IE63872B1

IE63872B1 - The use of substituted 3,4-dihydro-2h-benzopyrans as remedies for obstructive functional disorders of the lungs

Info

Publication number: IE63872B1
Application number: IE232389A
Authority: IE
Inventors: Heinrich Christian Englert; Erik Klaus; Dieter Mania; Bernward Schoelkens
Original assignee: Hoechst Ag
Priority date: 1988-07-19
Filing date: 1989-07-18
Publication date: 1995-06-14
Also published as: AU621388B2; PH26696A; DK355489D0; DK171782B1; PT91197A; FI893460A; EP0560399A1; IE892323L; DE3824446A1; NZ229961A; IL91015A; DK355489A; EP0351720A3; KR900001367A; HUT55988A; CZ417091A3; PT91197B; DE58908228D1; FI893460A0; EP0351720B1

Abstract

The use of 3,4-dihydro-2H-benzo[b]pyrans of the formula I <IMAGE> in which R<1> is H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR<4>R<5>, where R<4> and R<5> are identical or different and are H, (C1-C2)-alkyl or (C1-C3)-alkylcarbonyl, R<2> and R<3> are identical or different and are alkyl with 1-4 C atoms, Ar is an aromatic or heteroaromatic system which is unsubstituted or substituted by 1 to 3 identical or different radicals (C1-C2)-alkyl, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n is 1 or 2, X is a chain (CH2)r which can be interrupted by a heteroatom O, S or NR<6> where R<6> is H or (C1-C4)-alkyl and r is the numbers 2, 3, 4 or 5, for the production of a medicament for urinary tract disorders.

Description

Description The use of substituted 3,4-dihydro-2H-benzopyrans as remedies for obstructive functional disorders of the lungs The invention relates to the use of 3,4-dihydro-2H-benzo[b]pyrans of the formula I I, in which R1 represents H, OH, (C1-C2)-alkoxy, (Ci-Cj)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C^-Cj) alkyl or (Ci-Cj)-alkylcarbony 1, and R3 are identical or different and represent alkyl having 1-4 carbon atoms, Ar represents an aromatic or heteroaromatic system which is unsubstituted or substituted by 1 to 3 identical or different radicals (C1-C2) -alkyl, (CjC2)alkoxy, halogen, tri fluoromethyl, CN, NO2, CO-(C1C2) alkyl or SOa-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, represents a chain (CH2)r which car. be interrupted by a heteroatom O, S or NR4, where R4 denotes H or (^C«)-alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy functional disorders of the lungs. for obstructive An aromatic system Ar is preferably to be understood to be phenyl, naphthyl or biphenylyl, and a 5- or 6-membered heteroaromatic system Ar is preferably a radical of a 5or 6-membered 0, N and/or S heterocyclic ring, especially furyl, thienyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl.

Halogen is to be understood to be F, Cl, Br or I, preferably F and Cl.

Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzo [b] pyran system (also called chroman system hereinafter for brevity) of the formula X are asymmetrically substituted. In this connection, the invention relates only to those compounds which have opposite configurations at these centers, that is to say have a trans orientation of the substituents on these carbon atoms. If one of the substituents R1, ArSOn, R2 and/or R3 contains centers of asymmetry, or if R2 and R3 are not the same (and thus generate an asymmetric carbon atom), the invention relates to compounds with centers both of the S and of the R configuration.

The compounds can be in the form of optical isomers, diastereoisomers, racemates or mixtures thereof.

Preferably used are compounds of the formula I in which R1 to R3 and ArSOa have the abovementioned meanings, but X represents a chain (CH2)r with r = 3 or 4.

Very particularly preferably used are those compounds in which R1 to R3 have the abovementioned meanings, Ar represents phenyl which is unsubstituted or substituted as defined above, n represents 2, and X a chain (CHj)r with r = 3 or 4.

Especially preferably used are those compounds in which R1 denotes H, R2 and R3 represent (Cx-Ca) alkyl, Ar represents phenyl which is unsubstituted or substituted once by (Cj-C,)-alkyl, (Cx-C3)-alkoxy or halogen, n represents 2, and X a chain (CH3)r with r = 3 or 4.

Likewise preferred are compounds with R1 equal to H, R2 and R3 equal to (Cx-C3)-alkyl, Ar equal to phenyl, n equal to 2, and X equal to (CH3)3.

EP 0,176,689 describes the use of benzopyrans for respiratory tract diseases and/or disorders of the gastrointestinal tract and/or of the uterus, with special emphasis being placed on those disorders occurring in smooth muscular contractions.

