-dimethyl-isoxazol-5-ylsulfamoyl) -phenyl) -benzamide
57) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (thiazol-2-ylsulfamoyl) -phenyl) -benzamide
58) 5-chloro-2- (3,4-dichloro-phenylsulfonylamino) -N- (4-ethylmercapto-phenyl) -benzamide; M.p .: 171 ° C
59) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide

500 mg (0.95 mmol) 4 - ((2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoyl) - amino) -benzenesulfonic acid fluoride were dissolved in 1 ml of thiomorpholine and allowed to stand for 30 minutes Heated to 90 ° C. For workup was poured onto 50 ml of ice / 1N hydrochloric acid, the Suction filtered off, in a vacuum oven over phosphorus pentoxide dried and recrystallized from hexane / ethyl acetate. 378 mg (65%) of the Title compound of melting point 241 ° C.

By analogous reactions were obtained:

60) 2- (4-chloro-phenylsulfonylamino) -N- (4- (2,6-dimethyl-morpholine-4-sulfonyl) -phenyl) -nicotinamide; Mp .: 256-258 ° C
61) N- (4- (4-carbamoyl-piperidine-1-sulfonyl) -phenyl) -2- (4-chloro-phenylsulfonylamino) -nicotinamide; M.p .: 273-276 ° C
62) 2- (4-chloro-phenylsulfonylamino) -N- (4- (piperidine-1-sulfonyl) -phenyl) -nicotinamide; M .: 180-183 ° C
63) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 246 ° C
64) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (4-methylpiperazine-1-sulfonyl) -phenyl) -benzamide; M.p .: 219 ° C
65) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (2,6-dimethyl-morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 259 ° C
66) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (2,6-dimethyl-morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 251 ° C
67) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (4-hydroxy-piperidine-1-sulfonyl) -phenyl) -benzamide; Mp .: 255 ° C
68) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-sulfonyl) -phenyl) -benzamide; Mp .: 256 ° C
69) 5-chloro-2- (3,4-dichloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 253 ° C
70) 5-Chloro-2- (3,4-dichloro-phenylsulfonylamino) -N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 222 ° C
71) 5-chloro-2- (3,4-dichloro-phenylsulfonylamino) -N- (4- (4-methyl-piperazine-1-sulfonyl) -phenyl) -benzamide; Mp .: 246 ° C
72) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 172 ° C
73) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl) -phenyl) -benzamide; M .: 277 ° C
74) 2- (4-chloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -cyclopentanecarboxamide; M.p .: 180 ° C
75) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-diethylsulfamoyl-phenyl) -benzamide; M.p .: 226 ° C
76) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (piperidine-1-sulfonyl) -phenyl) -benzamide; Mp .: 240 ° C
77) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (2-methoxy-ethylsulfamoyl) -phenyl) -benzamide; M.p .: 209 ° C
78) 2- (4-chloro-phenylsulfonylamino) -5-methyl-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 203 ° C
79) 3- (4-chloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -thiophene-2-carboxamide; M .: 220 ° C
80) 3- (4-chloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -1H-pyrazole-4-carboxamide; oil
81) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (3- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 238 ° C
82) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (3- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 202 ° C
83) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (3- (4-methylpiperazine-1-sulfonyl) -phenyl) -benzamide; Mp .: 245 ° C
84) 3- (4-chloro-phenylsulfonylamino) -N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -thiophene-2-carboxamide; M .: 229 ° C
85) 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 228 ° C
86) 2- (4-chloro-phenylsulfonylamino) -5-methyl-N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 234 ° C
87) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (4-methylpiperazine-1-sulfonyl) -phenyl) -benzamide; M.p .: 172 ° C
88) 2- (4-chloro-phenylsulfonylamino) -N- (4- (2,6-dimethyl-morpholine-4-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; M.p .: 208 ° C
89) 2- (4-chloro-phenylsulfonylamino) -N- (4- (4-hydroxy-piperidine-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; Mp .: 244 ° C
90) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (piperidine-3-sulfonyl) -phenyl) -benzamide; Mp .: 258 ° C
91) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (thiazolidine-3-sulfonyl) -phenyl) -benzamide; M .: 261 ° C
92) 2- (4-chloro-phenylsulfonylamino) -N- (4- (2,5-dihydropyrrole-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; Mp .: 262 ° C
93) 2- (4-chloro-phenylsulfonylamino) -N- (4- (3,6-dihydro-2H-pyridine-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; Mp .: 252 ° C
94) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (2-methylpiperidine-1-sulfonyl) -phenyl) -benzamide; M .: 227 ° C
95) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (piperazine-1-sulfonyl) -phenyl) -benzamide; Mp .: 243 ° C
96) 4- (4- (2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxybenzoylamino) -phenylsulfonyl) -piperazine-1-carboxylic acid ethyl ester; Mp .: 245 ° C
97) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (4-methylpiperidine-1-sulfonyl) -phenyl) -benzamide; M.p .: 267 ° C
98) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (4-methyl- [1,4] diazepan-1-sulfonyl) -phenyl) -benzamide; M .: 274 ° C
99) 2- (4-chloro-phenylsulfonylamino) -N- (4- (4-ethylpiperazine-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; M.p .: 191 ° C
100) 2- (4-chloro-phenylsulfonylamino) -N- (4 - ((2-dimethylamino-ethyl) -ethyl-sulfamoyl) -phenyl) -4,5-dimethoxy-benzamide; M .: Zers. <119 ° C
101) 2- (4-chloro-phenylsulfonylamino) -N- (4- (5,6-dihydro-4H-pyrimidine-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; M .: Zers. <237 ° C
102) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (4- (pyrimidin-2-yl) -piperazine-1-sulfonyl) -phenyl) -benzamide; M .: Zers. <194 ° C
103) 2- (4-chloro-phenylsulfonylamino) -N- (4- (4- (4-chloro-phenyl) -piperazine-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; M .: Zers. <243 ° C
104) 2- (4-chloro-phenylsulfonylamino) -N- (4- (indan-1-ylsulfamoyl) -phenyl) -4,5-dimethoxy-benzamide; Mp .: 161 ° C
105) 2- (4-chloro-phenylsulfonylamino) -N- (4 - ((2- (1H-indol-3-yl) -ethyl) -methyl-sulfamoyl) -phenyl) -4,5-dimethoxy-benzamide; M.p .: 182 ° C
106) 1- (4 - ((2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoyl) -amino) -phenylsulfonyl) -piperidine-4-carboxylic acid amide; Mp .: 252 ° C
107) 2- (4-chloro-phenylsulfonylamino) -N- (4-cyclopropylsulfamoyl-phenyl) -4,5-dimethoxy-benzamide; Mp .: 222 ° C
108) 2- (4-chloro-phenylsulfonylamino) -N- (4- (3-hydroxy-pyrrolidine-1-sulfonyl) -phenyl) -4,5-dimethoxy-benzamide; M.p .: 272 ° C
109) N- (4- (allylcyclohexylsulfamoyl) -phenyl) -2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzamide; M.p .: 182 ° C
110) 1- (4 - ((2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-benzoyl) -amino) -phenylsulfonyl) -pyrrolidine-2-carboxylic acid; M.p .: 240 ° C (sintering)
111) 5-chloro-2-nitrobenzoyl chloride

