IL91015A

IL91015A - Pharmaceutical compositions for the treatment of obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages, containing substituted 3,4-dihydro-2h-benzopyrans

Info

Publication number: IL91015A
Application number: IL9101589A
Authority: IL
Original assignee: Hoechst Ag
Priority date: 1988-07-19
Filing date: 1989-07-18
Publication date: 1994-11-28
Also published as: DE3824446A1; EP0351720B1; IE63872B1; JPH0273015A; DK171782B1; FI893460A0; PT91197B; DK355489D0; DE58908228D1; DK355489A; FI893460A; KR900001367A; IE892323L; EP0351720A3; CA1336891C; HUT55988A; ZA895459B; CZ417091A3; AU621388B2; EP0351720A2

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

91015/2 PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OBSTRUCTIVE FUNCTIONAL DISORDERS OF THE LUNGS AND/OR DISORDERS EFFERENT URINARY PASSAGES, CONTAINING SUBSTITUTED 3.4-DIHYDR0-2H-BENZ0PYRANS rnnoin rn 7_ -ΐ3 niyiann ^la'D"? 0"nann O'Tunn Η2-1"Π7ΠΊ - 4,3 Epynnn ΊΠϋΠ 'Dm ^V) IN/1 ΓΠΝ'ΊΠ *7¥J . O'lnmn £Ρ_ΙΝ-Ι7ΕΠΤ JH ~ 4- .9.1.0,1.5/2 The invention relates to a pharmaceutical composition containing and efficient quantity of a compound I represents H, OH, (d -C2 )-alkoxy, (Cx C2) -alkyl or NR4 R5 , where R4 and are identical or different and represent H, (Cx C2) -alkyl or (d -C^ ) -alkyl-carbonyl , and R3 are identical or different and represent alkyl having 1-4 carbon atoms, represents phenyl system which is unsubstituted or substituted by 1 to 3 identical or different radicals (Ci -C2)-alkyl, (C.,. -C2)-alkoxy, halogen, trifluoromethyl , CN, N02 , CO-(Cx -C2),-alkyl or SO„, -(d -C2 ) -alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)y which can be interrupted by a heteroatom 0, S or NR6 , where R6 denotes H or (d -C4) -alkyl, and r represents the numbers 2, 3, 4 or 5.

Such compositions are useful as a remedy for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages.

An aromatic system Ar is preferably to be understood to be phenyl, naphthyl or biphenylyl .

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

Carbon atoms 3 and 4 of the 3 , 4-d i hyd r o-2H-ben z o C b ] p y r an system (also called "chroman system" hereinafter for brevity) of the formula I 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 sub-stituents R 1 , ArSOn, R2 and/or R3 contains centers of asymmetry, or if R 2 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, di-astereoisomers, racemates or mixtures thereof.

Preferably used are compounds of the formula I in which R 1 to R3 and ArSOn have the abovemen i. i oned meanings, but X represents a chain (CHgip with r = 3 or 4.

- Especially preferably used are those compounds in which 1 2 3 R denotes H, R and R represent ( C <| - C 2 ) -a I k y I , Ar represents phenyl which is unsubs t i tuted or substituted once by ( C i - C 2 ) - a I k y I , ( C -j - C 2 ) -a I k o x y or halogen, n represents 2, and X represents a chain (CH2 p with r = 3 0 r 4. 1 Likewise preferred are compounds with R equal to H, R2 and R3 equal to (C-j-Cg^alkyl, X equal to (CHg^^ Ar equal to C^H^Cl, and n equal to 2, as well as those 1 2 3 with R equal to H, R and R equal to ( C 1 -C 2 ) - a I k y I , Ar equal to phenyl, n equal to 2, and X equal to (CHg^.

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, 61 A describes the use of benzopyrans for incontinence. Furthermore, . J .

Med. Chem. 1986, 2_9, 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 l kewise suitable for use as remedies for respiratory tract diseases and/or disorders of the efferent urinary.passages.

