NO315556B1 - Chromogens, their preparation and use, as well as medications containing the compounds - Google Patents

Abstract

Sulfonamide-substituted chromanes of formula (I) and formula (Ia). wherein R (A), R (B), R (C) and R (1) to R (8) have various meanings, are excellently suitable for the manufacture of a drug for blocking the K channel opened by cyclic adenosine monophosphate (cAMP), for the manufacture of a medicament for inhibiting gastric acid secretion; For the treatment of ulcers in the stomach and intestinal area and in particular the duodenum, for the treatment of reflux esophagitis, for the treatment of diarrheal diseases, for the therapy and prevention of all types of arrhythmias, including ventricular and supraventricular arrhythmias and for the control of reentry arrhythmias and sudden cardiac arrest as a result of ventricular fibrillation.

Description

The present invention relates to chromans and the preparation of these compounds.

The invention further relates to their use for manufacturing

of drugs and the invention also relates to the drugs obtained.

More specifically, the present invention relates to chromanes which are characterized by the general formula (I):

there

Kl and R2

independently means C 1-3 alkyl; or Ri and R2

together means Cg-^-<a>alkylene;

R3 means R9-Cn-H2nI>TRllJiir1

E9 means hydrogen;

n means 0, 1, 2, 3 or 4;

m means 0 or 1;

R 1 means hydrogen or C 1-6 alkyl;

R 4 means R 2 -crH 2 r ;

<*>12

means hydrogen, C3-cycloalkyl, piperidyl, N-morpholino, N-methylpiperazino, CF3, pyridyl or phenyl,

which is unsubstituted or may be substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy;

r means 1, 2, 3, 4, 5, 6, 7, 8;

whereby the CHg group in the group CrH2r may be replaced by -0-, -CO-0-, -S(0)q- or -NR10-;

q means 0, 1 or 2; and

R-LQ means hydrogen, methyl or ethyl;

R5- R6> R7°S R8

independently means hydrogen, F, Cl, Br, I, C1_4-alkyl, -CN, -CF3, _N02, -C0NR13<R>14, <->C00R15, R^-^s<H>2s~<Y >>>

R^3 and <R>^4 are independently hydrogen;

R 5 is hydrogen, methyl or ethyl.

<R>l6 means hydrogen, C3-c<y>chloroalkyl, C00R15, pyridyl,

piperidyl, N-morpholino, <c>t<F>2t+1 or phenyl;

which is optionally substituted with 1 or 2 substituents selected from the group comprising F, Cl, Br, I, CF 3 , methyl or methoxy;

s means 0, 1 or 2;

t means 1, 2 or 3;

Y means S0q, -CO-, -O-, -NR10-;

whereby, however, Rf cannot be -OCF3 or -OC2Fg;

as well as pharmaceutically acceptable salts thereof.

In a preferred embodiment, the invention relates to chromans of formula (I) above where:

R1 and R2

independently of each other means C1-3-alkyl or together

means a C 4 -g alkylene chain;

R3 means R9-Cn-H2n[NR11V>

R 8 means hydrogen;

n means 0, 1, 2, 3 or 4;

m means 0 or 1;

R n means hydrogen or C 1-6 alkyl;

R 4 means R 12 -CrH 2 r ;

12

means hydrogen, CF3, pyridyl or phenyl,

which is optionally substituted with 1 or 2 substituents selected from the group consisting of F, Cl or CF3;

r means 1, 2, 3, 4, 5, 6, 7 or 8;

whereby a CHg group in the group Cr<H>2r may be replaced by -0-, -CO-, -CO-0- or -S(0)q-;

q means 0, 1 or 2;

R5, R6, R7 and R8

independently means hydrogen, F, Cl, Br, I, <C>1_2-alkyl, -CN, -CF3, -N02, -C0NR13<R>14j -C00R15 or <R>16-<c>s<H >2s_<Y_>;

R^3 and R^4 independently of each other mean hydrogen;

R15 means methyl or ethyl.

R-L6 is hydrogen, Cx?2t+ 1 or phenyl;

which is optionally substituted with a substituent selected from F, Cl, Br, CF3, methyl or methoxy;

t means 1, 2, or 3;

s means 0, 1 or 2;

Y means S0q, -CO-, -O- or -NR10-;

q means 0, 1 or 2;

R 2 q means hydrogen or methyl;

whereby, however, Rf cannot be -OCF3 or -OCgFg.

A particularly preferred embodiment of the invention relates to chromans of formula (I) as described above where:

RjL and R2

independently means methyl;

R3. means C 1-4 alkyl, dimethylamino or diethylamino;

R4 means R12-Cr<H>2r<;>

R 2 means hydrogen or CF 3 ;

r means 1, 2, 3, 4, 5, 6, 7 or 8;

whereby a CHg group in the group Cr<H>gr may be replaced by -0-, -CO-, -CO-0- or -S(0)q-;

q means 0, 1 or 2;

R5, R6, R7 and R8

independently of one another means hydrogen, F, Cl, Br, I, <C>j-alkyl, -CN, -NOg, -C00R15 or R16-CsH2s-Y-;

R15 means methyl or ethyl.

R 16 is hydrogen, CF 3 or phenyl;

s means 0, 1 or 2;

Y means S0q, -CO-, -O- or -NR10-;

q means 0, 1 or 2;

R₂O means hydrogen or methyl;

whereby, however, Rf cannot be -OCF3.

Particularly preferred according to the invention are the compounds: 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman, 6-cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2 -dimethylchroman, 4-(N-ethylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman, 6-cyano-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino -2, 2-dimethylchroman, 4-(N-butyl-N-ethylsulfonyl)amino-6-cyano-2,2-dimethylchroman, 4-(N-ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman , 7-chloro-4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman, 6,7-dichloro-4-(N-ethylsulfonyl-N-methyl)amino- 2,2-dimethylchroman, 4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman, 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2- tetramethylene-chroman, 4-[N-e ty 1 sulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-dimethylchroman,

4-(N-ethylsulfonyl-N-hexyl)amino-6-fluoro-2,2-dimethylchroman, 6-ethyl 1-4-[N-ethylsulfonyl-N-{4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman.

If the compounds of formula (I) contain an acidic or basic group or a basic heterocycle, the corresponding, pharmacologically and toxicologically acceptable salts are also the subject of the invention. Thus, the compounds of formula (I) which carry one or more COOH groups can, for example, be used as alkali metal salts, preferably as sodium or potassium salts. Compounds of formula (I) bearing a basic, protonatable group or a basic, heterocyclic residue can also be used in the form of organic or inorganic, pharmacologically and toxicologically acceptable acid addition salts, for example as hydrochlorides, methanesulfonates, acetates, lactates, maleinates, fumarates , malates, gluconates and so on. If the compounds of formula (I) contain an acidic or basic group in the same molecule, in addition to the described salt forms, the internal salts or the so-called betaines also belong to the invention.

If the substituents on the compounds of formula (I) or also of formula (Ia) contain groups with different stereochemical possibilities, the individual possible stereoisomers are also within the scope of the invention. Thus, the compounds of formula (I) and formula (Ia), respectively, contain a chiral center in position 4 in the chromane system, so that the individual, pure optical antipodes as well as any mixtures of the optical isomers also lie within the scope of the invention.

The compounds of formula (I) can be prepared in various chemical ways which are also within the scope of the invention.

Thus, a compound of formula (I) is obtained, as

a), reacts a compound of formula (II)

where Ri, R2, R5, Rf1, R7 and R8 have the indicated meaning and L means a nucleofuge cleavable group common for alkylation, especially Cl, Br, I, MeSO2-O-, a p-toluenesulfonyloxy acid residue, with a sulfonamide or a salt thereof of formula (III)

in a manner known per se, whereby R 3 and R 4 have the stated meaning, although r in the substituent R 4 also has the meaning zero, and M means hydrogen or preferably a metal atom and especially lithium, sodium or potassium;

or that one

b) reacts a compound of formula (IV)

where R-^, R2, R4, R5 > R&> K7°S R8 has the meaning stated above, with r in the substituent R4 also having the meaning zero,

with a sulfonic acid derivative of formula (V)

where R 3 has the meaning given above and W means a nucleofuge, cleavable group such as fluorine, bromine, 1-lmldazolyl or especially chlorine;

or that one

c) reacts a compound of formula (VI)

where Ri, R2, R5, Rf1, R7, R8°B M when the indicated meaning, in a manner known per se with an alkylating agent of formula VII

by an alkylation reaction, R 4 apart from hydrogen and L having the indicated meaning;

or that one

d) in a compound of formula (I)

where Ri to R4 has the meaning indicated, in at least one of the positions R5 to Rg carries out an electrophilic substitution reaction, where this position means hydrogen and the other substituents R5 to Rg have the meaning indicated above.

Procedure a)

describes the per se known alkylation of a sulfonamide or a salt thereof of formula (III) with a chromane derivative of formula (II) acting as an alkylating agent. Since the alkylation of a sulfonamide takes place from the salt form, by using a free sulfonamide (formula III, M = H), a sulfonamide salt (formula III, M >= cation) must be obtained by the action of a base, in order to achieve higher nucleophilicity and thereby higher reactivity. If free sulfonamide (M = H) is used, the deprotonation of the sulfonamide to salt takes place in situ with the preferred use of such bases which themselves are not or only to a small extent alkylated, for example sodium carbonate, potassium carbonate, a sterically strongly hindered amine such as dicyclohexylamine, N ,N,N-dicyclohexyl-ethylamine or other strong nitrogen bases with low nucleophilicity, for example DBU, N,N',N"'-triisopropylguanidine and so on. However, one can also use other commonly used bases for the reaction, for example potassium- tert-butylate, sodium methylate, alkali metal hydrogen carbonates, alkali metal hydroxides such as LiOH, NaOH or KOH, or alkali metal hydroxides such as Ca(OH)2.

Thereby, one preferably works in aprotic, polar solvents such as dimethylformamide, dimethylacetamide, tetramethylurea, hexamethylphosphoric triamd, tetrahydrofuran, and so on. In principle, however, one can also work in polar, protic solvents such as water, methanol, ethanol, isopropanol, ethylene glycol or their oligomers and their corresponding hemiethers and ethers. The reaction is carried out in a preferred temperature range from 20 to 14°C, and most preferably from 40 to 100°C. In the most favorable case, method a) can also be carried out under conditions for a two-phase catalysis. The compounds of formula (II) are obtained according to methods known in the literature, for example from the corresponding alcohols (formula III, L = -OH) by the action of hydrogen halide HL (L = Cl, Br, I) or by the action of an inorganic acid halide (POCI3, PCI3, PCI5, SOClg, SOBrg) or by radical halogenation of the corresponding chromane derivatives (formula II, L = H) with elemental chlorine or bromine, or with radical-activatable halogenating agents such as N-bromosuccinimide (NBS) or SOgClg ( sulfuryl chloride) In the presence of a radical chain initiator such as high-energy light in the visible or ultraviolet wave range, or by using a chemical radical initiator such as azodiisobutyronitrile.

Procedure b)

describes the per se known and often used reaction between an activated sulfonyl compound of formula V, in particular a chlorosulfonyl compound (W = Cl), with an amine of the general formula (IV), to the corresponding sulfonamide derivative of the general formula ( IN). The reaction can in principle be carried out without a solvent, but such reactions are carried out in most cases using a solvent.

The reaction is preferably carried out using a polar solvent, preferably in the presence of a base which can itself be used as a solvent, for example using triethylamine, pyridine or homologues thereof. Preferably used solvents are, for example, water, aliphatic alcohols such as methanol, ethanol, isopropanol, sec-butanol, ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA as well as TMU and HMPT. One thereby works at a temperature from 0 to 160°C and preferably from 20 to 100°C.

The amines of formula (IV) are obtained according to methods known in the literature, preferably from the corresponding carbonyl compounds of formula (X)

where , Rg, Rg» Rf,f R7 and Rg have the meaning given above and A means oxygen, either with ammonia or an amine of the general formula (XI)

where R4 has the stated meaning, whereby however r In the substituent R4 also has the meaning zero, under reductive; catalytic conditions, preferably at a higher temperature in an autoclave. Thereby, primarily, by condensation reactions, the ketone X (with A = oxygen) and amines (XI) are formed, in situ the Schiff base of formula (X) with A equal to R4-N=, which is immediately and without isolation reductively transferred to the amine with formula (IV). Similarly, the Schiff bases formed intermediately from (X) and (XI) by these reactions (formula X, A: R4-N=) can be prepared and isolated in order, in a subsequent separate step, to convert them with a suitable reducing agent which

NaBH4, LiAlH4, NaB^CN or by catalytic hydrogenation, to compounds of formula (IV). The compounds (IV) with R4 equal to hydrogen can be advantageously prepared according to methods known from the literature by reduction of oximes or oximeters (formula X, A equal to RO-N=), hydrazones (formula X: A equal to R18RlgN-N=), using a complex metal hydride or catalytic hydrogenation. The necessary oximes and hydrazones are prepared conveniently and in a manner known per se from ketones of formula X (A equal to oxygen) with hydrazine or with a derivative thereof or for example with hydroxylamine hydrochloride under water-splitting conditions.

Procedure c)

describes in the same way as method a) the I and per se known alkylation reaction of a sulfonamide or a salt thereof (VI) with an alkylating agent of formula (VII). Correspondingly, this reaction analogy applies to method c) the reaction conditions already thoroughly described under method a).