EP 207 614 describes the use of benzopyrans for incontinence.

EP 277611 describes the use of benzopyrans for the preparation of a pharmaceutical for disorders of the efferent urinary passages.

Furthermore, J. Med. Chem. 1986, 29, 2194 - 2201 discloses that compounds of this type may have hypotensive properties.

It has now been found, surprisingly, in pharmacological investigations that compounds I are likewise [lacuna] for use as remedies for respiratory tract diseases.

Hence the invention relates to the use of the compounds of the formula I for the treatment and prophylaxis of the diseases detailed above; particularly preferred in this connection are those diseases in which there is a disturbance of the smooth muscular contractions of the particular organs, such as, for example, asthma. Particularly important in this connection are those compounds I whose hypotensive properties are less pronounced.

The invention is furthermore directed at a pharmaceutical product for the treatment of obstructive functional disorders of the lungs, which contain a compound I as active substance besides customary additives, as well as at a compound I for use for the treatment of obstructive functional disorders of the lungs.

Very particularly preferred is the use of 3,4-dihydro2,2 -dimethyl - 6 -phenyl - sulfonyl - trans -4-(2- oxo -1 -pyrroli dinyl) -2H-benzo [b] pyran-3-ol for the preparation of a remedy for obstructive respiratory tract diseases.

The invention furthermore embraces the use of the compounds according to the invention for the preparation of pharmaceuticals which are used for the treatment and prophylaxis of the abovementioned diseases.

The compounds I can be prepared by the following processes : by a) reacting compounds of the formula II II, in which R1 to R3 and ArSOa are as defined above, with lactams of the formula III H b) reacting compounds of the formula IV Ar-50a R IV, in which R1 to R3 and ArSOa are as defined above, with the lactams of the formula III, c) acylating compounds of the formula V V, in which R1 to R3 and ArSOa are as defined above, to give the compounds VI in which Y is a leaving group such as, for example, chlorine or bromine, and R1 to R3 and ArSOa are as defined above, and cyclizing the latter to give the compounds I, d) oxidizing compounds of the formula VII in which R1 to R3 and ArSOa are as defined above, to give the compounds I.

Where the compounds I are prepared by methods a) or b), this is carried out by reacting the compounds II or IV in a suitable solvent, preferably in dipolar aprotic solvents such as, for example, dimethyl sulfoxide or THF, with the lactams III, preferably with the action of bases such as, for example, sodium hydride, potassium tert.butylate or similar bases known to he suitable for lactam N-alkylations. The temperature for this reaction can be varied within wide limits; it is preferably carried out between 0° and room temperature or at temperatures which may be slightly above room temperature.

Lactams of the formula III are known in many cases, or they can readily be prepared by methods known from the literature. Compounds II or IV are new. They can be prepared, for example, by the following synthetic route: Compounds of the formula VIII in which R1, R2 and R3 are as defined above, are reacted with acid chlorides Ar-SOa-Cl in a type of Friedel-Crafts acylation in a manner known per se to give compounds of the formula IX in which R1, R2, R3 and Ar and n are as defined above. The latter are converted by reductions under standard conditions, for example by NaBH, in methanol, into the compounds X CH and then subjected to elimination of water, for example by pyridine/phosphorus oxychloride, resulting in compounds of the formula XI: XI .

Compounds XI can now easily be converted by standard 5 methods into the epoxides IV or the bromohydrins II.

If in this reaction seguence R means NH2 or OH, protective groups may be necessary, such as, for example, the dimethylaminomethylene group for NH2 or the acetyl or methyl group for the OH group. These are eliminated again at suitable stages, preferably after the reactions described in process a) or b) have been carried out, by conventional methods.

Chromenes of the formula XI are, in some cases, prepared in a manner known per se by thermally induced cyclization of the corresponding propargyl ethers XII XII These in turn can be prepared in a manner known per se from the phenols XIII and the propargyl chlorides XIV. x:v ArSO, KC = C Cl CH R' It is possible and particularly beneficial to use processes c) and d) when the final products I are desired as pure enantiomers. Compounds V and VII are, in contrast to compounds I, basic and thus able to form salts with organic acids. It is possible, by crystallization with a suitable optically pure acid such as, for example, ( + )mandelic acid or (+)-lactic acid, in a manner known per se to obtain them as pure enantiomers, and convert them by processes c) and d) into final products I as pure enantiomers .