Hence the invention relates to compositions which contain compounds of the fomula 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, incontinence or renal colic. 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 contains a compound I as active substance besides customary additives, as well as at a compound 1 for use for the treatment of obstructive functional disorders of the lungs and/or of the efferent urinary passages.

Very particularly preferred is the use of 3 , 4-d i h yd r o-2 , 2 -dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-py r r o I i d i ny I ) -2 H -ben z o C b ] py r an-3-o I for the preparation of a remedy for disorders of the efferent urinary passages and the use of 3,4-dihydro-2,2-dimethyl-6-phenyl-sulfonyl-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]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 pharmaceut cals which are used for the treatment and prophylaxis of the abovement i oned diseases.

The compounds I can be prepared by the following processes: by a) reacting compounds of the formula II in which R to R and ArS0n are as defined above, with lactams of the formula III ) reacting compounds of the formula IV in which R to R and ArSOn are as defined above, with the Lactams of the formula III, ) acylating compounds of the formula V in which R 1 to R3 and ArSOn are as defined above, to give the compounds VI in which Y is a leaving group such as, for example, chlorine or bromine, and R 1 to R3 and ArSOn are as defined above, and cyclizing the latter to give the compounds I, ) oxidizing compounds of the formula VII 1 3 in which R to R and ArSOn are as def ined 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 be suitable for lactam N-a I k y I a t i ons . The temperature for this reaction can be varied within wide l imits; it is preferably carried out between 0° and room temperature or at temperatures which may be sl ightly 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 R , R and R are as Jef ined above, are reacted with acid chlorides Ar-S0n-Cl in a type of Friedel-Crafts acylation in a manner known per se to give compounds of the formula IX in which R , R , R and Ar and n are as def ined above. The latter are converted by reductions under standard conditions, for example by aBH in methanol, into the compounds X OH which are then subjected to el imination of water, for example by pyridine/phosphorus oxychloride, result ing in compounds of the formula XI : Compounds XI can now eas ily be converted by standard methods into the epox ides IV or the bromohydrins II.

If in this reaction sequence R means H or OH, protec-tive groups may be necessary, such as, for example, the dimethyl aminomethylene group for H2 or the acetyl or methyl group for the OH group. These are el iminated 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 nduced cycl ization of the corresponding propargyl ethers. XII These in turn can be prepared in a manner known per se from the phenols XIII and the propargyl chlorides XIV.

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 con-trast 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 enant iomers .

However, final products I can also be obtained as pure enantiomers from racemic final products I by conventional methods of race ate resolution such as, for example, chromatographic separation using chiral phases, or de r i v a t i z a t i on of the racemic products with optically pure acid derivatives (ester formation via the 3-hydroxy group of the chroman system) or with optically pure iso-cyanates (carbamate formation via the 3-hydroxy group). The d i as te r eo i some r c 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 3-OH group. Separation of the d i as te reomer c 3-menthoxyacetates 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 and/or for the treatment of disorders of the efferent urinary passages.

In this connection, pharmaceuticaLs which contain the compounds I can be administered orally, pa ren t e r a I 1 y , intravenously, rectally or by inhalation, with the preferred administration 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, preser ati es, solubilizers or pi gments .

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 example for attacks of asthma or of renal colic, 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 B2_agonists such as salbutamol, or with theophylline or with disodium c r omog I y c a t e .