The production of the sulfonamide derivatives (VI) and their precursors was already described under method b). The preparation of the alkylating agents (VII) takes place according to analogous regulations from the literature respectively as under method a), preferably from the corresponding hydroxy compounds (formula VII with L equal to -OH).

Procedure d)

describes the further chemical conversion of the invention's compounds of formula (I) into another compound of formula (I) by electrophilic substitution reactions in one or more of the positions indicated by R5 to Rg, which each time means hydrogen.

Preferred substitution reactions are

1. the aromatic nitration for the introduction of one or more nitro groups, as well as the subsequent reduction to NHg-, 2. the aromatic halogenation, in particular for the introduction of chlorine, bromine or iodine, 3. the chlorosulfonation for the introduction of a chlorosulfonyl group by the action of chlorosulfonic acid, 4. Friedel-Crafts acylation reactions for the introduction of an acyl residue <R>i6~csH2s_C0~ or a sulfonyl residue Ri6-<c>s<H>2s~ SOg- by the action of the corresponding acid chlorides Ri&-CSH2S-C0-C1 respectively Ri£ ,-CsH2s-SO2-Cl * presence of a Lewis acid as a Friedel-Crafts catalyst, preferably anhydrous aluminum chloride.

The compounds of formula (I) and (Ia) are related to the class of the 4-acylaminochroman derivative and especially 2,2-dialkyl-4-acylamino-3-chromanols, which have been intensively processed in the last decade in medicinal chemistry.

The most prominent representative of such 4-acylamino-chromans is chromakalim of formula (XII)

and numerous secondary preparations derived from this preparation (see, for example, Edwards and Weston, "TIPS", 11, 417-422

(1990), "Structure Activity Relationships of K<+> channel openers" ).

Chromakalim and other related 4-acylaminochroman derivatives are compounds with a relaxing effect on organs with smooth muscles, so that they can be used for the reduction of elevated blood pressure due to tissue muscle relaxation and in the treatment of asthma due to relaxation of the smooth muscle 1 airways. All these preparations have in common that they work at a cellular level, for example in smooth muscle cells and there lead to an opening of special ATP-sensitive K<+->channels. The rise of the negative charge in the cell ("hyperpolarization") induced by the exit of K<+-> ions counteracts via secondary mechanisms the increase of intracellular Ca^<+> and thereby a cell activation, for example a muscle contraction.

In contrast to these 4-acylaminochroman derivatives which, as mentioned, are identified as openers of the ATP-sensitive IT channel, the invention's compounds of formula (I) and the compounds of formula (Ia) respectively show

there

RA means hydrogen, OH, -O(CO)-alkyl of 1, 2, 3 or 4 C atoms or -O-SO 2 -alkyl of 1, 2, 3 or 4 C atoms; R 8 means hydrogen;

or

RA and RB

together means a bond;

Ri to R4 are as indicated above;

Rc means CN, acyl with 1, 2, 3, 4, 5 or 6 C atoms, F, Cl,

Br, I, NO 2 or alkyl of 1, 2, 3, 4, 5 or 6 carbon atoms; with 4-sulfonylamino structure, surprisingly a strong and specific blocking (closing) effect on a K<+> channel which is opened by cyclic adenosln monophosphate (cAMP) and which differs in principle from the aforementioned K<+> (ATP) channel. More recent investigations also show that this K<+>(cAMP) channel identified in the large intestine appears very similar, and even identical, to the Ig^ channel identified in the heart muscle. Due to this blocking of the K + (cAMP ) channel (= Isjj channel), the compounds develop pharmacological effects of high therapeutic importance in the living organism.

The preparation of the compounds of formula (Ia) from suitable 3,4-epoxyromanes with sulfonamides of formula (III) is described by Lohrmann et al. in "Pfluger's Arch. - Eur. J. Physiol.", (1995) 429: 517-530.

Thus, the compounds of formula (I) and (Ia), respectively, stand out as new active substance class of potent inhibitors against the stimulated gastric acid secretion. The compounds of formula (I) and (Ia) are therefore valuable drugs for the treatment of ulcers in the stomach and intestinal area, for example the duodenum. They are also suitable as excellent therapeutics for the treatment of reflux oesophagitis due to the strong gastric juice secretion-inhibiting effect.

The compounds of formula (I) and (Ia), respectively, are further distinguished by an anti-diarrheal effect and are therefore suitable as drugs for the treatment of diarrheal diseases.

The present invention also relates to the use of the compounds as described above for the production of medicines

for blocking the K<+->channel opened by cyclic adenosine monophosphate (cAMP),

for inhibition of gastric acid secretion,

for the treatment of ulcers 1 the stomach and the intestinal area, especially the duodenum,

for the treatment of reflux esophagitis,

for the treatment of diarrheal diseases,

for the therapy or prevention of all types of arrhythmias including ventricular and supraventricular arrhythmias,

for the control of reentry arrhythmias and for the prevention of sudden cardiac death due to ventricular fibrillation.

Finally, the invention also relates to medicines containing an effective amount of a compound as described above.

Thus, the compounds of formula (I) and (Ia), respectively, can be used as drugs for the treatment and inhibition of all types of arrhythmias, including atrial, ventricular and supra-ventricular arrhythmia. They can be used in particular to control reentry arrhythmias and to prevent acute cardiac death as a result of ventricular fibrillation.

There are publications from which a correlation is described between IsK channel inhibitory action and prevention of life-threatening cardiac arrhythmias, which are for example triggered by g<->adrenergic hyperstimulation (for example B.T.J. Colatsky, C.H. Follmer and CF. Starmer: "Channel Specificity in Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias", "Circulation", (1990) 82: 2235-2242; A.E. Busch, K. Malloy, W.J. Groh, M.D. Varnum, J.P. Adelman and J. Maylie; "The novel class III anti-arrhythmics NE-10064 and NE-10133 inhibit IsK channels in xenopus oocytes and IKS in guinea pig cardiac myocytes", "Biochem. Biophys. Res. Commun.", (1994) 202 : 265-270).

In addition to the above-mentioned chroma potassium and acylaminochroman derivatives, compounds with a 4-sulfonylaminochroman structure have also been described in the literature in recent years, which clearly differ from the invention's compounds of formula (I) and compounds of formula ( Ia), either as regards structure or as regards biological effect. Thus describes EP-publ. 315,009 chromane derivatives with 4-phenylsulfonylamino structure which are distinguished by anti-thrombotic and anti-allergic properties.

EP publ. 370,901 describes 3-hydroxychromane derivatives with a 4-phenylsulfonylamino group, in which the remaining valence on the N atom carries a hydrogen atom. These compounds are thereby substituted differently from formula (I) and (Ia) respectively in terms of essential groups. Correspondingly, effects on the central nervous system have been found for these compounds from EP 370 901 so that they also differ in pharmacological terms.

EP publ. 389,861 describes 3-hydroxychroman derivatives with 4-sulfonylamino group. Thereby, the benzopyran derivatives described in the EP document are activators or openers of the so-called adenosine triphosphate-sensitive K<+->channel [K<+>(ATP)-channel]. The pharmacological effects of K<+>(ATP) channel openers are now known to be completely different from the here described blockers of the IsK channel. Thus, typical vasodilatory and blood pressure-lowering properties have been demonstrated for the K+(ATP ) channel openers for this mechanism. As expected for this mechanism of K<+> channel opening, the K<+>(ATP) channel openers synthesized and described by the authors show typical, special antiarrhythmic properties. In a principled work, Lucchesi et al. ("J. Cardiovasc. Pharmacol.", 15, 452-464 [1990]) convincingly show that K<+>(ATP) channel openers are not antiarrhythmic in oxygen-undersupplied, diseased hearts or in sudden ischaemia, but, on the contrary, sogar causes life-threatening profibrillator effects. These dangerous conditions are triggered as a consequence of the shortening of the repolarization duration resulting from the activation of the K<+>(ATP) channel. In contrast to these, for diseased and poorly maintained hearts life-threatening profibrillator effects due to the action of K<+>(ATP) channel openers, blocking of the K<+>(cAMP) channels should under these conditions show antifibrillator action. As a prominent representative of the compounds of formula (Ia) synthesized here, meanwhile, 6-cyano-4-(n-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-3-chromanol found its way into the latest literature under the designation 293B as an example of a highly specific <k> Iks" respectively IBjf channel blockers with a corresponding prolongation of action potentials on hearts (SUpbrich et al., "Naunyn Schiedebergs Arch. Pharm.", [1996], 353 (4th suppl), R72 ; "Pflugers Arch.-Eur. J. Physiol.", 431 (6) [suppl.], R22 [1996]; A. Busch et al., "Pflugers Arch.-Eur. J. Physiol.", 432 ( 6) [Suppl.], 1094-1096 [1996].

Due to special, structural knowledge, the present applicants have synthesized and investigated certain compounds, they were admittedly known from the above-mentioned EP-publ. 389 861, but which had not been described, synthesized or recognized as far as therapeutic effects are concerned, by the authors. For these particular 3-hydroxy-substituted chromans prepared and investigated by the present applicants, a potent blockade of the K<+>(cAMP) channel has now been found very surprisingly ("Pflugers Arch.-Eur. J. Physiol.", [1995], 429, 517-530 "A new class of Inhibitors of cAMP-mediated Cl-secretion in rabbit colon, acting by the reduction of cAMP-activated K<+> conductance" ), and also inhibition of the Ii£S channel in the heart. The Isg channel-blocking effect of 3-hydroxy-substituted chromans is, however, clearly less pronounced than that of the corresponding hydroxyl group-free chromans of formula (I). The object of the present invention is therefore also the use of compounds of formula (Ia) for the treatment of "sudden cardiac death", ventricular fibrillation and in general of arrhythmias in diseased hearts which can be led back to the Ij(s) channel.

The publication "N-sulfonamides of benzopyran-related potassium channel openers: conversion of glyburide insensitive smooth muscle relaxants to potent smooth muscle contractors" in "Bioorg. Med. Chem. Lett." (1994), 4: 769-773 describes special, trifluoromethyl-substituted 4-sulfonylaminochroman derivatives which, however, in contrast to the structurally different K<+>(cAMP) channel blockers described here, have biological other pharmacological effects and thereby also other areas of therapeutic application .

In recent times, the literature has additionally described spiro[2H-1-benzopyran-2,4'-piperidines] with essential, basic side groups, for example MK-499 "Cardiac electro-physiology and 'antiarrhythmic actions of two long- acting spirobenzopyran piperidine class III agents", L-702,958 and L-706,000 (MK 499), "J. Pharmakol. Exp. Ther.", (1994) 269: 541-554; T.J. Colatsky and T.M. Argentieri, "Potassium channel blockers as antiarrhythmic drugs"; "Drug Develop. Ees.",

(1994), 33: 235-249.

These "spirobenzopyran-piperidln class III agents" are admittedly very clearly characterized in the literature with regard to mode of action [P.S. Spector, M.E. Curran, M.T. Keating, M.C. Sanguinetti, "Circulation Res.", (1996), 78: 499-503; J.J. Lynch et al., "J. Pharmacol. Exp. Ther.",

(1994), 269: 541-554]. Thereby, it is clearly described and demonstrated in the cited literature that the antiarrhythmic effect of these compounds is caused by the inhibition of the HERG channel and the fast-activating component of the "delayed rectifier K<+-> channel", the IKr channel. Thereby, spirobenzopyran-piperidln is characterized as substances with a proarrhythmic component and with the risk of increased mortality compared to placebo, as shown in the Sword study for this class of active substances. This is in clear contrast to the compounds of the invention whose advantage consists in the blocking of the slowly activating component of the "delayed rectifier K<+->channel", the lgs channel, which does not have this proarrhythmic component. The compounds of formula (I) and (Ia), respectively, can also be combined with other active ingredients to achieve a beneficial therapeutic effect. Thus, in the treatment of cardiovascular diseases, beneficial combinations with cardiovascular-active substances can be thought of. As such beneficial combination partners for cardiovascular diseases, one can for example mention other antiarrhythmics, thus class I, II or III antiarrhythmics come into consideration such as so-called IKr channel blockers such as dofetilide, further blood pressure-lowering substances such as ACE inhibitors ( for example enalapril, captopril, ramipril), anti-Iotensin antagonists, K<+-> channel activators as well as cx- and p-receptor blockers, but also sympathomimetic and adrenergic compounds, as well as Na<+>/H<+-> exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances with a positive inotropic effect such as digitalis glycosides or diuretics.

Furthermore, one can imagine a combination with antibiotic active substances and with antiulcer agents, for example with H2 antagonists (ranitidine, cimetidine, famotidine, and so on), for example when used for the treatment of gastrointestinal diseases.

Medicines containing a compound (1) or a compound (Ia) according to the invention can be administered orally, parenterally, intravenously, rectally or by inhalation, whereby the preferred form of administration depends on the relevant state of the disease. The compounds (I) and (Ia) can thereby be used alone or together with galenic excipients and are used in both veterinary and human medicine.

Which excipients are suitable for the desired drug formulations is known technology to the person skilled in the art. Alongside solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, one can for example use antioxidants, dispersants, emulsifiers, defoamers, flavor correctors, preservatives, solubilizers and dyes.

For an oral application form, the active compounds (I) and (Ia) respectively are mixed with the appropriate additives such as carriers, stabilizers or inert diluents and then brought to the desired administration form by usual methods in galenic practice, for example tablets, dragees, suppositories, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. Thereby, the preparation can take place both as dry and as moist granules. For example, vegetable or animal oils such as sunflower oil or cod liver oil can be used as oily carriers or as solvents.