However, final products I can also be obtained as pure enantiomers from racemic final products I by conventional methods of racemate resolution such as, for example, chromatographic separation using chiral phases, or derivatization of the racemic products with optically pure acid derivatives (ester formation via the 3-hydroxy group of the chroman system) or with optically pure isocyanates (carbamate formation via the 3-hydroxy group). The diastereoisomeric isocyanates or esters obtained in this way can be separated by conventional methods (crystallization or chromatography) and converted into the optically pure final compounds I with elimination of the optically active auxiliary group on the 3OH group. Separation of the diastereomeric 3menthoxyacetates has proven particularly advantageous in this connection.

As already mentioned, the compounds I can be used according to the invention as agents for the treatment of obstructive respiratory tract diseases. In this connection, pharmaceuticals which contain the compound I can be adminstered orally, parenterally, intravenously, rectally or by inhalation, with the preferred arim-in-j stration form being dependent on the disease which is to be treated. In this connection, the compounds I can be used alone or together with pharmaceutical auxiliaries, specifically both in veterinary and in human medicine.

The expert is familiar, on the basis of his expert knowledge, with the auxiliaries which are suitable for the desired pharmaceutical formulation. Besides solvents, gel-formers, suppository bases, tablet auxiliaries and other active substance vehicles, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoam agents, flavorings, preservatives, solubilizers or pigments.

For a form for oral use, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by the customary methods into suitable administration forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This preparation can be carried out both as dry and as wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compounds are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, into a solution, suspension or emulsion. Examples of suitable solvents are water, physiological saline or alcohols, for example ethanol, propanol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.

Examples of pharmaceutical formulations suitable for administration in the form of aerosols or sprays are solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents. The formulation can, if required, also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. A formulation of this type normally contains the active substance in a concentration of about 0.1 to 10, in particular of about 0.3 to 3, % by weight.

The dosage of the active substance of the formula I which is to be administered, and the frequency of administration, depend on the strength of action and duration of action of the compound used, and, additionally, on the nature and severity of the disease which is to be treated, as well as on the sex, age, weight and individual response of the mammal which is to be treated. On average, the recommended daily dose of a compound of the formula I for a patient weighing about 75 kg is at least 0.1 mg, preferably at least 1 mg, up to a maximum of 100 mg, preferably up to a maximum of 10 mg. In this connection, several, for example up to 4, single doses a day may be necessary for acute episodes of the disease, for exanple for attacks of asthma, whereas one dose may also suffice for prophylaxis.

In this connection, the compounds I can be administered alone or in combination with other compounds, for example when used for obstructive respiratory tract disorders with 03-agonists such as salbutamol, or with theophylline or with disodium chromoglycate.