100.00 g (0.50 mol) of 5-chloro-2-nitrobenzoic acid were dissolved in 72.20 g (0.61 mol) Slurried thionyl chloride and the mixture was heated under reflux for 2 h. The excess thionyl chloride was removed in vacuo. It remained 106.50 g (about 98%) of crude 5-chloro-2-nitrobenzoyl chloride (oil).

In an analogous way was obtained:

112) 5-methyl-2-nitrobenzoyl chloride; oil
113) 4- (5-chloro-2-nitro-benzoylamino) -benzenesulfonic acid fluoride

86.00 g (0.39 mol) of 5-chloro-2-nitrobenzoyl chloride were dissolved in 300 ml of toluene, a solution of 62.00 g (0.35 mol) Sulfanilsäurefluorid in 600 ml of toluene was added dropwise and the mixture heated at reflux for 4 h. It was then cooled, in Vacuum concentrated to half volume, cooled again and the failed Sucked down precipitate. 121.60 g (86%) of the title compound of Melting point 182-184 ° C.

In an analogous way were obtained:

114) 4- (5-methyl-2-nitro-benzoylamino) -benzenesulfonic acid fluoride; M.p .: 179 ° C
115) 5-Chloro-N- (4-ethylmercapto-phenyl) -2-nitro-benzamide
116) 5-Chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2-nitro-benzamide

120.00 g (0.33 mol) of 4- (5-chloro-2-nitro-benzoylamino) -benzenesulfonic acid fluoride, 29.10 g (0.33 mol) of morpholine and 33.85 g (0.33 mol) of triethylamine were dissolved in 1200 ml Toluene for 2 days at 60 ° C stirred. The precipitated solid was filtered off with suction and recrystallized from acetone / n-hexane. This gave 102.10 g (71%) of the title compound of melting point 243-245 ° C.

In an analogous way were obtained:

117) 5-chloro-2-nitro-N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 120 ° C
118) 5-methyl-N- (4- (morpholine-4-sulfonyl) -phenyl) -2-nitro-benzamide; Mp .: 249 ° C
119) N- (4- (morpholine-4-sulfonyl) -phenyl) -5- (morpholin-4-yl) -2-nitro-benzamide

20.00 g (0.56 mol) of 4- (5-chloro-2-nitro-benzoylamino) -benzenesulfonic acid fluoride were refluxed in 48.5 g (0.557 mol) of morpholine for 1 h. It was then cooled, poured onto ice / hydrochloric acid and filtered with suction. This gave 26.0 g (98%) of the title compound of melting point 252 ° C.