For subcutaneous or intravenous administration, the active compounds of formula (I) and (Ia), respectively, are brought into solution, suspension or emulsion, optionally together with those for this usual substance as dissolution mediators, emulsifiers or further excipients. Solvents that can be mentioned are water, physiological saline solution or alcohols such as ethanol, propanol or glycerol, also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned. Oligosaccharides such as cyclodextrin can be mentioned as dissolution mediators.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of formula (I) or of formula (Ia) in a pharmaceutically acceptable solvent, for example ethanol or water, or a mixture of such solvents. If necessary, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant gas. Such a preparation usually contains the active ingredient in a concentration of from 0.1 to 10, and preferably 0.3 to 3% by weight.

The dosage of the active ingredient with formula (I) or formula (Ia) to be administered and the frequency of administration depends on the potency and duration of exposure for the compounds used, and also on the nature and strength of the disease to be treated as well as the patient's sex, age, weight and individual condition.

On average, the daily dose of a compound of formula (I) in patients with a weight of approx. 75 kg, at least 0.1 mg, preferably 10 mg, to a maximum of 100 mg, and preferably a maximum of 1 g; respectively for compounds of formula (Ia) at least 1 mg, preferably 50 mg, at most 300 mg and preferably

1 g-

Explanation of abbreviations:

DMA Dimethylacetamide

HMPT hexamethylphosphoric acid triamide

TMU tetramethylurea

h hours

M mol

mM millimoles

min minutes

TEA triethylamine

THF tetrahydrofuran

EXAMPLES:

Example 1: 4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman

a) 2,2-dimethyl-4-chromanone oxime

A reaction mixture prepared from 10 mM 2,2-dlmethyl-4-chromane, 12 mM hydroxylamine hydrochloride in 5 ml methanol and 5 ml pyridine is heated with stirring for 2 hours to 80-85°C, after which the solvent is distilled off in a rotary evaporator and the oily residue is brought under water for crystal in sering.

crystalline substance,

melting point 115-118"C

b) 4-amino-2,2-dimethylchroman hydrochloride

A solution of 10 mM 2,2-dimethyl-4-chromanone oxime and 75 ml

methanol is hydrogenated after adding Raney nickel as a catalyst in an autoclave with hydrogen at 60°C and 100 atmospheres pressure for a period of 6 hours. After filtering and distilling off the solvent, the amorphous residue is dissolved in ethyl acetate and HCl gas-saturated diethyl ether is added for a strongly acidic reaction. The crystalline precipitate of 2,2-dimethyl-4-aminochroman hydrochloride is filtered off, washed several times with ethyl acetate and dried.

Colorless crystals,

melting point 268°C.

c) 4-N-ethylsulfonylamino-2,2-dimethylchroman

Variant 1: To a stirred solution, prepared from 4.3 mmol

4-amino-2,2-dimethylchroman hydrochloride, 15 ml THF and 1.25 ml

TEA is placed at 0°C and in portions a solution of 4.5 mmol of ethanesulfonic acid chloride in 5 ml of THF. You stir the whole thing for approx. 2 hours at 0°C and a further 1 hour at room temperature, filter the precipitate and distill off the solvent on a rotary evaporator. The remaining oil crystallizes under petroleum ether.

Colorless crystals,

melting point 106-108°C.

Variant 2: To a suspension of 1.06 g (0.005 M) 4-amino-2,2-dimethylchroman hydrochloride and 2.0 g (0.02 M) TEA in 25 ml DMA is added portionwise at a temperature between 0 and 5°C 0.83 g (0.0065 M) of ethanesulfonic acid chloride and the whole is allowed to stand under stirring for 2 days at room temperature. After distilling off the solvent on a rotary evaporator, water is added, after which the separated oil solidifies crystalline after a short time.

Melting point 106-109°C.

d) 4-N-ethylsulfonyl-N-methylamino-2,2-dimethylchroman To a sodium methylate solution, prepared from 0.0166 Tom

sodium in 20 ml of anhydrous methanol, a solution of 0.0111 M 4-N-ethylsulfonylamino-2,2-dimethylchroman in 15 ml of anhydrous methanol is slowly added. To this mixture is then added, in portions, a solution of 0.014 M methyl iodide in 5 ml of anhydrous methanol and heated for 6 hours under a reflux condenser to 50°C. The solvent is distilled off in a rotary evaporator, the residue is treated with acetic acid ethyl ester and extracted with 2N NaOH. The organic phase is dried over anhydrous sodium sulfate and 4-N-ethylsulfonyl-N-methylamino-2, 2-dimethylchroman is obtained by renewed distillation of the solvent.

Colorless, crystalline substance,

melting point 90-92°C.

Example 2: 4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman

To a suspension of 0.0122 M sodium hydride in 30 ml of anhydrous dimethylacetamide under argon, 0.0111 M 4-N-ethylsulfonylamino-2,2-dimethylchroman is added with stirring, in portions, after which the whole is stirred for a further 1 hour at room temperature. After addition of 0.0122 M ethyl chromide, the whole is stirred for a further 24 hours at room temperature. The solvent is distilled off under reduced pressure, the residue is then treated with vinegar, extracted with water and the organic phase is distilled off in a rotary evaporator after separation and drying over anhydrous sodium sulfate. 4-N-ethylamino-N-ethylsulfonyl-2,2-dimethylchroman is obtained by crystallization under petroleum ether and as a colorless, crystalline substance.

Melting point 85°C.

Example 3: 4-(N-benzyl-N-ethylsulfonyl)amino-2,2-dimethylchroman is obtained analogously to the protocol indicated in example 1 2 from 4-N-ethylsulfonylamino-2,2-dimethylchroman and benzyl bromide. Colorless crystals,

melting point 95-97<*>C.

Example 4: 4-[N-ethylsulfonyl-N-(2-dimethylaminoethyl)]amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-2,2-dimethylchroman and 2-chloroethyldimethylamine hydrochloride using twice the amount of sodium hydride.

Colorless crystals,

melting point 90-93°C.

Example 5: 4-N-ethylsulfonylamine-2,2-dimethyl-6,8-dinitrochroman

To 4.3 ml cooled to -15 to -20°C 100 #-ig nitric acid is added in portions and with stirring 3.71 mM 4-N-ethylsulfonylamino-2,2-dimethylchroman and the whole is stirred while maintaining the cooling for a further 20 minutes. The reaction mixture is poured into 50 ml of ice water and the yellow crystals are filtered and washed several times with water. The compound is purified by chromatography on silica gel with ethanol:ethyl acetate 3:7 and the whole is then crystallized with petroleum ether.

Yellow, crystalline compound,

melting point 140-142°C.

Example 6: 4-N-ethylsulfonylamino-2,2-dimethyl-6-nitrochroman

To a mixture of 3.71 mM 4-N-ethylsulfonylamino-2,2-dimethylchroman in 2.54 ml acetic acid, 0.54 ml 100 #-ig nitric acid is added in portions and at -20° C, and the whole is stirred for a further 5 minutes at -20°C. The reaction mixture is poured into 50 ml of ice water, the violet precipitate is filtered and washed several times with cold water on the filter. The crystals are dissolved in a little ethyl acetate and chromatographed on silica gel with petroleum ether: ethyl acetate 3:2.

Light yellow crystals,

melting point 198-201°C.

Example 7: 4-(N-ethyl-N-ethylsulfonyl)amlno-2, 2-dimethyl-6-nitrochroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-2,2-dlmethyl-6-nitrochroman and ethyl bromide. Light yellow crystals,

melting point 180-185'C.

Example 8: 4-(N-ethylsulfonyl-N-methyl)amino-2,2-diraethyl-6-nitrochroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-nitrochroman and methyl iodide. Light yellow crystals,

melting point 190-192°C.

Example 9: 6-amino-4-(N-ethyl sulfonyl-N-methyl)amino-2,2-dimethylchroman hydrochloride

is obtained by catalytic hydrogenation of 7.21 mM 4-N-ethylsulfonyl-N-methylamino-2,2-dimethyl-6-nitrochroman with hydrogen in 150 ml methanol with Raney nickel as catalyst, until uptake of the theoretical amount of hydrogen, in during 1.5 hours at 760 torr. After filtering and evaporating the solvent, the amorphous residue is dissolved in acetic acid and the product is purified by adding a saturated solution of HCl gas in diethyl ether by precipitation of the hydrochloride.

Colorless crystals,

melting point 75-78"C.

Example 10: 6-amino-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman hydrochloride

is obtained analogously to the protocol specified in example 9 from 4-N-ethyl-N-ethylsulfonylamino-2,2-dimethyl-6-nitrochroman by catalytic hydrogenation with Raney nickel.

Colorless crystals,

melting point 95-100°C.

Example 11: 4-N-(dimethylaminosulfonyl)amino-2,2-dimethylchroman

A solution of 0.03 mM TEA in 30 ml DMA is added to a suspension of 10 mM 4-amino-2,2-dlmethylchroman hydrochloride in 75 ml anhydrous THF. Stir for approx. 30 minutes at room temperature, after which the suspension, while cooling to approx. 10°C, a solution of 12 mM N,N-dimethylsulfamoyl chloride in 10 ml anhydrous THF is added dropwise. After removing the cooling bath, the whole is stirred at room temperature 1 for a further 24 hours. The solvent is then distilled off in a rotary evaporator and the residue is stirred under water, whereby crystallization occurs after a certain time. After filtering off the crystals and washing with water, 4-N-(dimethylamino)-sulfonylamino-2,2-dimethylchroman is obtained as colorless crystals.

Melting point 77-79°C.

Example 12: 4-N-methyl-N-(dimethylaminosulfonyl)amino-2,2^

dimethyl chroman

is obtained analogously to the protocol indicated in example 1 2 from 4-N-{dimethylaminosulfonyl)amino-2,2-dimethylchroman and methyl iodide. Colorless crystals,

melting point 146-148"C.

Example 13: 4-N-ethyl sulfonyl amino-6-fluoro-2,2-dimethylchroman

a) Acetic acid 4-fluorophenyl ester

is obtained as an oil-like residue by boiling 4-fluorophenol i

acetic anhydride and subsequent evaporation of the solvent.

b) 5-fluoro-2-hydroxy-acetophenone

is obtained from 0.0376 mol of acetic acid 4-fluorophenyl ester and

0.083 M anhydrous A1C13 (for Frledel-Craft reactions) at 120"C for 2 to 3 hours and subsequent cleavage with ice water after cooling. Extract with acetic acid and distill off the solvent after drying over sodium sulfate and bring the viscous residue to crystallization under cyclohexane.

Colorless, crystalline substance,

melting point 46-47°C.

c ). 6-fluoro-2,2-dimethyl-4-chromanone

one obtains analogously to the protocol specified in example 18 b) from 5-fluoro-2-hydroxy-acetophenone and acetone in the presence of pyrrolidine.

Colorless to slightly yellow, amorphous residue.

d) 6-fluoro-2,2-dimethyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6-fluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride, crystallization of the product under water and recrystallization from cyclohexane using activated charcoal.

Colorless crystals,

melting point 108-110"C.

e) 4-amino-6-fluoro-2,2-dimethyl-4-chroman hydrochloride is obtained analogously to the protocol given in example 1 b) by

catalytic hydrogenation in an autoclave from 6-fluoro-2,2-dimethyl-4-chromanone oxime, Eaney nickel, and hydrogen.

Colorless crystals,

melting point 226°C, sublimation from 296<*>C.

f) 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchromane To a suspension of 5 mM 4-amino-6-fluoro-2,2-dimethyl-4-chromane hydrochloride in 20 ml DMA and 15 mM TEA add 5.5 mM ethanesulfonic acid chloride while stirring and cooling to 10°C. The mixture is stirred for a further 24 hours at room temperature, the solvent is then distilled off in a rotary evaporator and the residue is stirred under 75 ml of water. The oil that separates is extracted with ethyl acetate, separated and dried over anhydrous sodium sulfate. After distilling off the solvent in a rotary evaporator, 4-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman is obtained as an amorphous product. Example 14: 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2- dimethyl chroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and methyl iodide.

Amorphous, oily product.

Example 15: 6-fluoro-4-N-(dimethylaminosulfonyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 11 from 4-amino-6-fluoro-2,2-dimethylchroman and N,N-dimethylsulfamoyl chloride in anhydrous DMA.

Colorless crystals,

melting point 86-88°C.

Example 16: 6-fluoro-4-[N-methyl-N-(dimethylaminosulfonyl)]-amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 6-fluoro-4-N-{dimethylaminosulfonyl)-2,2-dlmethylchroman and methyl iodide.

Amorphous, oily product.

Example 17: 6-cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman

a) 6-cyano-2,2-dimethylchroman

A suspension consisting of 10 mM 6-cyano-2,2-dimethyl-3,4-chrome, 50 ml methanol and approx. 500 mg of palladium catalyst on 10%-lg barium sulfate is shaken in a stainless steel container under a hydrogen atmosphere at 1 atmosphere and 20° C. until the theoretical amount of hydrogen is absorbed. After filtering off the catalyst, the solvent is distilled off in a rotary evaporator and 6-cyano-2,2-dimethylchroman is obtained as a colorless to slightly yellow oil.

b) 4-bromo-6-cyano-2,2-dimethylchroman

To a solution of 10 mM 6-cyano-2,2-dimethylchroman in 30 ml

carbon tetrachloride, 11 mM N-bromosuccinimide and 0.22 g of azodiisobutyronitrile (Aldrich) are added and the suspension thus obtained is heated for 3 hours under a reflux condenser to boiling. Insoluble succinimide is then filtered off, the solvent is distilled off and the residue is crystallized from a mixture of n-hexane and diisopropyl ether.