The compounds of the formula I compiled in the table which follows are particularly well suited: 1) 2,2-dime thyl - 3,4-dihydro-7 -methoxy-6- (p-chlorophenylsulfonyl) -trans-4- (2-oxo-l-pyrrolidinyl) -2Hbenzo[b]-pyran-3-ol, 2) 2,2-dimethyl-3,4-dihydro-6- (p-chlorophenylsulfonyl) 5 trans-4- (2-oxo-l-piperidinyl) -2H-benzo [b]pyran-3-ol, 3) 2,2-dimethyl-3,4-dihydro-6- (p-nitrophenylsulfonyl) trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3ol, 4) 2,2-dimethyl-3,4-dihydro-6- (p-cyanophenylsulfonyl) 10 trans-4- (2-oxo-l-pyrrolidinyl)-2H-benzo [b] pyran-3ol, ) 2,2-dimethyl-3,4-dihydro-6- (p-methoxyphenylsulfonyl) - trans-4- (2 -oxo-l-pyrrolidinyl) -2H-benzo [b]pyran-3-ol, 6) 2,2-dimethyl-3,4-dihydro-6-(p-trif luoromethy lphenyl sulfonyl) -trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo[b]pyran-3-ol, 7) 2,2-dimethyl-3,4-dihydro-6- (p-methylsulfonylphenylsulfonyl) -trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo20 [b]pyran-3-ol, 8) 2,2 -dimethyl-3,4-dihydro-6- (p-acetylphenylsulfonyl) trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b]pyran-3ol, 9) 2,2 - dimethyl-3,4 - dihydro-7 -methylamino -6 -phenyl25 sulfonyl-trans-4 - (2-oxo-l-pyrrolidinyl) -2H-benzo[b]pyran-3-ol, ) 2,2-dimethyl -3,4 -dihydro-7 - fluoro-6 -pheny 1 sulfonyltrans-4 - (2-oxo-l-pyrrolidinyl) -2H-benzo [b] pyran-3ol, 11) 2,2-diethyl-3,4-dihydro-7-fluoro-6 -phenylsulfonyltrans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3ol, 12) 2,2 -dimethyl-7-chloro-3,4-dihydro-6-phenylsulfonyl trans-4-(2-oxo-l-pyrrolidinyl) -2H-benzo[b pyran-3ol, 13) 2,2-dimethyl-3,4-dihydro-6- (4-chloro-3-methylphenylsulfonyl)-trans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol, 14) 2,2 - dime thyl - 3,4 - dihydro - 6 - (4 - chlorophenyl sul f onyl) trans- (5-oxo-3-thiazolidinyl) -2H-benzo [h]pyran-3-ol, ) 2,2-dimethyl-3,4-dihydro-trans-4- (4-methyl-2-oxo-lpiperazinyl) -6-phenylsulfonyl-2H-benzo [b] pyran-3-ol, 16) 2,2 -dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4(2-oxo-l-morpholinyl) -2H-benzo [b] pyran-3-ol, 17) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4(5-oxo-3-oxazolinyl) -2H-benzo [b]pyran-3-ol, 18, 3,4-dihydro-2,2-dimethyl-6- (p-f luorophenyl sulf onyl) trans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]pyran-3ol, 19) 3,4-dihydro-2,2-dimethyl-6- (o-f luoropheny lsulfonyl) trans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]pyran-3ol, ) 3,4-dihydro-2,2-dimethyl-6-(3-pyridylsulfonyl)trans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]pyran-3ol, 21) 3,4-dihydro-2,2-dimethyl-6- (2-pyrimidinylsulfonyl) trans-4 - (2-oxo-l-pyrrolidinyl) -2H-benzo [b] pyran-3 ol, 22) 3,4-dihydro-2,2-dimethyl-6- (2-furylsulfonyl) -trans4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b]pyran-3-ol.

Example 1 3,4-Dihydro-2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo[b]pyran-3-ol 4.3 g (0.0097 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl7-methoxy-6-(p-tolyl sulfonyl)-2H-benzo [b] pyran-4-ol are dissolved in 28 ml of dimethyl sulfoxide, and 3.5 ml of 2- pyrrolidinone (0.0465 mole) and 0.78 g of sodium hydride (80% suspension in oil) (0.0325 mole) are added, and the mixture is stirred at 40°C for 3 hours. It is left to stand overnight and then poured onto ice-water and filtered with suction. The precipitate is recrystallized from isopropanol. White crystals of melting point: 263 - 65°C.

Preparation of the starting compound: 3- Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl)-2H-benzo [b] pyran-4-ol is obtained from 2,2dimethyl-7-me thoxy-6- (p-tolylsulfonyl)-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and H20. Melting point: 200 - 201°C. 2,2-Dimethyl-7-methoxy-6- (p-tolyl sulfonyl) -2H-chromene is obtained from2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) chroman-4-ol with phosphorus oxychloride/pyridine in benzene. Melting point: 132 - 33°C. 2,2-Dimethyl-7-methoxy-6- (p-tolylsulfonyl) chroman-4-ol is obtained from2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) chroman-4-one with NaBH, in ethanol.

Melting point: 196 - 97°C. 2,2-Dimethyl-7-methoxy-6- (p-tolylsulfonyl) chroman-4-one is obtained from 2,2-dimethyl-7-methoxychroman-4-one and p-toluenesulfonyl chloride in the presence of aluminum chloride in methylene chloride.

Melting point: 221 - 23°C.

Example 2 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(p-to lyl sulfonyl) trans-4-(2-oxo-l-piperidinyl)-2H-benzo[b]pyran-3-ol g (0.011 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-7methoxy-6-(p-tolylsulfonyl)-2H-benzo[b]pyran-4-ol are dissolved in 32 ml of dimethyl sulfoxide, and 4.9 g of valerolactam (0.0526 mole) and 0.8 g (0.033 mole) of NaH, 80% suspension in oil, are added, and the mixture is stirred at 40°C for 5 hours. It is poured into ice-water and filtered with suction. The residue is extracted by boiling several times with methanol.

White crystals of melting point: 261 - 63°C.

Example 3 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyltrans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol The coapound is prepared in analogy to Example 1 from 320 bromo-3,4-dihydro-2, 2-dimethyl-7-methoxy-6-phenylsulf on yl-2H-benzo [b] pyr an-4-ol.