When used for disorders of the efferent urinary passages examples of partners in the combination are those having an t i bac t e r i a L or analgesic activity. he compounds of the formula I compiled in the table hich follows are particularly well suited: ) 2,2-dimethyl-3,4-dihydro-7-methoxy-6-(p-chlorophenyl sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb] pyran-3-ol, 2) 2,2-dimethyl-3,4 dihydro-6-(p-chlorophenylsulfonyl)- trans-4-(2-oxo-1 piperidinyl)-2H-benzoCb]pyran-3-ol, 3) 2,2-dimethyl-3,4 dihydro-6-(p-nitrophenylsulfonyl)- trans-4-(2-oxo-1 pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 4) 2,2-dimethyl-3,4 dihydro-6-(p-cyanophenylsulfonyl)- t r ans-4- ( 2-oxo- 1 pyrrol idinyl)-2H-benzoCb]pyran-3-ol, 5) 2,2-dimethyl-3,4 dihydro-6-(p-methoxyphenylsulfonyl)- trans-4-(2-oxo-1 pyrrol idinyl)-2H-benzo[bJpyran-3-ol, 6) 2,2-dimethyl-3,4-dihydro-6-(p-trifluoromethylphenyl- sulfonyl )-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]- py ran-3-ol , 7) 2,2-dimethyl-3,4-dihydro-6-(p-methylsulfonylphenyl- sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]- py ran-3-ol , 8) 2,2-dimethyl-3,4-dihydro-6-(p-acetylphenylsulfonyl)- trans-4-(2-oxo-1-pyrrol id nyl )-2H-benzoCb]pyran-3-ol, 9) 2,2-dimethyl -3/4-dihydro-7-methylamino- 6-phen su I f - onyl-trans-4 -(2-oxo-1-pyrrolidinyl)-2H- benzoCbDpy ran- 3-ol, 10) 2,2-dimi3thyL-3,4-dihydro-7-fLuoro-6-phenyLsuLfonyL- trans-4-(2-oxo-1-pyrroL idinyl )-2H-benzoCb]pyran-3-oL 11 ) 2,2-diethyL-3,4-dihydro-7-fLuoro-6-phenyLsuLfonyL- trans-4-(2-oxo-1-pyrroLidinyL)-2H-benzoCb]pyran-3-oL 12) 2,2-dimethyL-7-chloro-3/4-dihydro-6-phenyLsuLfonyl- trans-4-(2-oxo-1-pyrroL idinyl )-2H-benzo[b]pyran-3-oL 13) 2 2-dimethyL-3,4-dihydro-6-(4-chloro-3-methyLphenyL- sulfonyL )-trans-4-(2-oxo-1-pyrroL idinyL )-2H-benzoCb] pyran-3-oL, 14) 2,2-dimethyl-3/4-dihydro-6-(4-chlorophenyLsulfonyL )- trans-4-(5-oxo-3-thiazoLidinyL)-2H-benzoCb]pyran-3-o 15) 2,2-dimethyL-3,4-dihydro-trans-4-(4-methyL-2-oxo-1- piperazinyL)-6-phenyLsuLfonyL-2H-benzoL~b]pyran-3-oL, 16) 2,2-dimethyl-3,4-dihydro-6-phenyLsuLfonyL-trans-4- (2-oxo-1-morphoLinyL)-2H-benzoCb]pyran-3-oL, 17) 2,2-dimetbyL-3,4-dihydro-6-phenyLsuLfonyL-trans-4- (5-oxo-3-oxazolinyl)-2H-benzoCb]pyran-3-ol, 18) 3,4-dihydro-2,2-dimethyL-6-(p-fLuorophenyLsuL-fonyL)- trans-4-(2-oxo-1-pyrrol dinyL )-2H-benzoCb]pyran-3-oL, 19) 3, 4-d i hydro-2 ,2-d i me t hy I -6- ( o-f L uo ropheny I su L ony I ) - trans-4-(2-oxo-1-pyrrol idinyL )-2H-benzoCb]pyran-3-ol, ) 3,4-dihydro-2,2-dimethyL-6-(3-pyridyLsuLfonyL ) - 1 r ans - 4-(2-oxo-1-pyrroL idinyL)-2H-benzo[b]pyran-3-oL, ) 3,4-dihydro-2 2-dimethyL-6-(2-pyrimidinyLsuLfonyL)- trans-4-(2-oxo-1-pyrroL idinyL )-2H-benzoCb]pyran-3-oL, ) 4-(2-oxo-1-pyrro'L idinyl )-2H-benzoCb]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-b r omo-3 , 4-d