Pale yellow crystals,

melting point 93-94°C.

c) 6-cyano-4-[N-ethylsulfonyl-N-methyl]amino-2,2-dimethylchroman To a suspension of 11 mM sodium hydride as 80 5<*>>-Ig

oil suspension in 5 ml of anhydrous DMA, a solution of 1 mM ethanesulfonic acid-N-methylamide is dripped under a protective atmosphere of argon and the whole is stirred at room temperature for 1 hour. A solution of 10 mM 4-bromo-6-cyano-2,2-dimethylchroman in 7 ml of anhydrous DMA is then added and the whole is stirred for 72 hours at 70°C. The reaction mixture is poured into 75 ml of water while stirring, the oily amorphous precipitate is extracted with ethyl acetate and the organic phase is dried over anhydrous sodium sulfate. The solvent is distilled off on a rotary evaporator and the amorphous residue

are separated on a silica gel column with toluene:ethyl acetate 1:1. After distilling off the elution liquid in a rotary evaporator, 6-cyano-4-[N-ethylsulfonyl-N-methyl]amino-2,2-dimethylchroman is obtained as a colorless, crystalline product.

Melting point 166-168°C.

Example 18: 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman

a) 3-acetyl-4-hydroxybenzoic acid

36.6 g (0.274 M) of AlCl 3 are suspended in 50 ml of 1,2,4-trichlorobenzene and 9 g (50 mM) of 4-acetoxybenzoic acid are added. After adding dropwise 7.84 g (0.1 M) acetyl chloride, the reaction mixture is heated to 130-140°C, whereupon an evolution of HCl gas occurs from about 60°C. Stir for approx. 1 hour at approx. 130°C, allow the whole to cool to 60-7CC and carefully pour the mixture into stirred ice water. It is extracted several times with ethyl acetate, then the combined organic phases are extracted with saturated aqueous sodium bicarbonate solution and the combined aqueous phases are adjusted to pH < 1 with concentrated HCl, whereby 3-acetyl-4-hydroxybenzoic acid is separated as a poorly soluble precipitate.

Colorless, crystalline substance,

melting point 228-233°C.

b) 6-carboxy-2,2-dimethyl-4-chromanone

13.8 g of pyrrolidine and 40 ml of acetone are added to a suspension of 14.7 g (0.0815 M) of 3-acetyl-4-hydroxybenzoic acid in 200 ml of acetonitrile. The slowly colored solution is allowed to stand for 2 days at room temperature, the solvent is distilled off on a rotary evaporator, water is added to the residue, the pH is adjusted to an acidic pH < 1 with concentrated hydrochloric acid and the crystalline substance is filtered off.

Colorless crystals,

melting point 154-160°C.

c) 6-carboxy-2,2-dimethyl-4-chromanone oxime

Dissolve 14.9 g of 6-carboxy-2,2-dimethyl-3-chromanone in 1,100 ml

ethanol and 100 ml of pyrlidine and heated to 80°C after the addition of 5.16 g of hydroxylamine hydrochloride for 6 hours with stirring. The solvent is distilled off on a rotary evaporator. Water is added to the residue, the pH value is adjusted to < 1 with concentrated hydrochloric acid and the colorless crystals are filtered off.

Melting point 223-225°C.

d) 4-amino-6-carboxy-2,2-dimethylchroman

35.2 g (0.15 M) 6-carboxy-2,2-dimethyl-4-chromanone oxime

is brought into solution in 300 ml of methanol by the addition of 600 ml of concentrated, aqueous ammonia and then the whole is hydrogenated after the addition of a few grams of Raney nickel catalyst under a hydrogen pressure of 100 atmospheres at 80°C for 10 hours. After filtering off the catalyst, approximately 3/4 of the solvent is distilled by 1 a rotary evaporator. The crystalline precipitate of 4-amino-6-carboxy-2,2-dimethylchroman is filtered off.

Colorless crystals,

melting point 307-310°C.

e) 4-amino-6-methoxycarbonyl-2,2-dimethylchroman To 0.05 M 4-amino-6-carboxy-2,2-dimethylchroman in 200 ml

methanol, 9.5 ml of concentrated sulfuric acid are added and the dark solution is heated to reflux for 6 hours. During ice-cooling, the reaction mixture is adjusted by portionwise addition of saturated, aqueous potassium carbonate solution to a pH equal to 9 and the precipitated salt is filtered off. The solvent is distilled off in a rotary evaporator, water is added to the oily residue and the whole is extracted several times with diethyl ether. After distilling off the solvent, the oily-amorphous residue is crystallized from n-heptane. Colorless, crystalline substance,

melting point 62-65°C.

f) 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman is obtained analogously to the protocol specified in example 1 c) from

0.0184 M 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with 0.021 M ethanesulfonic acid chloride in THF with excess TEA. Colorless crystals,

melting point 111-113<*>C.

Example 19: 4-(N-ethylsulfonyl-N-methyl)amino-6-methoxy-carbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0155 M 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.0232 M NaH (as 80 #-ig suspension in oil) and 0.0217 M methyl iodide in anhydrous DMA.

Colorless, crystalline substance,

melting point 184-187<*>C.

Example 20: 6-methoxycarbonyl - 4-N-(dimethylaminosulfonyl)-amino-2,2-dimethylchroman is obtained analogously to the protocol indicated in example 11 from 4-amino-6-carboxy-2,2-dlmethylchroman, dimethylamidosulfonic acid chloride and triethylamine in THF.

Colorless crystals,

melting point 127-129°C.

Example 21: 6-methoxycarbonyl-4-[N-methyl-N-(dimethylaminosulfonyl)]amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 6-methoxycarbonyl-4-N-(dimethylamino)sulfonylamino-2,2-dimethylchroman, NaH and methyl iodide in DMA.

Colorless, crystalline substance,

melting point 125-129°C.

Example 22: 4-(N-butyl-N-ethyl sulfonyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, NaH and 1-butyl iodide in DMA.

Colorless to slightly yellow, oily-amorphous product.

Example 23: 6-carboxy-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman

A suspension consisting of 1 g (0.00305 M) of 4-N-ethylsulfonyl-N-methylamino-6-methoxycarbonyl-2,2-dimethylchroman, 30 ml of methanol and a solution of 0.36 g (0.0091 M) in 20 ml of water is stirred under reflux until a solution is formed within approx. 10 hours. The solvent is distilled off in a rotary evaporator, water is added to the residue, the pH is adjusted to 1 with HC1 and the colorless crystals are filtered off.

Melting point 235-237°C.

Example 24: 6-aminocarbonyl-4-(N-ethylsulfonyl-N-methyl)-amino-2,2-dimethylchroman

0.38 g (0.0023 M) carbonyldiimidazole, one stirs for 3 hours at room temperature and then adds 10 ml of concentrated, aqueous ammonia solution (25 5É-ig). After stirring at room temperature for approx. After 15 hours, the solvent is distilled off on a rotary evaporator, after which water is added to the residue and the white, crystalline substance is filtered off.

Melting point 202-204°C.

Example 25: 6-cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman

To 0.5 g (0.0015 M) 6-aminocarbonyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman in mixture with 0.72 g (0.0045 M) N-trimethylsilylpyrrolidone and 0.0013 g (0.000075 M) of sodium bis(trimethylsilyl)amide under an argon atmosphere, after which the whole is heated to 90°C (bath temperature). From the initially solid mixture, a solution is formed which is then stirred for 4 hours at 90°C and left overnight at room temperature. After removal of the inert protective gas and stirring with water, the oil crystallizes. The crystals are sucked off and purified from the starting product still present by chromatography on silica gel with methylene chloride/methanol 10:1 as eluent.

Melting point 164-167°C.

Example 26: 6-carboxy-4-N-ethylsulfonylamino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 1 a) from 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with isopropyl sulfonic acid chloride in THF with excess TEA.

Colorless crystals,

melting point 112-115<*>C.

Example 27: 4-[N-ethylsulfony 1-N-(4,4,4-trifluorobutyl)-amino]-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol described in example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and 4,4,4-trifluoro-1-iodobutane in DMA.

Pale yellow to colourless, oily-amorphous product.

Example 28: 6-carboxy-4-[N-ethylsulfonyl-N-{4,4,4-trifluorobutyl)amino]-2,2-dimethylchroman

is obtained analogously to the protocol described in example 23 by alkaline hydrolysis of 4-N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline substance,

melting point 189-192<*>C.

Example 29: 4-(N-butyl-N-ethylsulfonyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol described in example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and butyl iodide in DMA.

Colorless, crystalline substance,

melting point 81-84°C.

Example 30: 6-methoxycarbonyl-4-N-methylsulfonylamino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 1 c) from 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with methanesulfonic acid chloride.

Colorless, crystalline substance,

melting point 159-163"C.

Example 31: 6-aminocarbonyl-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 6-carboxy-4-N-ethylsulfonyl-N-{4,4,4-trifluorobutyl)amino-2,2-dimethylchroman, carbonyldimidazole and ammonia. Colorless, crystalline substance,

melting point 170-174°C.

Example 32: 6-carboxy-4-[K-methyl-N-(dimethylaminosulfonyl)amino]-2,2-dimethylchroman

is obtained analogously to the protocol described in example 23 from 6-me to sycarbonyl-4-[N-methyl-N-(dimethylaminosulfonyl)amino]-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 245-248<*>C.

Example 33: 6-cyano-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]-2,2-dimethylchroman

one obtains analogously to the protocol indicated in example 25 from 6-aminocarbonyl-4-N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)-amino-2,2-dimethylchroman, and then subsequent purification by column chromatography on silica gel with methylene chloride :methanol 10:1 as eluent.

Colorless to pale yellow, crystalline substance,

melting point 172-176°C.

Example 34: 6-aminocarbonyl-4-[N-methyl-N-(dimethylamino)-sulfonylamino]-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 24 from 6-carboxy-4-[N-methyl-N-(dimethylaminosulfonyl)amino]-2,2-dimethylchroman•

Colorless, crystalline substance,

melting point 215-218°C.

Example 35: 6-cyano-4-[N-methyl-N-(dimethylaminosulfonyl)-amino]-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 25 from 6-aminocarbonyl-4-[N-methyl-N-(dimethylaminosulfonylamino]-2,2-dimethylchroman).

Colorless, crystalline substance,

melting point 100-102°C.

Example 36: 4-(N-butyl-N-ethylsulfonyl)amino-6-carboxy-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 23 from 4-N-(butyl-N-ethyl sulfonyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Farewell, crystalline compound,

melting point 148-151°C.

Example 37: 6-aminocarbonyl-4-(N-butyl-N-ethylsulfonyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 24 from 4-(N-butyl-N-ethylsulfonyl)amino-6-carboxy-2,2-dimethylchroman. Colorless, crystalline substance,

melting point 195-199°C.

Example 38: 4-(N-butyl-N-ethylsulfonyl)amino-6-cyano-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 25 from 6-aminocarbonyl 1-4-N-butyl-N-ethyl sulfonylamino-2,2-dimethylchroman.

Colorless, crystalline substance,

melting point 96-98<*>C.

Example 39: 4-[N-ethylsulfonyl-N-(4-picolyl)amino]-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.005 M 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.015 M NaH and 0.007 M 4-picolyl chloride.hydrochloride. Dark colored, oily-amorphous substance. Example 40: 6-carboxy-4-[N-ethylsulfonyl-N-(4-picolyl)-amino]-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 23 from 4-[N-ethylsulfonyl-N-(4-picolyl)amnol]-6-methoxycarbonyl-2,2-dimethylchroman•

Colorless, crystalline substance,

melting point 210-212'C.

Example 41: 6-aminocarbonyl-4-[N-ethylsulfonyl-N-(4-picolyl)amino]-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 24 from 6-carboxy-4-N-ethylsulfonyl-N-{4-picolyl)amino-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 193-196'C.

Example 42: 6-piperidinocarbonyl-4-N-ethylsulfonyl-N-methylamino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 24 from 0.003 M 6-carboxy-4-[N-ethylsulfonyl-N-methylamino]-2,2-dimethylchroman, 0.0033 M N,N-carbonyldiimidazole and 0.012 M piperidine. Colorless crystals from ethanol,

melting point 184'C.

Example 43: 4-N-isopropylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 1 c) from 0.024 M 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with 0.0319 M ethanesulfonic acid chloride with excess TEA in THF under reflux conditions during 12 hours and by further purification of the product by column chromatography on silica gel with ethyl acetate:toluene 1:3 as eluent.

Colorless crystals,

melting point lll-llST.

Example 44: 4-(N-isopropylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol described in example 2 from 4-N-isopropylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and methyl iodide.

Colorless crystals,

melting point 115-119°C.

Example 45: 6-carboxy-4-(N-isopropylsulfonyl-N-methyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 23 from 4-(N-isopropyl sulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless crystals,

melting point 228-233°C.

Example 46: 6-aminocarbonyl-4-(N-isopropyl sulfonyl-N-methyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 6-carboxy-4-{N-isopropylsulfonyl-N-methyl)amino-2,2-dimethylchroman.

Colorless, crystalline product,

melting point 217-220°C.