White crystals of melting point: 227 - 29°C.

Separation of the antipodes, Example 3a. 1.075 g (0.0025 mole) of (±)-3,4-dihydro-2,2-dimethyl-725 methoxy-6-phenylsulfonyl-trans-4- (2-oxo-1-pyrrolidinyl) 2H-benzo[b]pyran-3-ol are dissolved in 5 ml of 1,2dichlorobenzene, and 0.9 g of S(-)-1-phenylethyl isocyanate is added, and the mixture is stirred at 140°C for about 12 h. The complete mixture is subsequently chro3 0 matographed on silica gel with the solvent system toluene/ethyl acetate 1:1. The diastereomeric carbamate which migrates slower can be enriched and obtained pure by crystallization from toluene (melting point 243 245°C). Hydrolysis with NaOH in EtOH at 80°C results in (+)-3,4- dihydro - 2,2 - dime thyl - 7 -me thoxy - 6 - phenyl sul f ony 1 trans-4- (2-oxo-l-pyrrolidinyl)-2H-benzo [b] pyran-3-ol of melting point: 209 - 211°C and [a] D = + 109° (c = 0.28; CHClj) Preparation of the starting material: - Bromo - 3,4 - dihydro - 2,2 - dime thyl - 7 -me thoxy - 6 -phenyl sulfonyl-2H-benzo[b]pyran-4-ol is obtained from 2,2dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromeae and Nbromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and H20. Melting point: 202 - 203 °C. 2,2 - D ime thyl - 7 - me thoxy - 6 - phenyl su 1 f ony 1 - 2 H - chr omene i s obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchromene with pyridine/phosphorus oxychloride in benzene. Melting point: 140 - 141°C. 2,2-Dimethyl-4-hydroxy-7 -methoxy-6 -phenylsulf onylchroman is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonylchroman-4-ore with sodium borohydride in methanol. Melting point: 146 - 147°C. 2,2 - Dime thyl - 7 -me thoxy - 6 - phenyl sul f onylchroman - 4 - one i s obtained from phenylsulfonyl chloride, 2,2-dimethyl-7methoxychroman-4-one and aluminum chloride in methylene chloride.

Melting point: 223 - 25°C.

Example 4 3,4 - Dihydro-2,2-dimethyl-6- (4-methylphenylsulfonyl) trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b] pyran-3-ol 0.75 g (0.025 mole) of 80% NaH is introduced into 8.2 g (0.02 mole) of 3 -bromo-3,4-dihydro-2,2-dimethyl-616 (4-methylphenylsulfonyl)-2H-benzo[b]pyran-4-ol in 30 ml of dimethyl sulfoxide. After stirring at 20° for one hour, a further 0.75 g (0.025 mole) of 80% NaH and 1.9 ml (0.025 mole) of 2-pyrrolidone are added, and the mixture is stirred at 40° for 45 minutes and at 20° for 6 hours. It is introduced into ice-water and then the precipitate is filtered off with suction, dried and recrystallized from methanol several times.

Crystals of melting point: 242 - 243 °C.

Preparation of the starting material 3-Bromo-3,4-dihydro-2,2-dimethyl-6-(4-methylphenylsulfonyl)-2H-benzo[b]pyran-4-ol 14.2 g (0.08 mole) of freshly recrystallized N-bromosucc in imide are introduced into 12.6 g (0.04 mole) of 2,2-dimethyl-6-(4-methylphenylsulfonyl)chromene in a solution composed of 70 ml of dimethyl sulfoxide and 1.4 ml of water while cooling (isopropanol/dry ice) at about 15°C. The temperature rises transiently to 27°. It is cooled to 20°C and, after stirring for one hour, introduced into ice/ethyl acetate. The ethyl acetate phase is washed several times with water and dried over Na3SO4. The bromohydrin derivative crystallizes on concentration. Crystals of melting point: 141 - 142°C.

Example 5 3.4 - D ihydr o - 2,2 - dime thy 1 - 6 -phenyl sul f onyl - trans -4-(2- oxo 1-pyrrolidinyl) -2H-benzo(b]pyran-3-ol A solution of 6.3 g (0.02 mole) of 3,4-dihydro-2,2dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-benzo[b]pyran in 20 ml of DMSO is added dropwise, at 20°C, to a suspension of 0.6 g (0.02 mole) of 80% NaH in 10 ml of DMSO. Then 2.3 ml (0.03 mole) of 2-pyrrolidinone are added, and the mixture is stirred at 45° for one hour. After it has stood at 20° overnight it is introduced into ice-water. The precipitate is filtered off with suction, washed to neutrality, dried and chromatographed on silica gel with methylene chloride/methanol 19:1. 30 ml fractions are collected. Fractions 12-25 are concentrated, and the residue is recrystallized from acetonitrile.