i h d r o-2 , 2-d i me t h y L -7-methoxy-6-(p-tolylsulfonyl)-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 recrystal lized 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-tolyl-sul fony I )-2H-benzoCb]py ran-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-chromene and N-bromosucc in imide in a 9:1 mixture of dimethyl sulf-oxide and H20. Melting point: 200-201°C 2,2-Dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-chromene is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulf-onyl)chroman-4-ol w th phosphorus oxychloride/pyridine in benzene. Melting point: 132 - 33°C 2,2-0imethyl-7-methoxy-6-(p-tolylsulfonyl)chroman-4-ol is obtained from 2,2-dimethy l-7-methoxy-6-(p-tolylsulf-onyl ) 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- to I uene s u I fony I 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-tolylsulfonyl)- trans-4-(2-oxo-1-piperidinyl)-2H-benzoCb]pyran-3-ol 5 g (0.011 mole) of 3-b romo-3 ,4-d i h yd ro-2 , 2-d i me t hy I -7-methoxy-6-(p-tolylsulfonyl )-2H-benzoCb]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-phenylsulfonyl-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol The compound is prepared in analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfon-y l-2H-benzoCb]py r 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-d i hyd ro-2 , 2-d i me t h y I -7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]py ran-3-ol are dissolved in 5 ml of 1,2-di-chlorobenzene, 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 chromato-graphed on silica gel with the solvent system toluene/ ethyl acetate 1:1. The d i as tereomer i c carbamate which migrates slower can be enriched and obtained pure by c r ys t a L L i z a t i on from toluene (meLting point 243-245°C). Hydrolysis with NaOH in EtOH at 80°C results in (+)- 3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl- t r ans -4- ( 2-0 x o- 1 -py r r o I i d i ny I ) -2 H-ben z o C b ] py r a n-3-o I of melting point: 209-211°C and Ca]D = + 109° (c = 0.28; CHC I 3 ) Preparation of the starting material: 3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenyl-sulf ony I -2 H-ben zo C b ] py r a n-4-o I is obtained from 2,2-d i me t h y I -7-me t ho x y-6-p h en I s u I f ony I -2H-c h r ome ne and N-b romos u c c i n i m i de in a 9:1 mixture of dimethyl sulfoxide and H2O. Melting point: 202 - 203°C. 2,2-Dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene is obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenyl-s u I ony I c h r o ene with pyr i d i ne/phosphorus oxychloride in benzene. Melting point: 140 - 41°C. 2,2-Dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchroman is obtained from 2 , 2-d i me t hy I -7-me t hoxy-6-ph eny I s u I f ony I -c h roman-4-one with sodium borohydride in methanol.