Example 47: 6-cyano-4-(N-isopropyl sulfonyl-N-methyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 25 from 6-aminocarbonyl-4-(N-isopropylsulfonyl-N-methyl)amino-2,2-dimethylchroman. After isolating the product by filtration, it is purified by chromatography on silica gel with methylene chloride:methanol 10:1 and subsequent crystallization from diisopropyl ether after distilling off the solvent.

Colorless crystals,

melting point 129-135°C.

Example 48: 4-N-butylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol described in example 1 c) from 4-amino-2,2-dimethylchroman hydrochloride and 1-butylsulfonyl chloride.

Melting point 117-120°C.

Example 49: 4-(N-butylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol described in example 2 from 4-N-butyl sulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and methyl iodide.

Colorless to pale yellow, amorphous oily product.

Example 50: 4-(N-butylsulfonyl-N-methyl)amino-6-carboxy-2,2-dimethylchroman

is obtained analogously to the protocol described in example 23 from 4-(N-butylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline product,

melting point 200-205°C.

Example 51: 6-aminocarbonyl-4-(N-butylsulfonyl-N-methyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 4-(N-butylsulfonyl-N-methyl)amino-6-carboxy-2,2-dimethylchroman.

Colorless, crystalline product,

melting point 162-166°C.

Example 52: 6-cyano-4-N-butylsulfonyl-N-methylamino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 25 from 6-aminocarbonyl-4-(N-butylsulfonyl-N-methyl)amino-2,2-dimethylchroman. After isolating the product by filtration, it is purified by chromatography on silica gel with methylene chloride:methanol 10:1 and after distilling off the solvent, the substance is crystallized from diisopropyl ether.

Colorless crystals,

melting point 57-62°C.

Example 53: 6-methoxycarbonyl-4-(N-methyl-N-methylsulfonyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 2 from 6-methoxycarbonyl-4-N-methylsulfonylamino-2,2-dimethylchroman and methyl iodide.

Colorless, crystalline substance,

melting point 160-164°C.

Example 54: 6-carboxy-4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 23 from 6-methoxycarbonyl-4-N-methyl-N-methylsulfonylamino-2,2-dimethyl-chroman by alkaline hydrolysis.

Colorless, crystalline compound,

melting point 214-216<*>C.

Example 55: 6-aminocarbonyl-4-(N-methyl-N-methylsulfonyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 6-carboxy-4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethylchroman. Colorless, crystalline substance,

melting point 179-182<*>C.

Example 56: 6-cyano-4-(N-methyl-N-methylsulfonyl)amlno-2,2-dlmethylchroman

is obtained analogously to the 1 example 25 described protocol from 6-aminocarbonyl-4-(N-methyl-N-methylsulfonyl)amlno-2,2-dimethylchroman. After isolation of the product by filtration, it is purified by chromatography on silica gel with methylene chloride:methanol 10:1 and after distilling off the solvent, the substance is brought to crystallization from diisopropyl ether.

Colorless crystals,

melting point 196-200°C.

Example 57: 4-(N-ethylsulfonyl-N-ethyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0091 M 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 M NaH (as 80 µg suspension in oil) and 0.0126 M ethyl iodide in anhydrous DMA.

Colorless, crystalline substance,

melting point 114-116°C.

Example 58: 4-(N-ethylsulfonyl-N-propyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0091 M 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 M NaH (as 80% suspension in oil) and 0.0126 M 1-propyl iodide in anhydrous DMA.

Colorless, crystalline substance,

melting point 106-108'C.

Example 59: 4 - (N-ethylsulfonyl-N-cyclopropyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0091 M 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.0.13 M NaH (as 80 #-ig suspension in oil) and 0.0126 M bromomethyl -cyclopropane in anhydrous DMA.

Colorless, crystalline substance,

melting point 108-110°C.

Example 60: 4-(N-ethylsulfonyl-N-1-pentyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0091 M 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 M NaH (as an 80% suspension in oil) and 0.0126 M pentyl iodide in anhydrous DMA.

Oily, amorphous product.

Example 61: 4-(N-ethylsulfonyl 1-N-1-hexyl)amino-6-methoxycarbonyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0091 M 4-N-ethysulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 M NaH (as 80 5µg suspension in oil) and 0.0126 M hexyl iodide in anhydrous DMA.

Oily, amorphous product.

Example 62: 4-(N-ethylsulfonyl-N-methyl)amino-6,7-dimethoxy-2,2-dimethylchroman

a) 6,7-dimethoxy-2,2-dimethyl-4-chromanone oxime

obtained by reacting 0.0189 M 6,7-dimethoxy-2,2-dimethyl4-chromanone with 0.02 M hydroxylamine hydrochloride in a mixture of 20 ml methanol and 20 ml pyridine during 20 hours at 60-80' C. After distilling off the solvent, the colourless, crystalline product is obtained by treating the residue with water.

Melting point 110°C.

b) 4-amino-6,7-dimethoxy-2,2-dimethyl-4-chroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 6,7-dimethoxy-2,2-dimethyl-4-chloroanone-oxime and subsequent work-up in the presence of hydrochloric acid. Colorless, crystalline substance,

melting point 210-215°C.

c) 4-N-ethylsulfonylamino-6,7-dimethoxy-2,2-dimethylchroman is obtained analogously to example lc) (variant 1) from 4-amino-6,7-dimethoxy-2,2-dimethyl-4-chroman hydrochloride and ethanesulfonic acid chloride in THF in the presence of triethylamine.

Colorless, crystalline product,

melting point 132-135°C.

d) 4-(N-ethylsulfonyl-N-methyl)amino-6,7-dimethoxy-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 0.0036 M 4-N-ethylsulfonylamino-6,7-dimethoxy-2,2-dimethylchroman, 0.00504 M NaH (as 80 #-ig suspension in oil) and 0.0054 M methyl iodide in anhydrous DMA.

Amorphous, viscous oil.

Example 63: 7-chloro-4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman

a) 2-Fluoro-5-acetoxychlorobenzene

is obtained by reacting 3-chloro-4-fluorophenol in acetic anhydride at 80°C during 6 hours.

Colorless, crystalline product,

melting point 42-46°C.

b) 4-chloro-5-fluoro-2-hydroxyacetophenone

is obtained by heating a mixture of 0.0705 M 2-fluoro-5-acetoxychlorobenzene with 0.148 M anhydrous aluminum chloride under mechanical stirring at 120°C for 3 hours, splitting the reaction mixture with an ice-water/ice mixture and filtering the precipitate. A colorless, crystalline substance is obtained by treatment with activated carbon 1 methanol and after distillation of the solvent by subsequent digestion with a mixture of n-heptane and diisopropyl ether.

Colorless crystals,

melting point 66-71°C.

c ) 7-chloro-6-fluoro-2,2-dimethyl-4-chromanone

one obtains analogously to the protocol specified in example 18 b) from 4-chloro-5-fluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Colorless to slightly yellow, amorphous residue.

d) 7-chloro-6-fluoro-2,2-dimethyl-4-chromanone oxime is obtained analogously to the protocol specified in example 1 a) from

7-chloro-6-fluoro-2-dimethyl-4-chromanone and hydroxylamine hydrochloride.

Crystalline product,

melting point 120-125°C.

e) 7-chloro-6-fluoro-2,2-dimethyl-4-aminochroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 7-chloro-6-fluoro-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Two melting points:

1. melting point: 258-260"C during recrystallization of the melt,

2. melting point: >310°C.

f) 7-chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman is obtained analogously to the protocol specified in example 1 c) by

reaction of 7-chloro-6-fluoro-2,2-dimethyl-4-amino-chroman hydrochloride with ethanesulfonic acid chloride in the presence of TEA in

THF.

g) 7-chloro-4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 by reacting 7-chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman with sodium hydride and methyl iodide.

Colorless, crystalline substance,

melting point 104-107°C.

Example 64: 4-(N-ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman

a) 2,2,6-trimethyl-4-chromanone

one obtains analogously the 1 example 18 b) indicated protocol from

5-methyl-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Amorphous, oily product.

b) 2,2,6-trimethyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

2,2,6-trimethyl-4-chromanone and hydroxylamine hydrochloride. Crystalline product,

melting point 120-125°C.

c) 4-amino-2,2,6-trimethyl-4-amlnochroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 2,2,6-trimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Two melting points:

1. melting point: 245-248°C during recrystallization of the melt,

2. melting point: >310°C.

d) 4-ethylsulfonylamino-2,2,6-dimethylchroman

analogously to the protocol specified in example 1 c) is achieved by

reaction of 4-amino-2,2,6-trimethylchroman hydrochloride with ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline product,

melting point 114-117°C.

4-(N-ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman is obtained analogously to the protocol indicated in example 2 by reacting 4-ethylsulfonylamino-2,2,6-dimethylchroman with sodium hydride and methyl iodide.

Colorless, crystalline substance,

melting point 107°C.

Example 65: 6,7-dichloro-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman

a) 4,5-dichloro-2-hydroxyacetophenone

analogously, the protocol specified in example 63 b) is obtained from

Acetic acid-(3,4-dichlorophenylester) and anhydrous, active aluminum chloride.

Colorless to slightly yellowish, crystalline substance, melting point 100-103°C.

The acetic acid (3,4-dichlorophenyl ester) used is obtained from 3,4-dichlorophenol and acetic anhydride analogously to example 63 a) as a brown oil.

b) 6,7-dichloro-2,2-dimethyl-4-chromanone

analogously, the protocol specified in example 18 b) is obtained from

4,5-dichloro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Amorphous, brown, oily product.

c) 6,7-dichloro-2,2-dimethyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6,7-dichloro-2,2-dimethyl-4-chromanone and hydroxylamine.hydrochloride.

Crystalline product,

melting point 115-121<*>C.

d) 4-amino-6,7-dichloro-2,2-dimethylchroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 6,7-dichloro-2,2-dimethyl-4-chromanone-oxime and work-up in the presence of hydrochloric acid.

Two melting points:

1. melting point: 260-262°C during recrystallization of the melt,

2. melting point: >310°C.

e) 6,7-dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman is obtained analogously to the protocol specified in example 1 c) by

reaction of 4-amino-6,7-dichloro-2,2-dimethylchroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline product,

melting point 116-120°C.

f) 6,7-dichloro-4-(N-ethylsulfonyl-K-methyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 2 by reacting 6,7-dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman with sodium hydride with methyl iodide.

Colorless, crystalline substance,

melting point 102-106<*>C.

Example 66: 4-(N-ethylsulfony 1-N-methyl)amino-6-fluoro-7-pyrrolidino-2,2-dimethylchroman

a) 4,5-difluoro-2-hydroxyacetophenone

analogously, the protocol specified in example 63 b) is obtained from

acetic acid-(3,4-difluorophenyl)ester and anhydrous, active aluminum chloride.

Colorless to slightly yellowish colored crystalline substance, melting point 43-46°C (crystallization from n-heptane).

The acetic acid (3,4-difluorophenyl)ester used is obtained from 3,4-difluorophenol and acetic anhydride analogously to example 63 a) as a light oil.

b) 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone

is obtained analogously to the protocol specified in example 18 b) from

4.5-difluoro-2-hydroxyacetophenone and acetone in the presence of 1.1 mol equivalents of pyrrolidine in acetonitrile as solvent, whereby, in addition to the chromanone ring closure, the F atom present in the 7-position is exchanged for pyrrolidine. For further purification, the product can be separated by chromatography on silica gel with toluene:ethyl acetate 8:1 as eluent. Crystallization from n-heptane.

Colorless to slightly yellow, crystalline product,

melting point 96-98°C.

c) 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone oxime is obtained analogously to the 1 example 1 a) specified protocol from

6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.

Crystalline product,

melting point 148-152<*>C.

d) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-aminochroman.dihydro-chloride

is obtained analogously to the protocol indicated in example 1 b) by catalytic hydrogenation of 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid. Colorless, crystalline product,

melting point 124-137<*>C during cleavage.

e) 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonylamino-chroman

is obtained analogously to the protocol specified in example 1 c) by reaction from 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-amino-chroman dihydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline product,

melting point 157-159°C (from a mixture of diisopropyl ether and methanol).

f) 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-7-pyrrolidino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 by reaction from 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethyl-sulfonylaminochroman with sodium hydride and methyl iodide. Colorless, crystalline substance,

melting point 136-138°C.

Example 67: 4-(N-ethylsulfonyl-N-methyl)amino-6-fluorochroman

a) 6-fluoro-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6-fluoro-4-chromanone and hydroxylamine.hydrochloride. Crystalline product,

melting point 106-107'C.

b) 6-fluoro-4-aminochroman hydrochloride

analogously, the protocol specified in example 1 b) is obtained by

catalytic hydrogenation of 6-fluoro-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Melting point 252°C (decomposition).

c) 6-fluoro-4-ethylsulfonylaminochroman

one obtains analogously the protocol specified in example 1 c) from

6-fluoro-4-aminochroman.hydrochloride and ethanesulfonic acid chloride in the presence of TEA 1 THF.

Colorless, crystalline product,

melting point 107-108'C.

d) 4-(N-ethylsulfonyl-N-methyl)amino-6-fluorochroman is obtained analogously to the protocol specified in example 2 by

reaction of 6-fluoro-4-ethylsulfonylaminochroman with sodium hydride and methyl iodide.

Colorless to pale yellow oil.

Example 68: 4-(N-butyl-N-ethylsulfonyl)amino-6-fluorochroman

is obtained analogously to the protocol specified in example 2 by reacting 6-fluoro-4-ethylsulfonylaminochroman with sodium hydride and iodobutane.