Melting point: 201-202° Preparation of the starting material: 3,4-Dihydro-2,2 - dimethyl-3,4-epoxy- 6-phenylsulfonyl-2Hbenzo [b] pyran is obtained from 3-bromo-3,4-dihydro-2,2dimethyl-6rphenylsulfonyl-2H-benzo [b] pyran-4-ol with NaH in DMSO.

Melting point: 103-105° - Bromo-3,4-dihydro-2,2 - dimethyl - 6 -phenylsulf onyl-2Hbenzo[b]pyran-4-ol is obtained from 2,2-dimethyl-6phenylsulfonyl-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and H2O.

Melting point: 126’ 2,2-Dime thyl-6-phenyl sulf onyl-2H-chromene, with melting point 70-71°, was prepared by known methods from 4phenylsulfonylphenyl 1,1-dimethylpropargyl ether. This ether is obtained, likewise in a known manner, from 4phenylsulfonylphenol and 3-methyl-3-chlorobutyne. ( + ) -3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2-oxo-lpyrrolidinyl)-2H-benzo [b] pyran-3-ol (Example 5a) ( + ) -3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2-oxo-lpyrrolidinyl) -2H-benzo [b]pyran-3-ol is esterified with (-)menthoxyacetyl chloride by standard methods. The diastereomeric esters are separated on a silica gel column with methylene chloride/ethyl acetate (9:1) and hydrolyzed by stirring at 20° with alcoholic sodium ethylate solution. After dilution with cold water, the precipitate is filtered off with suction and washed to neutrality and triturated with ether. ( + ) -3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2-oxo-lpyrrolidinyl) -2H-benzo [b] pyran-3-ol Melting point: 122-123° [a]D = + 39.5° (c = 1, ethanol) Example 6 6- (4-Chlorophenylsulfonyl) - 3,4-dihydro-2,2-dimethyl-7 methoxy-trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b]pyran3-ol The compound is prepared in analogy to Example 1 from 3bromo-6-(4-chlorophenylsulfonyl)-3,4-dihydro-2,2 dimethyl-7 -methoxy-2H-benzo [b] pyran-4-ol.

White crystals with melting point: 260-262"C Preparation of the starting compounds: In analogy to Example 1: 3-Bromo-6- (4 -chlorophenyl sulf onyl) -3,4-dihydro-2,2dimethyl-7-methoxy-2H-benzo [b]pyran-4-ol with melting point: 175-177 °C 6-(4- Chlorophenyl sul f onyl )-2,2- dime thy 1 - 7 -me thoxy chr omene with melting point: 142-143°C Example 7 - (4-Bromophenyl sulf onyl) - 3,4 - dihydro-2,2-dimethyl-7 methoxy-trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo [blpyran3-ol In analogy to Example 1 from 3-bromo-6-(4-bromophenylsulfonyl) -3,4-dihydro-2,2-dimethyl-7-methoxy-2H-benzo[b] pyran-4-ol.

White crystals of melting point: 281-282°C.

Example 8 3,4-Dihydro-2,2 -dimethyl-7-methoxy-6- (4-methoxyphenylsulfonyl) -trans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]-pyran3-ol The compound is prepared in analogy to Example 1 from -bromo - 3,4 - dihydro - 2,2 - dime thy 1 - 7 -me thoxy - 6 - (4 -me thoxy 19 phenylsulfonyl)-2H-benzo[b]pyran-4-ol and has a melting point of 286-287°C.

Example 9 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(2-thienyl sulfonyl) trans-4- (2-oxo-1-pyr rol idinyl) -2H-benzo [b] pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2 dimethyl-7-methoxy-6- (2-thienylsulfonyl) -2H-benzo [b] pyran-4-ol, melting point: 135-136°C.

Example 10 3,4 - Dihydro-2,2 - dimethyl-7-ethoxy-6-phenylsulfonyl-trans4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b] pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2dimethyl - 7 - ethoxy- 6 -phenylsulfonyl - 2H-benzo [b] pyran-4 -ol, melting point: 197-198°C Example 11 3,4 - Dihydro-2,2 - dimethyl-7 -methoxy-6-phenylsulfonyltrans -4-(2- oxo-1 -piper idinyl) - 2H-benzo [b] pyran-3 - ol In analogy to Example 2 from 3-bromo-3,4-dihydro-2,2dimethyl-7 -methoxy-6-phenylsulfonyl-2H-benzo [b] pyran4-ol. White crystals of melting point: 157-158°C.