120) 2-Amino-5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide

11.10 g (26.1 mmol) of 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2-nitro-benzamide were dissolved in 440 ml of tetrahydrofuran / methanol (1: 1) and a solution of 27.23 g (156.4 mmol) of sodium dithionite in 330 ml of water was added dropwise. After 1 h Stirring at room temperature, the organic solvents were on Removed rotary evaporator, the precipitate sucked off and on Silica gel with methylene chloride / methanol (9: 1) chromatographed. 5.68 g were obtained (55%) of the title compound of melting point 229-231 ° C.

In an analogous way were obtained:

121) 2-Amino-5-chloro-N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 177 ° C
122) 2-amino-N- (4- (morpholine-4-sulfonyl) -phenyl) - (5-morpholin-4-yl) -benzamide; M.p .: 228 ° C
123) 2-amino-5-chloro-N- (4-ethylsulfonyl-phenyl) -benzamide; Mp .: 159-161 ° C
124) 5-Chloro-2- (5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl-amino) -N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzamide

250 mg (0.60 mmol) of 2-amino-5-chloro-N- (4- (thiomorpholine-4-sulfonyl) -phenyl) - benzamide were dissolved in 10 ml of dry pyridine and at 0 ° C a solution of 195 mg (0.85 mmol) of 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride in 5 ml Pyridine added dropwise. After 2 h was poured onto ice, the precipitated solid filtered off and chromatographed on silica gel with methylene chloride / methanol (98: 2). This gave 250 mg (69%) of the title compound of melting point 215-216 ° C.

In an analogous way were obtained:

125) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (4-methyl-phenylsulfonylamino) -benzamide; M.p .: 214 ° C
126) 5-Chloro-2- (3,4-dimethoxy-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 245 ° C
127) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (4-trifluoromethoxyphenylsulfonylamino) -benzamide; Mp .: 195 ° C
128) 2 - ((4-acetylamino-phenyl) sulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 198 ° C
129) 5-chloro-2- (5-chloro-thiophene-2-sulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 112 ° C
130) 5-Chloro-2- (5-chloro-1,3-dimethyl-pyrazole-4-sulfonyl-amino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 161 ° C
131) 5-chloro-2 - ((1-methyl-imidazole-4-sulfonyl) -amino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 141 ° C
132) 5-Chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (pyridine-3-sulfonylamino) -benzamide; Mp .: 222 ° C
133) 2- (4-Benzoyloxy-phenylsulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 245 ° C
134) 5-chloro-2- (ethylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 274-276 ° C
135) 2 - ((2-acetamido-4-methyl-thiazole-5-sulfonyl) -amino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 257 ° C
136) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (thiophene-2-sulfonylamino) -benzamide; Mp .: 216 ° C
137) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (4-trifluoromethyl-phenylsulfonylamino) -benzamide; M.p .: 264 ° C
138) 2- (4-Bromo-phenylsulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 232 ° C
139) 2- (3,5-bis-trifluoromethylphenylsulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 209 ° C
140) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (4-nitro-phenylsulfonylamino) -benzamide; Mp .: 239 ° C
141) 5-Chloro-2- (4-cyanophenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 238 ° C
142) 5-Chloro-2- (4-methylsulfonyl-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 181 ° C
143) 5-Chl 16319 00070 552 001000280000000200012000285911620800040 0002019903126 00004 16200or-2- (4-isopropyl-phenylsulfonyfamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M .: 105 ° C
144) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2 - ((2-phenyl-ethenyl) -sulfonylamino) -benzamide; mp .; 278 ° C
145) 5-Chloro-2- (4,5-dibromo-thiophene-2-sulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 232 ° C
146) 5-Chloro-2- (4-fluoro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 245 ° C
147) 5-Chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (5-phenylsulfonyl-thiophene-2-sulfonylamino) -benzamide; M .: 103 ° C
148) 5-Chloro-2- (3-chloro-4-methoxy-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M .: 274 ° C
149) 5-Chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (quinoline-8-sulfonylamino) -benzamide; Mp .: 262 ° C
150) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (2,4,6-trimethyl-phenylsulfonylamino) -benzamide; Mp .: 240 ° C
151) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (3-nitro-phenylsulfonylamino) -benzamide; M .: 220 ° C
152) 5-Chloro-2- (4-methoxy-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M .: 269 ° C
153) 5-chloro-2-methylsulfonylamino-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 248 ° C.
154) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2-phenylmethylsulfonylaminobenzamide; M.p .: 106 ° C
155) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (2,2,2-trifluoro-ethylsulfonylamino) -benzamide; M.p .: 208 ° C
156) 2- (butylsulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 102 ° C
157) 5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (3-trifluoromethyl-phenylsulfonylamino) -benzamide; M.p .: 212 ° C
158) 2- (4-bromo-2,5-dichloro-thiophene-3-sulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 267 ° C
159) 5-Chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (2-trifluoromethyl-phenylsulfonylamino) -benzamide; Mp .: 234 ° C
160) 5-Chloro-2- (3-chloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 206 ° C
161) 2- (4-bromo-2-methoxy-phenylsulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 260 ° C
162) 5-Chloro-2- (2,6-dichloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; Mp .: 244 ° C
163) 5-Chloro-2- (2-cyano-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M .: 200 ° C
164) 2- (4-butoxy-phenylsulfonylamino) -5-chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 225 ° C
165) 5-Chloro-2- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-sulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 120 ° C
166) 5-Chloro-2- (3-fluoro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 204 ° C
167) 2- (4-chloro-phenylsulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -5-morpholin-4-yl-benzamide; M.p .: 264 ° C
168) 5-chloro-N- (4-ethylsulfonyl-phenyl) -2- (4-methylphenylsulfonylamino) -benzamide; M .: 188-192 ° C
169) 5-Chloro-2- (5-chloro-thiophene-2-sulfonylamino) -N- (4-ethylsulfonyl-phenyl) -benzamide; M.p .: 195-197 ° C
170) 5-Chloro-2- (4-chloro-3-nitro-phenylsulfonylamino) -N- (4-ethylsulfonyl-phenyl) -benzamide; M.p .: 196-198 ° C
171) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-ethylsulfonyl-phenyl) -benzamide; M.p .: 180-185 ° C
172) 5-Chloro-2- (3,5-dimethyl-isoxazole-4-sulfonylamino) -N- (4-ethylsulfonyl-phenyl) -benzamide; Mp .: decomposition <249 ° C
173) 5-chloro-2-ethylsulfonylamino-N- (4-ethylsulfonyl-phenyl) -benzamide; M .: 103 ° C
174) 4-Chloro-N- (2- (1H-benzimidazol-2-yl) -4-chloro-phenyl) -benzenesulfonamide