Colorless to pale yellow oil.

Example 69: 4-(N-ethylsulfonyl-N-ethyl)amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and ethyl iodide. Amorphous, oily product. Example 70: 4-(N-ethy1sulfony1-N-propyl)-amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and propyl iodide.

Amorphous, oily product.

Example 71: 4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and butyl-iodold.

Amorphous, oily product.

Example 72: 4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]-amino-6-fluoro-2,2-dimethylchroman

one obtains analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and 4,4,4-trifluorobutyl 3-odide.

Amorphous, oily product.

Example 73: 4-(N-ethylsulfonyl-N-hexyl)amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and hexyl iodide.

Amorphous, oily product.

Example 74: 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylenechroman

a) 6-fluoro-2,2-tetramethylene-4-chromanone

one obtains analogously the 1 example 18 b) indicated protocol from

5-fluoro-2-hydroxyacetophenone and cyclopentanone in the presence of pyrrolidine in acetonitrile as solvent.

Amorphous, brown product.

b) 6-fluoro-2,2-tetramethylene-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6-fluoro-2,2-tetramethylene-4-chromanone and hydroxylamine hydrochloride.

Colorless to light brown, crystalline substance,

melting point 107-110°C.

c) 4-amino-6-fluoro-2,2-tetramethylenechroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 6-fluoro-2,2-tetramethylene-4-chromanone-oxime and work-up In the presence of hydrochloric acid.

Melting point 259-261°C during cleavage.

d) 4-ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman is obtained analogously to the protocol specified in example 1 c) from

4-amino-6-fluoro-2,2-tetramethylenechroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline substance,

melting point 111-113°C.

e) 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylene-chroman

is obtained analogously to the protocol specified in example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman and methyl iodide.

Amorphous, oily product.

Example 75: 4-[N-ethyl sulfonyl-N-(4,4,4-trifluorobutyl)]-amino-6-fluoro-2,2-tetramethylenechroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylaraino-6-fluoro-2,2-tetramethylenechroman and 4,4,4-trifluorobutyl iodide.

Viscous, oily-amorphous product.

Example 76: 4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino-6-fluoro-2,2-pentamethylenechroman

a) 6-fluoro-2,2-pentamethylene-4-chromanone

analogously, the protocol specified in example 18 b) is obtained

from 5-fluoro-2-hydroxyacetophenone o cyclohexanone in the presence of pyrrolidine in acetonitrile as solvent.

Bright, amorphous product.

b) 6-fluoro-2,2-pentamethylene-4-chromanone oxime

analogously, the protocol specified in example 1 a) is obtained from

6-fluoro-2,2-pentamethylene-4-chromanone and hydroxylamine.hydrochloride.

Viscous, amorphous product.

c) 4-amino-6-fluoro-2,2-pentamethylenechroman hydrochloride is obtained analogously to the protocol specified in example lb) by

catalytic hydrogenation of 6-fluoro-2,2-pentamethylene-4-chromanone-oxime and work-up in the presence of hydrochloric acid.

Melting point 262-264°C during cleavage.

d) 4-ethylsulfonylamino-6-fluoro-2,2-pentamethylenechroman is obtained analogously to the 1 example 1 c) specified protocol from

4-amino-6-fluoro-2,2-pentamethylenechroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Viscous, amorphous product.

e) 4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-pentamethylenechroman

is obtained analogously to the protocol specified in example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman and methyl iodide.

Amorphous, oily product.

Example 77: 6-ethyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylenechromane

a) 5-ethyl-2-hydroxyacetophenone

analogously, the protocol specified in example 63 b) is obtained

from acetic acid-(4-ethylphenylester) and anhydrous, active aluminum chloride.

Faint yellowish oil.

The acetic acid (4-ethylphenyl)ester used is obtained from 4-ethylphenol and acetic anhydride analogously to that in example 63 a) as an oil.

b) 6-ethyl-2,2-dimethyl-4-chromanone

analogously, the protocol specified in example 18 b) is obtained from

5-ethyl-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Light, oily amorphous product.

c) 6-ethyl-2,2-dimethyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6-ethyl-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride. Viscous, oily amorphous product.

d) 4-amino-6-ethyl-2,2-dimethylchroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 6-ethyl-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Melting point 201-204"C.

e) 6-ethyl-4-N-ethylsulfonylamino-2,2-dimethylchroman is obtained analogously to the protocol specified in example 1 c) from

4-amino-6-ethyl-2,2-dimethylchroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline substance,

melting point 104-108<*>C.

f) 6-ethyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman is obtained analogously to the protocol indicated in example 2 from 6-ethyl-4-N-ethylsulfonylamino-2,2-dimethylchroman and methyl iodide. Colorless, crystalline product,

melting point 76-77'C.

Example 78: 6-ethyl 1-4-[N-ethyl sulfonyl-N-= (4,4,4-trifluorobutyl)amino-2,2-dimethylchroman

one obtains analogously to the protocol specified in example 2 from 6-ethyl-4-N-ethylsulfonylamino-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide.

Colorless to candle oil oil.

Example 79: 7-chloro-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 by reacting 7-chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman with sodium hydride and 4,4,4-trifluorobutyl iodide.

Viscous, pale yellow oil.

Example 80: 4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]-amino-2,2,6-trimethylchroman

is obtained analogously to the protocol specified in example 2 by reacting 4-ethylsulfonylamino-2,2,6-trimethylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide.

Viscous, pale yellow oil.

Example 81: 6,7-dichloro-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 by reacting 6,7-dichloro-4-N-ethylsulfonylamino-2,2-dimethylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide. Viscous, light brown oil. Example 82: 4-(N-ethylsulfonyl-N-methyl)amino-6-phenyl-2,2-dimethylchroman

a) 2-hydroxy-5-phenylacetophenone

analogously, the protocol specified in example 63 b) is obtained

from 4-acetoxybiphenyl and anhydrous active aluminum chloride. Slightly yellowish oil that partially crystallizes. The 4-acetoxybiphenyl used is obtained from 4-hydroxybiphenyl and acetic anhydride according to example 63 a) as a colorless, crystalline solid,

fixed point 84-86<s>C.

b) 2,2-dimethyl-6-phenyl-4-chromanone

analogously, the protocol specified in example 18 b) is obtained from

2-hydroxy-5-phenylacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Dark, oily amorphous product, which partially crystallizes.

c) 2,2-dimethyl-6-phenyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6-phenyl-4-chromanone and hydroxylamine.hydrochloride. Crystalline solid,

fixed point 130-134<*>C.

d) 4-amino-2,2-dimethyl-6-phenylchroman hydrochloride is obtained analogously to the protocol indicated in example 1 b) by

catalytic hydrogenation of 2,2-dimethyl-6-phenyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Melting point 213-214<*>C (decomposition).

e) 4-N-ethylsulfonylamino-2,2-dimethyl-6-phenylchroman is obtained analogously to the protocol specified in example 1 c) from

4-amino-2,2-dimethyl-6-phenylchroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline substance,

melting point 162-164°C.

f) 4-(N-ethylsulfonyl-N-methyl)amino-6-phenyl-2,2-dimethylchroman is obtained analogously to the protocol indicated in example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-phenylchroman and methyl iodide. Colorless, crystalline product,

melting point 184-186°C.

Example 83: 4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]-amino-6-phenyl-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 by reacting 4-N-ethylsulfonylamino-2,2-dimethyl-6-phenylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide.

Colorless to pale yellow crystalline substance,

melting point 112-114<*>C.

Example 84: 6,8-difluoro-4-(N-ethyl sulfonyl-N-methyl Jamino-2,2-dlmethylchroman

a) 3,5-difluoro-2-hydroxyacetophenone

analogously, the protocol specified in example 63 b) is obtained

from acetic acid-(2,4-difluorophenylester) and anhydrous, active aluminum chloride.

Colorless, crystalline solid,

melting point 80-94<*>C.

The acetic acid (2,4-difluorophenyl ester) used is obtained from 2,4-difluorophenol and acetic anhydride analogously to the protocol described in Example 63 a) as a faint yellowish liquid.

b) 6,8-difluoro-2,2-dimethyl-4-chromanone

analogously, the protocol specified in example 18 b) is obtained from

3,5-difluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Dark, oily, amorphous product.

c) 6,8-difluoro-2,2-dimethyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6,8-difluoro-2,2-dimethyl-4-chromanone and hydroxylamine.hydrochloride.

Crystalline solid,

fixed point 130-134<*>C.

d) 4-amino-6,8-difluoro-2,2-dimethylchroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 6,8-difluoro-2,2-dlmethyl-4-chromanone-oxime and work-up in the presence of hydrochloric acid.

Melting point > 310°C (sublimation from 300°C, 1 atmosphere).

e) 4-N-ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman is obtained analogously to the protocol specified in example 1 c) from

4-amino-6,8-difluoro-2,2-dimethylchroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline substance,

melting point 124-127°C.

f) 6,8-difluoro-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman and methyl iodide.

Colorless, crystalline product,

melting point 84-86°C.

Example 85: 6,8-difluoro-4-[N-ethy1sulfony1-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide.

Colorless, crystalline product,

melting point 127-129°C.

Example 86: 4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]-amino-6-fluoro-7-pyrrolidino-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 by reacting 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonylaminochromen with sodium hydride and 4,4,4-trifluorobutyl iodide.

Colorless, crystalline substance,

melting point 137-140°C.

Example 87: 6-carboxy-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 23 by hydrolysis of 4-(N-ethylsulfonyl-N-ethyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 217-220<*>C.

Example 88: 6-carboxy-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 23 by hydrolysis of 4-(N-ethylsulfonyl-N-propyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 165-169°C.

Example 89: 6-carboxy-4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-dlmethylchroman

is obtained analogously to the protocol indicated in example 1 23 by hydrolysis of 4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 184-188°C.

Example 90: 6-carboxy-4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 23 by hydrolysis of 4-(N-ethylsulfonyl-N-pentyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 156-158°C.

Example 91: 6-carboxy-4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol indicated in example 1 23 by hydrolysis of 4-(N-ethylsulfonyl-N-hexyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless, crystalline compound,

melting point 154-158<*>C.

Example 92: 6-carboxamido-4-(N-ethyl-N-ethylsulfonyl Jamino-2,2-dimethylchroman

one obtains analogously to the protocol described in Example 24 from 6-carboxy-4-(N-ethylsulfonyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.

Colorless, crystalline substance,

melting point 173-175°C.

Example 93: 6-carboxamido-4-(N-ethylsulfonyl-N-propyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 6-carboxy-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.

Colorless, crystalline substance,

melting point 185-188°C.

Example 94: 6-carboxamido-4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 6-carboxy-4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.

Colorless, crystalline substance,

melting point 196-199°C.

Example 95: 6-carboxamido-4-(N-ethylsulfonyl-N-pentyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 24 from 6-carboxy-4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.

Colorless, crystalline substance,

melting point 168-172°C.

Example 96: 6-carboxamido-4-(N-ethylsulfonyl-N-hexyl)-amino-2,2-dimethylchroman

is obtained analogously to the protocol described in example 1 24 from 6-carboxy-4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.

Colorless, crystalline substance,

melting point 148-152<*>C.

Example 97: 6-cyano-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman

the protocol specified in example 25 is obtained analogously from 6-carboxy-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman with subsequent cleaning by column chromatography on silica gel with methylene chloride:methanol 10:1 as eluent.

Colorless to pale yellow, crystalline substance,

melting point 127-130°C.

Example 98: 6-cyano-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman

one obtains analogously to the protocol indicated in example 25 from 6-carboxy-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman with subsequent cleaning by column chromatography on silica gel with methylene chloride:methanol 10:1 as eluent. Colorless to pale yellow, crystalline substance,

melting point 127-130°C.

Example 99: 6-cyano-4-(N-cyclopropylmethyl-N-ethylsulfonyl)-amino-2,2-dimethylchroman

the protocol specified in example 25 is obtained analogously from 6-carboxamido-4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman with subsequent cleaning by column chromatography on silica gel with methylene chloride."methanol 10: 1 as eluent.

Colorless to pale yellow, crystalline substance,

melting point 127-130°C.

Example 100: 6-cyano-4-(N-ethyl sulfonyl-N-pentyl)amino-2,2-dimethylchroman

one obtains analogously to the protocol indicated in example 25 from 6-carboxamido-4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman with subsequent cleaning by column chromatography on silica gel with methylene chloride:methanol 10:1 as eluent.

Viscous, oily liquid.

Example 101: 6-cyano-4-(N-ethyl sulfonyl 1-N-hexyl)amino-2,2-dimethylchroman

one obtains analogously to the protocol specified in example 25 from 6-carboxamido-4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman with subsequent cleaning by column chromatography on silica gel with methylene chloride imethanol 10:1 as eluent.

Viscous, yellow, oily liquid.

Example 102: 4-(N-ethoxycarbonylmethyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and bromoacetic acid ethyl ester.

Colorless, crystalline product,

melting point 112-114°C.

Example 103: 4-[N-ethylsulfonyl-N-methyl]amino-6-fluoro-2,2-pentamethylenechroman

is obtained analogously to the protocol specified in example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-pentamethylenechroman and methyl iodide.

Colorless, crystalline compound,

melting point 73-74"C.

Example 104: 4-(N-isopropyloxycarbonylmethyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman

one obtains analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and bromo-acetic acid isopropyl ester.