Example 12 6- (4-Cy anophenyl sulfonyl) - 3,4-dihydro-2,2-dime thy 1-trans4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b] pyran-3-ol In analogy to Example 1 from 3-bromo-6-(4-cyanophenylsulfonyl) -3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-4-ol. White crystals of melting point: 234-235°C.

Preparation of the starting material: - Bromo - 6 - (4 - cyanopheny 1 sulfonyl) -3,4 - dihydro -2,2 dimethyl-2H-benzo[b]pyran-4-ol is obtained as described in Example 3 from 6- (4-cyanophenylsulfonyl) -2,2-dimethyl20 -chromene.

Melting point: 157-158°C.

Example 13 3.4- Dihydro-2,2-dimethyl-6- (2-methoxyphenylsulfonyl) trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo[b]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2dimethyl-6- (2-me thoxyphenyl sulfonyl) -2H-benzo [b]pyran-4ol. White crystals of melting point: 196-198°C.

Example 14 3.4- Dihydro-2,2-dimethyl-6 -(2-methylphenylsulfonyl)trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo[b]pyran-3-ol In analogy to Example 1. White crystals of melting point: 214-216°C.

Example 15 3.4- Dihydro-2,2-dimethyl- 6 -(2-chlorophenylsulfonyl)trans-4- (2-oxo-l-pyrrolidinyl) -2H-benzo [b]pyran-3-ol In analogy to Example 1. White crystals of melting point: 85-87’C.

Example 16 Preparation of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyltrans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol (compound of Example 5 by process variant c) A solution of 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo [b] pyran-4-ol in ethanol is shaken under a pressure of 8 bar of NH3 at 50° in an autoclave for 8 hours. The mixture is cooled and then evaporated to dryness and recrystallized from ethyl acetate. 4-Amino3,4-dihydro-2,2 -dimethyl - 6 -phenylsulf onyl-2H-benzo [b] pyran-3-ol of melting point: 160-163°C is obtained and is •immediately subjected to acylation with 4-chlorobutyryl chloride. For this purpose, the substance is dissolved together with the acid chloride in CH3C13 and stirred in a two-phase mixture with 2N sodium hydroxide solution at room temperature for 24 hours. The usual working up results in 4-(4-chlorobutyrylamino)-3,4-dihydro-2,2 5 dimethyl-6-phenylsulfonyl-2H-benzo [b] pyran-4-ol of melting point 155-157°C. Cyclization to give the title compound is carried out by dissolving the substance in tetrahydrofuran, addition of a stoichiometric amount of 80% NaH suspension in oil and stirring the mixture at room temperature for 24 hours. The final product is identical to the product obtained by process b) . Melting point: 200-201°C. If 4-amino-3,4-dihydro-2,2-dimethyl-6phenylsulfonyl-2H-benzo [b] pyran-3-ol is subjected to racemate resolution, it is possible to obtain from its (+) enantiomer the pure (+) enantiomer from Example 5a with the data indicated there.

Example 17 3,4 -Dihydro - 2,2 - dime thyl - 6 -phenyl sul f oxy- trans -4-(2- oxo 1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol In analogy to Example 1. Melting point: 211 - 212°C.

Pharmacological data a) Effect on respiratory tract disorders Effect on histamine-induced bronchoconstriction in guinea-pigs Method: White guinea-pigs of both sexes and weighing between 450 and 550 g were anesthetized with 60 mg/kg pentobarbital i.p. After tracheotomy, they were ventilated with a Starling pump (from Braun, Melsungen) . The tidal volume was selected for generous ventilation of the lungs. The ventilation pressure was adjusted to 80 mm H20 with the aid of a water column (Rosenthal and Dervinis) . The breathing rate was 30 breaths/min. An excess of available respiratory air can pass through a bypass in the inhalation tube to a washbottle which is designed as a water pressure-relief valve. When air is blown by the Starling pump through the inhalation tube into the lungs they are inflated until the pressure in the system has reached the value set by the height of the water column (80 mm H20) . The continuing inflow of air flows through the pressurerelief valve into the washbottle. This excess air which escapes into the bottle after the set pressure has been exceeded is measured with the aid of a piston recorder and is taken as a measure of the change in the airway resistance. Measurement was carried out in a manner slightly modified from the original Konzett-Rossler method, in that the piston recorder was replaced by a Fleisch dynamic pressure tube (type 0000). The difference in pressure which occurred was detected with a Statham PM 97 TC differential pressure transducer. A Hellige multichannel pen recorder was used to record the measurements .