1.00 g (2.7 mmol) of 5-chloro-2- (4-chloro-phenylsulfonylamino) -benzoic acid chloride and 296 mg (2.7 mmol) of o-phenylenediamine were refluxed in 150 ml of toluene for 1 h. A small amount of solid was filtered off with suction and the filtrate was concentrated. The residue was taken up in 50 ml of toluene, treated with 600 mg of thionyl chloride and again heated under reflux for 10 h. It was then cooled and the precipitated solid was filtered off with suction. 280 mg (25%) of the title compound of melting point 225-228 ° C. were obtained.

175) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (1,1-dioxo-thiomorpholine-4-sulfonyl) -phenyl) -benzamide

and

176) 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (1-oxo-thiomorpholine-4-) sulfonyl) -phenyl) -benzamide

500 mg (0.82 mmol) of 2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (Thiomorpholin-4-sulfonyl) phenyl) benzamide were presented in 50 m) of acetone and cooled to 0 ° C. A solution of 371 mg (1.23 mmol) of 57% m-chloro perbenzoic acid in 20 ml of acetone was added and the mixture was added overnight Room temperature stirred. For workup was added to water / ice and aspirated. The two products present as a mixture were Chromatography on silica gel with methylene chloride / methanol (97: 3) separated.

In an analogous way were obtained:

177) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (1,1-dioxo-thiomorpholine-4-sulfonyl) -phenyl) -benzamide; M.p .: 182 ° C
178) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (1-oxo-thiomorpholine-4-sulfonyl) -phenyl) -benzamide; M .: 233 ° C
179) 5-chloro-2- (3,4-dichloro-phenylsulfonylamino) -N- (4-ethylsulfonyl-phenyl) -benzamide; Mp .: 240 ° C
180) 5-chloro-N- (4-ethylsulfonyl-phenyl) -2-nitro-benzamide
181) 4-Chloro-N- (4-chloro-2- (6- (morpholine-4-sulfonyl) -1H-benzimidazol-2-yl) -phenyl) -benzenesulfonamide

200 mg (0.5 mmol) of 4-chloro-N- (2- (1H-benzimidazol-2-yl) -4-chlorophenyl) -benzenesulfonamide were added at 0 ° C. to 1 ml of chlorosulfonic acid and heated to 60 ° C. for 30 minutes heated. It was then poured onto water / ice, filtered off with suction, the solid was dried and added at 0 ° C to 1 ml of morpholine. After stirring for 1 h at room temperature, it was poured onto ice / hydrochloric acid, extracted with ethyl acetate, concentrated and the residue remaining on silica gel was chromatographed with hexane / ethyl acetate (1: 1). This gave 20 mg (7%) of the title compound of melting point 225-228 ° C.
¹ H-NMR (D ₆ -DMSO): δ (ppm) = 2.9 (m, 4H, morpholine-H), 3.6 (m, 4H, morpholine-H), 7.5 (dd, 4H, phenylene-H), 7.4 -8.2 (m, 6H, benzo-H, phenyl-H)

182) 5-Chloro-N- (4- (morpholine-4-sulfonyl) -phenyl) -2- (2- (pyrrolidin-1-yl) - ethylsulfonylamino) -benzamide