Colorless to pale yellow liquid.

Example 105: 4-(N-ethyl sulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman

a) 6-hydroxy-2,2-dimethyl-4-chromanone

analogously, the protocol specified in example 18 b) is obtained

from dlhydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

crystalline compound,

melting point 147-149°C.

b) 6-methoxy-2,2-dimethyl-4-chromanone

To a suspension of 0.03 M 6-hydroxy-2,2-dimethyl-4-chromanone, 75 ml of acetone and 16.1 g of anhydrous, powdered potassium carbonate is added an excess of 3.6 ml of methyl iodide and the reaction mixture is heated for 20 hours more 50-55°C. The solvent is removed by vacuum distillation, after which water is added to the residue and the oil that separates is extracted with ethyl acetate. After drying the organic phase over anhydrous sodium sulfate, the solvent is distilled off and 6-methoxy-2,2-dimethyl-4-chromanone is obtained as an oily liquid.

c) 6-methoxy-2,2-dimethyl-4-chromanone oxime

one obtains analogously the protocol specified in example 1 a) from

6-methoxy-2,2-dimethyl-4-chromanone and hydroxylamine.hydrochloride.

Crystalline solid,

solid point 108-112°C.

d) 4-amino-6-methoxy-2,2-dimethylchroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 6-methoxy-2,2-dimethyl-4-chromanone-oxime and work-up in the presence of hydrochloric acid.

Melting point 250-251°C.

e) 4-N-ethylsulfonylamino-6-methoxy-2,2-dimethylchroman is obtained analogously to the protocol specified in example 1 c) from

4-amino-6-methoxy-2,2-dimethylchroman.hydrochloride in the presence of

TEA in THF.

Colorless, crystalline substance,

melting point 131-133°C.

f) 4-(N-ethylsulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman

is obtained analogously to the protocol specified in example 2 from 4-N-ethylsulfonylamino-6-methoxy-2,2-dimethylchroman and methyl iodide.

Colorless, crystalline product,

melting point 68-70°C.

Example 106: 4-N-ethylsulfonyl amino-2,2-dimethyl-6-methyl-

sulphonyloxyromane

a) 2,2-dimethyl-6-methylsulfonyloxychromanone

A mixture of 0.03 M 6-hydroxy-2,2-dimethyl-4-chromanone, 16.1

g of anhydrous, powdered potassium carbonate and 10 ml of methanesulfonic acid in 80 ml of anhydrous DMF are heated for 10 hours to 80" C. The solvent is then distilled off under reduced

pressure and the residue is stirred after adding 150 ml of water for 2 hours. The crystalline precipitate is filtered off, washed several times with water and dried in a stream of air. Colorless solid,

melting point 108-110°C.

b) 2,2-dimethyl-6-methylsulfonyloxymanonoxime is obtained analogously to the protocol specified in example 1 a) from

2,2-dimethyl-6-methylsulfonyloxychromanone and hydroxylamine hydrochloride.

Crystalline solid,

solid point 166-167°C.

c) 4-amino-6-methylsulfonyloxy-2,2-dimethylchroman hydrochloride is obtained analogously to the protocol specified in example 1 b) by

catalytic hydrogenation of 2,2-dimethyl-6-methylsulfonyloxy-chromanone oxime and work-up in the presence of hydrochloric acid. Melting point 229-231°C.

e) 4-N-ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyloxychroman

is obtained analogously to the protocol indicated in example c) from 4-amino-6-methylsulfonyloxy-2,2-dimethylchroman hydrochloride and ethanesulfonic acid chloride in the presence of TEA in THF.

Colorless, crystalline substance,

melting point 97-100°C.

Example 107: 4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-6-methylsulfonyloxychroman is obtained analogously to the protocol specified in example 1 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6- methylsulfonyloxychroman and methyl iodide.

Colorless, crystalline product,

melting point 137-139°C.

Example 108: 4-(N-methylsulfonyl-N-methyl)amino-2,2,6,7-tetramethylchroman

was obtained analogously to the method described in example 2 from 4-N-methylsulfonylamino-2,2,6,7-tetramethylchroman and ethyl iodide.

Colorless crystals,

melting point 119-121°C.

The hydrochloride of 4-amino-2,2,6,7-tetramethylchroman (melting point > 270°C) was prepared by hydrogenation of 2,2,6,7-tetramethyl-4-chromanone oxime (melting point 162-163°C). The oxime was formed in a manner known per se as described above from the corresponding 2,2,6,7-tetramethyl-4-chromanone. Conversion of 4-amino-2,2,6,7-tetramethylchroman with the corresponding alkylsulfonyl chlorides as described in example 1 (variant 1) resulted in raethylsulfonylamino-2,2,6,7-tetramethylchroman (colorless oil) respectively ethylsulfonylamino-2, 2,6,7-tetramethylchroman (colorless oil).

Example 109: 4-(N-methylsulfonyl-N-methyl)amino-2,2,6,7-tetramethylchroman

was obtained analogously to the procedure indicated in Example 2 from 4-N-methylsulfonylamino-2,2,6,7-tetramethylchroman and methyl iodide.

Colorless crystals,

melting point 105-107"C.

Example 110: 4 - (N-ety 1 sulfony 1 -N-hex sy 1 )amino-2,2,6,7-tetramethylicromane

was obtained analogously to the procedure indicated in Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and hexyl iodide.

Colorless oil

Example 111: 4-(N-ethylsulfonyl-N-ethyl)amino-2,2,6,7-tetramethylchroman was obtained analogously to the procedure indicated in example 2 from 4-N-ethylsulfonylamino-2,2,6,7 -tetramethylchroman and ethyl iodide.

Colorless crystals,

melting point 93-95°C.

Example 112: 4-(N-ethy1sulfony1-N-buty1)amino-2,2,6,7-tetramethylchroman

was obtained analogously to the procedure indicated in Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and butyl iodide.

Colorless crystals,

melting point 81-83°C.

Example 113: 4-(N-ethylsulfonyl-N-methyl)amino-2,2,6,7-tetramethylchroman

was obtained analogously to the procedure indicated in 1 Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and methyl iodide.

Colorless crystals,

melting point 132-134°C.

Example 114: 4-(N-ethylsulfonyl-N-butyl)amino-7-methoxy-2,2-dlmethylchroman

was obtained analogously to the procedure indicated in Example 2 from 4-N-ethylsulfonylamino-7-methoxy-2,2-dimethylchroman and butyl iodide.

Colorless oil.

The hydrochloride of 4-amino-7-methoxy-2,2-dimethylchroman (melting point 239-241°C) was prepared by hydrogenation of 7-methoxy-2,2-dimethyl-4-chromanone oxime (melting point 124-126<*>C ). The oxime was obtained in a manner known per se from the corresponding 7-methoxy-2,2-dimethyl-4-chromanone. Conversion of 4-amino-7-methoxy-2,2-dimethylchroman with the corresponding alkylsulfonyl chlorides as described in example 1 (variant 1) resulted in methylsulfonylamino-7-methoxy-2,2-dimethylchroman (colorless oil) respectively ethylsulfonylamino-7- methoxy-2,2-dimethylchroman (melting point 111-113°C).

Example 115: 4-(N-ethyl sulfonyl-N-ethyl)amino-7-methoxy-2,2-dimethylchroman was obtained analogously to the procedure indicated in example 2 from 4-N-ethylsulfonylamino-7-methoxy-2 ,2-dimethylchroman and ethyl iodide.

Colorless oil.

Example 116: 4-(N-ethyl sulfonyl-N-methyl)amino-7-methoxy-2,2-dimethylchroman

was obtained analogously to the procedure indicated in Example 2 from 4-N-ethylsulfonylamino-7-methoxy-2,2-dimethylchroman and methyl iodide.

Colorless oil

Example 117: 4-(N-ethylsulfonyl-N-methyl)amino-6-(4,4,4-trifluorobutyl)oxy-2,2-dimethylchroman

was obtained analogously to the procedure indicated in Example 2 from 4-N-ethylsulfonylamino-5-(4,4,4-trifluorobutyl)oxy-2,2-dimethylchroman and methyl iodide. Colorless, crystalline compound from n-heptane:diisopropyl ether,

melting point 68-72°C.

4-N-ethylsulfonylamino-6-(4,4,4-trifluorobutyl) and sy-2,2-dimethylchroman (melting point 84-90°C) was obtained in the

sequence of synthetic steps indicated above from 6-hydroxy-2,2-dimethyl-4-chromanone (obtained from 2-acetoxyhydroquinone and acetone, mp 147-149°C) via 6-(4,4,4, -trifluorobutyl )oxy-2,2-dimethyl-4-chromanone (obtained from 6-hydroxy-2,2-dimethyl-4-chromanone and 4,4,4-trifluorobutyl iodide, melting point 53-55°C) and 6-( 4,4,4-trifluorobutyl)oxy-2,2-dimethyl-4-chromanone oxime (obtained from 6-(4,4,4-trifluorobutyl)oxy-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride , melting point 94-97°C) and 4-amino-6-(4,4,4-trifluorobutyl)oxy-2,2-dimethylchroman (obtained from 6-(4,4,4-trifluorobutyl)oxy-2,2 -dimethyl-4-chromanone oxime and catalytic hydrogenation with Saney nickel, melting point 47-49°C) and subsequent reaction of 4-amino-6-(4,4,4-trifluorobutyl)-oxy-2,2-dimethylchroman and ethanesulfonyl chloride .

Example 118: 6-(4-bromophenyl)-4-(N-ethylsulfonyl-N-methyl)-amino-2,2-dimethylchroman

was obtained analogously to the procedure indicated in Example 2 from 6-(4-bromophenyl)-4-N-ethylsulfonylamino-2,2-dimethylchroman and methyl iodide.

Melting point 160-170°C.

6-(4-Bromophenyl)-4-N-ethylsulfonylamino-2,2-dimethylchroman (m.p. 122-135°C) was obtained in the sequence of synthetic steps indicated above from 3-acetyl-4'-bromo-4 -hydroxybiphenyl (obtained from 4'-bromo-4-acetoxybiphenyl and aluminum chloride by a Friess rearrangement, dark brown oil) via 6-(4-bromophenyl)-2,2-dimethyl-4-chromanone (obtained from 3-acetyl-4 '-bromo-4-hydroxybiphenyl and acetone, viscous oil) and 6-(4-bromophenyl)-2,2-dimethyl-4-chromanone oxime (obtained from

6-(4-bromophenyl)-2,2-dimethyl-4-chromanone, viscous oil) and 6-(4-bromophenyl)-4-amino-2,2-dimethylchroman.hydrochloride (obtained from 6-(4-bromophenyl )-2,2-dimethyl-4-chromanone oxime and catalytic hydrogenation with Raney nickel and treatment with a solution of HCl 1 diethyl ether, melting point 166-170°C) and subsequent reaction of 4-amino-6-(4-bromophenyl) -2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the presence of triethylamine.

Example 119: 4 - (N-ethyl sulfonyl-N-methyl)amino-2,2-diroethyl-6-methoxychroman

was obtained analogously to the procedure described in example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-methoxychroman and butyl iodide.

Colorless, crystalline product,

melting point 78-80°C.

Example 120:

The enantiomers of (+)-4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman and (ø)-4-(N-ethylsulfonyl-N-methyl)amino-8-fluoro -2,2-dimethylchroman (cx = -24.5")

was obtained from a racemic mixture of 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman by chlral chromatography (CSP Chiralpak AD 250<*>4.6, eluent n-hexane:ethanol 40: 1).

Example 121:

The enantiomers of {+)-4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman and (- )-4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro- 2,2-Dimethylchromane (cx= -53.5°) was obtained from a racemic mixture of 4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchromane by chiral chromatography (CSP Chiralpak AD 250M.6, eluent n-hexane:ethanol 80:1). Example 122: 4-(N-methylsulfonyl-N-isopropyl)amino-2,2,6- trimethylchroman

was obtained analogously to the procedure described in Example 2 from 4-N-methylsulfonylamino-2,2,6-trimethylchroman and isopropyl iodide.

Colorless, crystalline product,

melting point 140°C.

Example 123: 4-[N-methylsulfony 1-N-{3-methylbutyl)]amino-2,2,6,-trimethylchroman

was obtained analogously to the procedure described in example 2 from 4-N-methylsulfonylamino-2,2,6-trimethylchroman and 3-methylbutyl iodide.

Viscous oil.

Example 124: 4-[N-ethylsulfonyl-N-(3-ethoxypropyl)]amino-2,2,6-trimethylchroman

was obtained analogously to the procedure described in example 2 from 4-N-ethylsulfonylamino-2,2,6-trimethylchroman and 3-ethoxypropyl iodide.

Viscous oil.

Pharmacological investigations:

IgG channels from humans, rats and guinea pigs are expressed in Xenopus oozytes. For this purpose, Xenopus Laevis oocytes are first isolated and defolliculated. The oocytes are then injected with in vitro synthesized Ig^-encoding TNA. After 2 to 8 days of IgG protein expression, the IgG currents are measured with the two-microvoltage-clamp technique. In this way, the Isk~ channels are activated as a rule with 15-second voltage jumps of -10 mV and the bath is flushed with a control solution with the following composition (mM): NaCl 96, KC1 2, CaCl2 1.8, MgClg 1, HEPES 5 (titrated with NaOH to pH 7.5). These experiments were carried out at room temperature. The software used for data processing and analysis were: Geneclamp amplifier (Axon Instruments, Foster City, USA) and MacLab D/A converter and software {ADInstruments, Castle Hill, Australia). The chromanols were tested, being added in different concentrations of the control solution. The effect of the chromanols was calculated as percentage inhibition of the I gjf-control current. The data obtained were then extrapolated with the Hlll equation to determine the ICgø values for the substances in question.