The test substances are administered as aerosol with the aid of an ultrasonic atomizer (Monaghan M 650) . The atomizer chamber is interpolated in the inhalation tube of the ventilation pump and allows the animals to inhale the aerosol for 1 min. The volume to be atomized is 0.02 ml/min.

Used for atomization is a physiological saline solution to which the substance to be tested is added in the form of a solution in propanediol.

It is ensured, in a control experiment, that the solvent propanediol/physiological saline solution has no action itself .

Bronchoconstriction is induced by doses of histamine dihydrochloride (6 - 12 gg/kg i.v.). Injection is through a catheter introduced into the jugular vein. The dose is selected so that a respiratory overflow of 60% of the offered tidal volume occurs during the histamine-induced bronchoconstriction. The histamine doses are given at intervals of 5 minutes. After at least 3 well-reproduced bronchoconstrictions, the test substances are admini5 stered as aerosol for 1 min and, after an action time of 2 min, the bronchoconstriction is induced anew and repeated at intervals of 5 minutes.

The degree of inhibition of the his famine-induced bronchoconstriction after pretreatment with the test sub10 stance is regarded as a measure of the bronchodilator activity and is reported at % change from the control.

All results are subjected to linear regression, and the ID50 is determined.

Results: % inhibition of his famine-induced bronchoconstriction Compound Dose n % inhibition Example 5a 1 Mg/kg 6 14 ± 4 (+) -3,4-dihydro-2,2- 3 Mg/kg 6 35+4 dime thyl-6-phenylsulfon- 10 gg/kg 6 77+7 yl-trans-4-(2-oxo-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol IDS0: 4.39 /ig/kg

Claims

1. Patent Claims

1. The use of a compound I in which R 1 represents H, OH, (C2-C2) -alkoxy, (C1-C2) -alkyl or NR 4 R 5 , where R 4 and R s are identical or different and represent H, (C1-C 2 ) alkyl or (C x -C 3 )-alkylcarbonyl, R A 3 and R 3 are identical or different and represent alkyl having 1-4 carbon atoms, Ar represents an aromatic or heteroaromatic system which is unsubstituted or substituted by 1 to 3 identical or different radicals (C^Cj)-alkyl, (C 1 -C 3 ) alkoxy, halogen, trifluoromethyl, CN, NO 2 , CO-(C 2 -C 2 ) alkyl or SO,-(C 2 -C 2 )-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (C& 2 ) r which can be interrupted by a heteroatom O, S or NR 6 , where R 6 denotes H or (C 2 -C 4 )-alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy for obstructive functional disorders of the lungs. A pharmaceutical product for the treatment of obstructive functional disorders of the lungs, which contains a compound I as active substance besides customary additives. 4. 5. 6. 7. 25 8. 9. Λθ· A compound I for use for the treatment of obstructive functional disorders of the lungs. The use of a compound I as claimed in claim 1, in which R 1 to R 3 and ArSo n are as defined in claim 1, and X denotes (CH 2 ) r with r = 3 or 4. The use as claimed in claim 1, wherein R 1 to R 3 have the abovementioned meanings, Ar represents phenyl which is unsubstituted or substituted as in claim 1, and X denotes (CH 2 ) r with r = 3 or 4. The use as claimed in claim 1, wherein R 1 denotes hydrogen, R 2 and R 3 represent (C x -C 2 )-alkyl, Ar denotes phenyl which is unsubstituted or substituted once by (C x -C 2 )-alkyl, (C x -C 2 )-alkoxy or halogen, n denotes 2, and X denotes (CH 2 ) r with r = 3 or 4. The use as claimed in claim 1, wherein R 1 denotes hydrogen, R 2 and R 3 represent (C x -C 2 )-alkyl, Ar denotes phenyl, n denotes 2, and X denotes (CH 2 ) 3 . The use of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-trans - 4 - (2-oxo-l-pyrrolidinyl)-2Hbenzo [b] pyran-3-ol for the preparation of a remedy for obstructive respiratory tract diseases. Use according to claim 1, substantially as hereinbefore described and exemplified. A pharmaceutical product according to claim 2, substantially as hereinbefore described.