The compound was prepared using 2-chloroethylsulfonyl chloride. The intermediate isolated 1- (2- (4-chloro-2- (4- (morpholine-4-sulfonyl) -phenylcarbamoyl) -phenylsulfamoyl) -ethyl) -pyridinium chloride was reacted with pyrrolidine to give the title compound.
¹ H-NMR (D ₆ -DMSO): δ (ppm) = 1.8 (m, 4H, pyrrolidine-H), 2.65 (m, 4H, pyrrolidine-H), 3.0 (m, 4H, morpholine-H), 3.1 (t, 2H, ethylene-H), 3.35 (t, 2H, ethylene-H), 3.75 (m, 4H, morpholine-H), 7.50 (dd, 1H, H-4), 7.7 (d, 1H, H -3), 7.75 (dd, 1H, H-6), 7.85 ("dd", 4H, phenylene-H)

183) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-isopropylmercapto-phenyl) - benzamide

1.00 g (2.21 mmol) of 5-chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-mercapto-phenyl) - Benzamide was dissolved in 25 ml of dimethylformamide and 0.25 g (2.21 mmol) of potassium Tert-butylate was added. The mixture was stirred at room temperature for 15 minutes stirred, then 0.27 g (2.21 mmol) of isopropyl bromide were added dropwise and it was 8 h stirred at 60 ° C. For workup was poured onto water, with ethyl acetate extracted, the combined extracts were evaporated and the residue on silica gel with hexane: ethyl acetate (3: 1) chromatographed. 420 mg (39%) of the Title compound of melting point 168-169 ° C.

In an analogous way were obtained:

184) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-cyanomethylmercapto-phenyl) -benzamide; Mp .: 104 ° C
185) (4 - ((5-chloro-2- (4-chloro-phenylsulfonylamino) -benzoyl) -amino) -phenylmercapto) -acetic acid ethyl ester; Mp .: 133 ° C
186) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (2- (morpholin-4-yl) -ethylmercapto) -phenyl) -benzamide; M .: 95 ° C
187) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (2- (2-methoxy-ethoxy) -ethyl-mercapto) -phenyl) -benzamide; oil
188) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4- (prop-2-ynyl) -mercapto-phenyl) -benzamide; Mp .: 185 ° C
189) 5-Chloro-2- (4-chloro-phenylsulfonylamino) -N- (4-isopropylmercapto-phenyl) -benzamide; M .: 169 ° C
190) 5-Chloro-2- (5-chloro-thiophene-2-sulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide sodium salt

A mixture of 0.48 g of finely powdered sodium hydroxide and 7 g of 5-chloro-2- (5-chloro-thiophene-2-sulfonylamino) -N- (4- (morpholine-4-sulfonyl) -phenyl) -benzamide in 250 ml of ethanol was dissolved by brief heating. The mixture was then evaporated in vacuo, treated with 50 ml of water and again evaporated to dryness in vacuo. This process was repeated twice. The resulting product was dried at 50 ° C in vacuo.
M.p .: 343 ° C (Zers.)

Pharmacological investigations 1) Activation of soluble guanylate cyclase

The activation of soluble guanylate cyclase (sGC), which is the transformation of Guanosine triphosphate (GTP) in cyclic guanosine monophosphate (cGMP) and Pyrophosphate catalyzed by the compounds of the invention was with Using an enzyme immunoassay (EIA) Amersham quantified. To The test substances were first incubated with sGC in microtiter plates and then the amount of cGMP formed is determined.  

The sGC used had been isolated from bovine lung (see Methods in Enzymology, Volume 195, p. 377). The test solutions (100 μl per well) contained 50 mM triethanolamine (TEA) buffer (pH 7.5), 3 mM MgCl ₂ , 3 mM reduced glutathione (GSH), 0.1 mM GTP, 1 mM 3-isobutyl-1-methylxanthine (IBMX ), suitably diluted enzyme solution and the test substance or solvent in the control experiments. The test substances were dissolved in dimethyl sulphoxide (DMSO) and the solution was diluted with DMSO / water so that the final concentration c of test substance in the test batch was 50 μM. The DMSO concentration in the assay was 5% (v / v). The reaction was started by adding the sGC. The reaction mixture was incubated for 15 to 20 minutes at 37 ° C and then stopped by ice-cooling and addition of the stop reagent (50 mM EDTA, pH 8.0). An aliquot of 50 μl was withdrawn and used to determine cGMP content with the acetylation protocol of the Amersham cGMP EIA kit. The absorbance of the samples was measured at 450 nm (reference wavelength 620 nm) in a microtiter plate reader. The cGMP concentration was determined by a calibration curve obtained under the same experimental conditions. The activation of sGC by a test substance is given as n-fold stimulation of the basal enzyme activity found in the control experiments (with solvent instead of test substance) (calculated according to the formula

n-fold stimulation = [cGMP] _{test substance} / [cGMP] _control ).