The data obtained are given as mean values with standard deviation (S.E.M.). n indicates the number of completed trials. Statistical significance was determined by the paired Student's t-test.

References:

Busch, A.E., Kopp, H.-G., Waldegger, S., Samarzija, I., Suøbrich, H., Raber, G., Kunzelmann, K., Ruppersberg, J.P. and Lang, F., (1995) "Inhlbition of both exogenously expressed

*sK and endogenous K<+> channels in Xenopus oocytes by isosorbldinitrate", "J. Physiol., 491: 735-741;

Takumi, T., Ohkubo, H. and Nakanischi, S. (1989) "Cloning of a membrane protein that induces a slow voltage-gated potassium current", "Science", 242: 1042-1045;

Varnum, M.D., Busch, A.E., Bond, C.T., Maylie, J., and Adelman, J.P. (1993) "The minK channel underlies the cardiac potassium current and mediates species-specific responses to protein kinase" ["C Proe Nati Acad Sei USA" 90: 11528-11532].

Inhibition of gastric acid secretion, antiulcer effect:

Method: The high-pressure perfusion of the rat stomach was carried out according to the description given by Berghlind and Obrink (1) and using some modifications, as has been reported elsewhere (2). Rabbits (males and females, 2-3 kg) were euthanized without pain and under anesthesia by cervical dislocation and the stomach was perfused as stated in the literature (1). Mucosa from the gastric fundus was removed with a scraper and finely divided with scissors. The mucosa fragments thus obtained were treated with 1 mg/ml collagenase in a medium consisting of 100 mM NaCl, 5 mM KC1, 0.5 mM NaH2PO4, 1 mM Na2HP04, 1 mM CaCl2, 1.5 mM MgClg, 20 mM NaHCO3, 20 mM HEPES, 2 mg/ml glucose and 1 mg/ml canalicular albumin for 30-45 minutes at 37°C, whereby the pH value in the mixture was adjusted to 7.4 with Tris buffer. The gastric glands were filtered through a nylon mesh to remove coarse fragments and washed 3 times with incubation medium. The tubes were then suspended in medium at a concentration of 2-4 mg dry weight/ml. As a measure of the ability of the gastric glandular tubes to produce acid, the accumulation of <14>C-aminopyrine (<14>C-AP) was determined (3). For this purpose, samples of 1 ml of gland-tube suspension with <l>^C-AP (1 pM, 200,000 cpm) and the compound to be tested were incubated and treated for 20-30 minutes at 37<*>C in a shaken water bath. Then hlstamine (100 µM), dbcAMP (0.3 or 1 mM) or Carbachol (100 µM) was added, followed by a second incubation period of 30-45 minutes. The incubation was then terminated by centrifuging the samples for half a minute. The supernatant was removed and the obtained pellets dissolved in 1 ml of NaOH. The samples of pellets and the supernatant were measured in a scintillation counter. The AP ratio for the intraglandular and extraglandular radioactivity was calculated according to Sack and Spenney (4). All determinations were carried out three times.

Result: 6-cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-3-chromanol caused a concentration-dependent inhibition of the stimulated AP accumulation with ICgø values of 20 uM after histamine and dbc -AMP stimulation as well as at 5 jM after stimulation with Carbachol.

Literature references:

1. Berghlind, T., Obrink, K.J., "A method for preparing isolated glands from the rabbit gastric mucosa", "Acta Physiol. Sean.", 96, 150-159 (1976); 2. Herling, A.W., Becht, M., Keiker, W., Ljungstrom, M. , Bickel, M. "Inhibition of <14>C-amlnopyrine accumulation in isolated rabbit gastric glands by the Hg-receptor antagonist", HOE 760 (TZU-0460). "Agents and Actions", 20: 35-39 (1987).

3. Berghlind, T. , Helander, H.F., Obrink, K.J., "Effect of secretagogues on oxygen consumption, amlnopyrine accumulation and morphology ln isolated gastric glands", "Acta

Physiol. Scand., 97: 401-414 (1976).

4. Sack, J. Spenney, J.G., "Amlnopyrine accumulation by mammalian gastric glands: an analysis of the technique", "Am. J. Physiol.", 243: G 313 - G 319 (1982).

In experiments, the ICgg value has been determined for 28 of the compounds according to the invention and the data obtained are summarized in the following table:

Claims (20)

1. Chromanes, characterized by the general formula (I): there R1 and R2 independently means C 1-3 alkyl; or Ri and R2 together means C2-6 alkylene; R3 means R9-Cn-H2n[NRii]ni-; R 8 means hydrogen; n means 0, 1, 2, 3 or 4; m means 0 or 1; R 1 means hydrogen or C 1-2 alkyl; R 4 means R 1 -CrHgr; 12 means hydrogen, C3-cycloalkyl, piperidyl, N-morpholino, N-methylpiperazino, CF3, pyridyl or phenyl, which is unsubstituted or may be substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy; r means 1, 2, 3, 4, 5, 6, 7, 8; whereby the CH2 group in the group CrHgr can be replaced by -0-, -CO-0-, -S(0)q- or -HR1G~; q means 0, 1 or 2; and R 10 means hydrogen, methyl or ethyl; R5, R6, R7 and R8 independently means hydrogen, F, Cl, Br, I, C1_4-alkyl, -CN, -CF3, -N02, -C0NR13<R>14, <->C00R15, <R>16-<C>s<H >2s_<Y>-'R^3 and R^4 independently of each other are hydrogen; R 8 is hydrogen, methyl or ethyl. R^f, means hydrogen, C3-cycloalkyl, COOR^g, pyridyl, piperidyl, N-morpholIno, C-^Fgt+i or phenyl; which is optionally substituted with 1 or 2 substituents selected from the group comprising F, Cl, Br, I, CF 3 , methyl or methoxy; s means 0, 1 or 2; t means 1, 2 or 3; Y means S0q, -CO-, -O-, -NR10-; whereby, however, Rf cannot be -OCF3 or -OC2Fg; as well as physiologically acceptable salts thereof. 2. Chromanes of formula (I) according to claim 1, characterized in that: R1°g R2 independently means C 1-3 alkyl or together means a C 4-8 alkylene chain; R3 means Rg-Cn-<H>2n[NRn]m-; R 9 means hydrogen; n means 0, 1, 2, 3 or 4; m means 0 or 1; Rn means hydrogen or C1-2 alkyl; R4 means R12-<C>rH2r; 12 means hydrogen, CF3, pyridyl or phenyl, which is optionally substituted with 1 or 2 substituents selected from the group consisting of F, Cl or CF3; r means 1, 2, 3, 4, 5, 6, 7 or 8; whereby a CH2 group in the group CrHgr may be replaced by -0-, -CO-, -CO-O- or -S{0)q-; q means 0, 1 or 2; R5, R6, R7 and R8 independently means hydrogen, F, Cl, Br, I, C1-6 alkyl, -CN, -CF3, <->N02, -C0N<R>13<R>14> -C00<R>15 or < R>16"<c>s<H>2s"Y"! R^3 and R^4 independently of each other mean hydrogen; R^5 means methyl or ethyl. Ulf, means hydrogen, C^Fgt+i or phenyl; which is optionally substituted with a substituent selected from F, Cl, Br, CF3, methyl or methoxy; t means 1, 2, or 3; s means 0, 1 or 2; Y means S0q, -CO-, -O- or -NR10-; q means 0, 1 or 2; Rio means hydrogen or methyl; whereby, however, Rf cannot be -OCF3 or -OC2F5. 3. Chromanes with formula (I) according to claim 1 or 2, characterized in that Kl and R2 independently means methyl; R 3 means C 1-4 alkyl, dimethylamino or diethylamino; R 4 means R 1 -C 1 -Hgr*; 12 means hydrogen or CF3; r means 1, 2, 3, 4, 5, 6, 7 or 8; whereby a CHg group in the group CrHgr may be replaced by -0-, -CO-, -CO-0- or -S(0)q-; q means 0, 1 or 2; R5, R6, R7 and R8 independently of each other means hydrogen, F, Cl, Br, I, C-L-g-alkyl, -CN, -NO2, -CO0R15 or R16-cs<H>2s~<Y>~<; > R-L5 means methyl or ethyl. R 1 f , means hydrogen, CF 3 or phenyl; s means 0, 1 or 2; Y means S0q, -CO-, -O- or -NRiq-; q means 0, 1 or 2; Rlø means hydrogen or methyl; whereby, however, Rf cannot be -OCF3. 4. Chromanes with formula (I) according to claims 1 to 3, characterized in that they are selected from the group: 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchromane, 6-cyano-4- (N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman, 4-{N-ethylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman, 6-cyano-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethylchroman, 4-(N-butyl-N-ethylsulfonyl)amino-6-cyano-2, 2-dimethylchroman, 4-(N-ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman, 7-chloro-4-(N-ethyl sulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman, 6,7-dichloro-4-(N-ethylsulfonyl-N-methyl)amino-2 ,2-dimethylchroman, 4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman, 4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylene -chromane , 4-[N-ethyl 1 sulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-dimethylchromane, 4-{N-ethylsulfonyl-N-hexyl)amino-6 -fluoro-2,2-dimethylchroman, 6-ethyl-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethylchroman. 5. Process for producing a compound of formula (I) according to claim 1, characterized in that one aj reacts a compound of formula (II) where Rlf R2 , R5■ R6• R7 °S R8 when the stated meaning and L means a typical for an alkylation, nucleofuge cleavable group, especially Cl, Br, I, MeSOg-O-, a p-toluenesulfonyloxy acid residue, with a sulfonamide or a salt thereof of formula (III) where R 3 and R 4 have the indicated meaning, and M means hydrogen or preferably a metal atom and especially lithium, sodium or potassium; or that one b) reacts a compound of formula (IV) where R 1 , R 8 , R 4 . Rg, R&. R7 and Rg have the meaning stated above, with r in the substituent R4 also having the meaning zero, with a sulfonic acid derivative of formula (V) where R 3 has the above meaning and W means a nucleofuge, cleavable group such as fluorine, bromine, 1-imidazolyl or especially chlorine; or that one c) converts a compound of formula (VI) where Rj, Rg, R5, Rf1, R7, Rg and M have the indicated meaning, in a manner known per se with an alkylating agent of formula VII by an alkylation reaction, R 4 apart from hydrogen and L having the indicated meaning; or that one d) 1 a compound of formula (I) where Rj to R4 have the indicated meaning, in at least one of the positions Rg to Rg carries out an electrophilic substitution reaction, where this position means hydrogen and the other substituents Rg to Rg have the above indicated meaning. 6. Medicine, characterized in that it contains an effective amount of a compound of formula (I) according to one of claims 1 to 4. 7. Use of a compound of formula (I) according to claim 1 for the preparation of a drug for blocking the K<+->channel-. which is opened by cyclic adenosine monophosphate (cAMP). 8. Use of a compound of formula (I) according to claim 1 for the preparation of a drug for inhibiting gastric acid secretion. 9. Use of a compound of formula (I) according to claim 1 for the production of a drug for the treatment of ulcers in the stomach and intestinal area, in particular the duodenum. 10. Use of a compound of formula (I) according to claim 1 for the preparation of a drug for the treatment of reflux oesophagitis. 11. Use of a compound of formula (I) according to claim 1 for the production of a drug for the treatment of diarrheal diseases. 12. Use of a compound of formula (I) according to claim 1 for the preparation of a drug for the therapy or prevention of all types of arrhythmias including ventricular and supraventricular arrhythmias. 13. Use of a compound of formula (I) according to claim 1 for the preparation of a medicament for the control of reentry arrhythmias and for the prevention of sudden cardiac death as a result of ventricular fibrillation. 14. Use of a compound of formula (Ia) there RA means hydrogen, OH, -O(C0)-alkyl with 1, 2, 3 or 4 C—atoms or -O-SOg-alkyl with 1,2, 3 or 4 C atoms; R 8 means hydrogen; or RA and RB together means a bond; Rj to R4 are as stated in claim 1; Rc means CN, acyl with 1, 2, 3, 4, 5 or 6 C atoms, F, Cl, Br, I, NO 2 or alkyl of 1, 2, 3, 4, 5 or 6 carbon atoms; for the manufacture of a drug for blocking the K<+> channel opened by cyclic adenosine monophosphate (cAMP). 15. Use of a compound of formula (Ia) according to claim 6 for the production of a drug for inhibiting gastric acid section. 16. Use of a compound of formula (Ia) according to claim 6 for the preparation of a drug for the treatment of ulcers in the stomach and intestinal area, particularly the duodenum. 17. Use of a compound of formula (Ia) according to claim 6 for the preparation of a drug for the treatment of reflux oesophagitis. 18. Use of a compound of formula (Ia) according to claim 6 for the preparation of a drug for the therapy or prevention of all types of arrhythmias including ventricular and supraventricular arrhythmias. 19. Use of a compound of formula (Ia) according to claim 6 for the preparation of a medicament for the control of reentry arrhythmias and for the prevention of sudden cardiac death as a result of ventricular fibrillation. 20. Use of 6-cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-3-chromanol as a compound of formula (Ia) According to claim 6 for the preparation of a drug for inhibition of gastric acid secretion.