The following results were obtained:

Compound of Example No. n-fold stimulation at c = 50 μM 23 14.7 59 34.8 63 33.9 64 23.9 65 24.6 66 33 67 29.6 68 12.1 69 28.3 70 25.1 71 13.4 72 27 73 16.5 75 5.1 76 10.6 77 5.9 79 15.4 84 23.7 86 32.9 87 12.5 88 24.4 89 11.6 124 31.2 129 8.6 130 35.3 132 9.9 134 7.2 136 24.2 137 4.6 139 21.9 145 8th 146 10.2 148 15.5 150 15.3 151 19.9 155 7.8 156 7.8 157 4.6 175 21.1 176 13.9

2) Relaxation of the rat aorta

For this test, 16-month-old male spontaneously hypertensive rats were killed by a blow to the neck. The abdomen and thorax were opened by a middle sternotomy. Subsequently, the descending aorta was removed, freed of connective tissue and divided into 8 rings of about 4 mm in length. Into the lumen of 4 of the 8 rings, a tweezer tip was inserted. The endothelium was removed by careful rolling movements of the rings over the forceps tip. All 8 aortic rings (4 with endothelium and 4 without endothelium) were then suspended in an organ bath (Schuler-Organbad, Hugo Sachs Elektronik) with a constant temperature of 37 ° C for the isometric measurement of contractile tone. The rings were incubated for 30 minutes at a resting tension of 1 g in carbonated (95% O ₂ , 5% CO ₂ ) Krebs-Henseleit solution (composition: Na ⁺ 144.0 mM, K ⁺ 5.9 mM, Cl ^- 126.9 mM, Ca ²⁺ 1.6 mM, Mg ²⁺ 1.2 mM, H ₂ PO ₄ ^- 1.2 mM, SO ₄ ^2- 1.2 mM, HCO ₃ ^- 25.0 mM, D-glucose 11.1 mM), pH 7.4. In addition, 1 μmol / L indomethacin was added to the Krebs-Henseleit solution to inhibit prostaglandin biosynthesis. Subsequently, the rings were precontracted by the addition of phenylephrine (concentration in the solution: 1 μM) and the endothelium-dependent relaxation or the functional loss of the endothelium was tested by administration of acetylcholine (concentration in the solution: 1 μM). Following a 30-minute wash period, the rings were then pre-contracted again by the addition of phenylephrine (1 μM) and their relaxant activity determined by administration of cumulative doses of the test substances of the formula I. The evaluation of the data was carried out according to standard methods. Indicated is the concentration IC ₅₀ , which inhibits the contraction by 50% (50% relaxation).

The following results were obtained:

3) Hemodynamic effect in the pig

Three pigs (Deutsche Landrace) were anesthetized (ketamine 20 mg / kg i.m., Methomidate 8 mg / kg i. p., xylazine 2.5 mg / kg i. m. and pentobarbital 25 mg / kg i. v. when Bolus plus 0.16 mg / kg per minute). The trachea was intubated and the animals were artificially ventilated with air. Oxygen was added to the Keep blood gas values in the normal range. A catheter was placed in the right A.  Femoral measurement of blood pressure (BP; BD (s) = systolic blood pressure, BD (d) = diastolic blood pressure) using a Statham 23-Db pressure transducer inserted. Left ventricular pressure (LVD), the left ventricular enddiastolic pressure (LVEDD), contractility (dP / dt) and heart rate (HR) were using a Millar PC 350 catheter "tipmanometer", which in the left Ventricle was inserted, measured. After a stabilization period of Hemodynamic parameters of 30 minutes, the test substance in the administered dose by means of a catheter in the exposed duodenum. The evaluation of the measured data was carried out according to standard methods. Be given the mean values with the standard deviations (M ± SEM) of the initial values and the maximum changes of the individual parameters (= maximum effects).

The following results were obtained:

Compound of Example 88 (Dosage 10 mg / kg id)

Claims (12)

1. Compounds of the formula I,
in the
A ^{1 is} a bivalent radical selected from the group consisting of phenylene, naphthylene and heteroarylene, all of which are substituted by one or more identical or different substituents selected from halogen, (C ₁ -C ₅ ) -alkyl, phenyl, tolyl, CF ₃ , NO ₂ , OH, -O- (C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₂ ) -alkylenedioxy , NH ₂ , NH- (C ₁ -C ₃ ) -alkyl, N ((C ₁ -C ₃ ) -alkyl) ₂ , NH-CHO, NH-CO- (C ₁ -C ₅ ) -alkyl, CN, CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -C ₅ ) Alkyl, heterocyclyl, CHO, CO- (C ₁ -C ₅ ) -alkyl, S (O) _n - (C ₁ -C ₄ ) -alkyl, S (O) _n -phenyl and S (O) _n -tolyl may be substituted;
the ring A ² , which comprises the carbon atoms carrying the groups C (= X) -NH- and NH-SO ₂ R ² , for a benzene ring, a naphthalene ring, a saturated or partially unsaturated 3-membered to 7-membered carbocycle , a saturated, partially unsaturated or aromatic monocyclic 5-membered to 7-membered heterocycle containing one or more ring heteroatoms from the series N, O and S, or a saturated, partially unsaturated or aromatic bicyclic 8-membered to 10- a membered heterocycle containing one or more ring heteroatoms from the series N, O and S;
R ^{1 is} aryl, heterocyclyl or (C ₁ -C ₁₈ ) -alkyl, which may be substituted by one or more identical ones of the different radicals R ⁴ , or when n in the group R ¹ -S (O) _n - for the number 2 also stands for NR ⁵ R ⁶ , or if n in the group R ¹ -S (O) _n - stands for the number 0, then also stands for CN;
R ^{2 is} aryl, heterocyclyl, NR ⁵ R ⁶ or (C ₁ -C ₁₀ ) -alkyl which may be substituted by one or more identical or different radicals R ⁴ ;
R ^{3 represents} one or more identical or different substituents from the group consisting of hydrogen, halogen, CF ₃ , OH, -O- (C ₁ -C ₇ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O-, (C ₁ -C ₇ ) -alkyl, -O-aryl, (C ₁ -C ₂ ) -alkylenedioxy, NO ₂ , CN, NR ⁷ R ⁸ , CO-NR ⁷ R ⁸ , CO-OH, CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl, S (O) _n - (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkyl which is substituted by one or more identical or different radicals R ⁴ can be, stands;
R ^{4 is} fluorine, OH, -O- (C ₁ -C ₁₀ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₇ ) -alkyl, -O-aryl, CN, NR ⁷ R ⁸ , CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl or oxo;
R ^{5 is} hydrogen, (C ₁ -C ₁₀ ) -alkyl which may be substituted by one or more identical or different substituents R ⁴ and / or by aryl, aryl, heterocyclyl, CO-NR ⁷ R ⁸ , CO-aryl or CO- (C ₁ -C ₁₀ ) -alkyl, wherein the alkyl radical may be substituted by one or more identical or different radicals R ⁴ ;
R ⁶ independently of R ^{5 has} one of the meanings given for R ⁵ , or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 5-membered to 8-membered saturated or partially unsaturated ring which in addition to in which the nitrogen atom bearing the groups R ⁵ and R ⁶ may contain one or more further ring heteroatoms from the series N, O and S and which may be substituted by one or more identical or different substituents from the series fluorine, (C ₁ -C ₅ ) Alkyl, (C ₁ -C ₃ ) -hydroxyalkyl, - (C ₁ -C ₃ ) -alkyl-O- (C ₁ -C ₄ ) -alkyl, aryl, CF ₃ , OH, -O- (C ₁ -) C ₇ ) -alkyl, -O-aryl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₇ ) -alkyl, (C ₂ -C ₃ ) -alkylenedioxy, NR ⁷ R ⁸ , CN, CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -) C ₅ ) -alkyl, CHO, CO- (C ₁ -C ₅ ) -alkyl, S (O) _n - (C ₁ -C ₄ ) -alkyl, S (O) _n -NH ₂ , S (O) _n -NH- (C ₁ -C ₃ ) -alkyl, S (O) _n -N ((C ₁ -C ₃ ) -alkyl) ₂ , oxo, - (CH ₂ ) _m -NH ₂ , - (CH ₂ ) _{m is} -NH- (C ₁ -C ₄ ) -alkyl and - (C H ₂ ) _m -N ((C ₁ -C ₄ ) -alkyl) ₂ may be substituted, wherein in the substituent - (CH ₂ ) _m -N ((C ₁ -C ₄ ) alkyl) _2, the two alkyl groups a single bond can be linked and then form together with the nitrogen atom carrying them a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms additionally also an oxygen atom, a sulfur atom or a group NR ^{5 can} contain as a ring member;
R ^{7 is} hydrogen or (C ₁ -C ₇ ) -alkyl which is substituted by one or more identical or different substituents from the group OH, -O- (C ₁ -C ₅ ) -alkyl, NH ₂ , -NH- (C ₁ -C ₄ ) - alkyl and -N ((C ₁ -C ₄ ) -alkyl) ₂ may be substituted, wherein in the substituent N ((C ₁ -C ₄ ) alkyl) _2, the two alkyl groups by a Single bond can be linked and then form together with the nitrogen atom carrying them a 5-membered to 7-membered ring, which in addition to the nitrogen atom and the carbon atoms may additionally contain an oxygen atom, a sulfur atom or a group NR ⁵ as a ring member;
R ⁸ independently of R ^{7 has} one of the meanings of R ⁷ or is CO- (C ₁ -C ₄ ) -alkyl;
Aryl is phenyl, naphthyl or heteroaryl, all of which are substituted by one or more identical or different substituents selected from halogen, (C ₁ -C ₅ ) -alkyl, phenyl, tolyl, CF ₃ , NO ₂ , OH, -O- ( C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₂ ) -alkylenedioxy, NH ₂ , -NH- (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , NH-CHO, -NH-CO- (C ₁ -C ₅ ) -alkyl, CN, CO-NH ₂ , CO-NH- (C ₁ -C ₃ ) -alkyl, CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , CO-OH, CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl , CHO, CO- (C ₁ -C ₅₎ alkyl, S (O) _n - _n tolyl may be substituted phenyl and S (O) - (C ₁ -C ₄₎ alkyl, S (O) _n;
Heteroaryl and heteroarylene is the radical of a monocyclic 5-membered or 6-membered aromatic heterocycle or a bicyclic 8-membered to 10-membered aromatic heterocycle, each containing one or more ring heteroatoms from the series N, O and S;
Heterocyclyl is the radical of a monocyclic or polycyclic, 5-membered to 11-membered saturated or partially unsaturated heterocycle containing one or more ring heteroatoms from the series N, O and S, and by one or more identical or different substituents fluorine, (C ₁ -C ₅ ) -alkyl, OH, -O- (C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -Alkyl, NH ₂ , -NH- (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , CN, CO-NH ₂ , CO-NH- (C ₁ -) C ₃ ) alkyl, CO-N ((C ₁ -C ₃ ) alkyl) ₂ , CO-OH and CO-O- (C ₁ -C ₅ ) alkyl may be substituted;
n is 0, 1 or 2;
m is 2, 3 or 4;
X is O or NH, or X represents a nitrogen atom that is bonded via a single bond to a ring carbon atom in the group A ^1, where the group -NH-C (= X) - adjacent carbon atom carrying in A ¹ directly is such that the group -NH-C (= X) - together with the carbon atoms carrying them in A ¹ forms a fused imidazole ring;
in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts;
wherein the compound of the formula I is excluded, in which at the same time the ring A ² , which comprises the carbon atoms carrying the groups C (= X) -NH- and NH-SO ₂ R ² , is a benzene ring which in the Positions 3 and 5 is substituted by chlorine, R ^{2 is} methyl, X is oxygen and R ¹ -S (O) _n -A ¹ - is a 2- (4-chlorophenylmercapto) -5-chlorophenyl radical. 2. Compounds of the formula I according to Claim 1, in which A ^{1 is} phenylene or a 5-membered or 6-membered heteroaryl radical, where these radicals may be unsubstituted or substituted, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. 3. Compounds of formula I according to claim 1 and / or 2, wherein A ^{2 forms} together with the two atoms carrying the group R ² -SO ₂ -NH and the group C (= X) -NH an aromatic ring which is unsubstituted or may be substituted, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. 4. Compounds of the formula I according to one or more of claims 1 to 3, wherein X is oxygen, in all its stereoisomeric forms and mixtures of which in all proportions, and their physiologically acceptable salts. 5. Compounds of the formula I according to one or more of claims 1 to 4, wherein R ^{2 is} unsubstituted or substituted aryl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. 6. Compounds of formula I according to one or more of claims 1 to 5, wherein R ^{1 is} (C ₁ -C ₇ ) alkyl, aryl or NR ⁵ R ⁶ , which radicals may be unsubstituted or substituted, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. 7. Compounds of formula I according to one or more of claims 1 to 6, wherein R ^{1 is} NR ⁵ R ⁶ and R ⁵ and R ^{6 are} independently hydrogen, (C ₁ -C ₉ ) alkyl, - (C ₁ -C ₃ ) -alkyl-O- (C ₁ -C ₄ ) -alkyl or 5-membered or 6-membered aryl or form together with the nitrogen atom carrying R ⁵ and R ⁶ a 5-membered to 7-membered heterocycle, which may contain, in addition to the nitrogen atom carrying the groups R ⁵ and R ^6, yet another ring heteroatom from the series N, O and S and which may be replaced by one or more identical or different radicals from the series (C ₁ -C ₃ ) - Alkyl, (C ₁ -C ₃ ) -hydroxyalkyl, 5-membered or 6-membered aryl, carbamoyl, hydroxy and oxo may be substituted, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. 8. A process for the preparation of compounds of the formula I according to one or more of claims 1 to 7, characterized in that a cyclic aminocarboxylic acid of the formula II is converted into a sulfonylaminocarboxylic acid of the formula III and this is converted into a compound of formula I,
or in that a cyclic nitrocarboxylic acid of the formula IX is converted into a compound of the formula XII and this is converted into a compound of the formula I by reduction of the nitro group to the amino group and sulfonylation of the amino group,
where in the formulas I, II, III, IX and XII the groups A ¹ , A ² , R ¹ , R ² , R ³ and X and n have the meanings given in claims 1 to 7 or radicals or functional groups also in Form precursors or in protected form. 9. Compounds of the formula I according to one or more of claims 1 to 7 and / or their physiologically acceptable salts for use as medicaments. 10. Pharmaceutical preparation, characterized in that it contains one or more Compounds of the formula I according to one or more of Claims 1 to 7 and / or their physiologically tolerated salts in addition to pharmaceutically contains flawless excipients and / or additives. 11. Compounds of the formula I according to one or more of claims 1 to 7 and / or their physiologically acceptable salts for use as activators of soluble guanylate cyclase.   12. Compounds of the formula I according to one or more of claims 1 to 7 and / or their physiologically acceptable salts for use in therapy or prophylaxis of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, arteriosclerosis, hypertension, angina pectoris, Thrombosis, restenosis, myocardial infarction, strokes, heart failure, Pulmonary hypertension, erectile dysfunction, bronchial asthma, chronic Renal insufficiency, diabetes or cirrhosis or to improve one limited learning ability or memory performance.