Melting point: 146 - 147°C. 2,2-Dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one is obtained from pheny I s u I f ony I chloride, 2,2-dimethyl-7-methoxychroman-4-one and aluminum chloride in methylene chloride.

Melting point: 223 - 25°C Example 4 3,4-Di ydro-2,2-dimethyl-6-(4-methylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol 0.75 g (0.025 mole) of 80% NaH is introduced into 8.2 g (0.02 mole) of 3-b romo-3 , 4-d i h yd r o-2 , 2-d i me t h y I -6- ( 4-methylphenylsulfonyl)-2H-benzo[b-lpyran-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% a H and 1.9 ml (0.025 mole) of 2-pyrrol idone 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 r e c r y s t a 11 i z ed 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-methylphenyl-sulfonyl)-2H-benzoCb]pyran-4-ol 14.2 g (0.08 mole) of freshly rec r y s t a 11 i zed N-bromo-succinimide 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 ( sopropanol /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 NagSO^. The bromohydrin derivative crystallizes on concentration. Crystals of melting point: 141 - 142°C.

Example 5 3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-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-2,2-di-methyl-3,4-epoxy-6-phenylsulfonyl-2H-benzoCb]pyran in 20 ml of DMS0 is added dropwise, at 20°, 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-pyrrol idinone 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 c h I or i de/me t hano I 19:1. 30 ml fractions are collected. Fractions 12-25 are concentrated, and the residue is r e c r y s t a 11 i z ed from aceton t r i I e .

Melting point: 201-202° Preparation of the starting material: 3,4-Dihydro-2,2-dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-benzoC b ] p r an is obtained from 3-b r omo- , 4-d i h yd r o-2 , 2-dimethyl-6-phenylsulf onyl-2H-benzoCb]pyran-4-ol with NaH in DMS0.

Melting point: 103-105° 3-Bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol is obtained from 2,2-dimethyl-6-pheny I s u I fony I -2 H-c h romene and N-b romos u c c i n i m i de in a 9:1 mixture of dimethyl sulfoxide and H 20.

Melting point: 126° 2 , 2-D me t h I -6-ph en I s u I f on I -2H- c h r omene , with melting point 70-71°, was prepared by known methods from 4-phenylsulfony Iphenyl 1 , 1-d i me t hy I p r opa r gy I ether. This ether is obtained, likewise in a known manner, from 4-phenylsulfonylphenol and 3-methyl-3-chlorobutyne. (+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrol idinyl ) -2 H-ben zo C b ] py r an-3-o I (Example 5a) (+)-3,4-Dihydro-2,2-di methyl-6 -phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol is esterified w th (-)-menthoxyacetyl chloride by standard methods. The d i as tereomer i c 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- 1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol Melting point: 122-123° Ca]D = + 39.5° (c = 1, ethanol) Example 6 6- (4-Chlorophenylsulfonyl)-3,4~dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-oL The compound is prepared in analogy to Example 1 from 3-bromo-6-(4-chlorophenylsulfonyl)-3,4-dihydro-2,2-dimethyl- 7-methoxy-2H-benzoCb]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-chlorophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-2H-benzoCb]pyran-4-ol with melting point: 175-177°C 6-(4-Chlorophenylsulfonyl)-2,2-dimethyl-7-methoxychromene with melting point: 142-143°C Example 7 6-(4-Bromophenylsulfonyl)-3 4-dihydro-2 2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-6-(4-bromophenyl-sulfonyl)-3 4-dihydro-2,2-dimethyl-7-methoxy-2H-benzoCb]-py ran-4-ol .

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

Example 8 3,4-Dihydro-2,2-dimethyl thoxy-6-(4-methoxyphenyl-sulfonyl)-trans-4-(2-oxo rrol idinyl )-2H-benzoCb]- py ran-3-ol The compound is prepared in analogy to Example 1 from 3- bromo-3/4-dihydro-2.2-dimethyl-7-methoxy-6-(4-methoxy- phenylsul onyl ) -2 H-benz o[ b ] py r a n-4-o I and has a melting 5 point of 286-287°C.

Example 9 Not Part of 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(2-thienylsulfonyl)-Invention trans-4- (2-oxo- 1-pyrrol dinyl )-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2- 10 dimethyl-7-methoxy-6-(2-thienylsulfonyl)-2H-benzo[b]pyran- 4-o I , melting point: 135-136°C.

Example 10 3,4-Dihydro-2,2-dimethyl-7-ethoxy-6-phenylsulfonyl-trans- 4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol 15 In analogy to Example 1 from 3-bromo-3,4-d i hydro-2,2- dimethyl-7-ethoxy-6-phenylsulfonyl-2H-benzoCbDpyran-4-ol, melting point: 197-198°C.

Example 11 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl- 20 trans-4-(2-oxo-1-piperidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 2 from 3-b r omo-3 , -d i h yd ro-2 , 2- dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4- ol. White crystals of melting point: 157-158°C.

Example 12 25 6-(4-Cyanophenylsulfonyl)-3,4-dihydro-2,2-dimethyl- trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-6-(4-cyanophenyl- sulfonyl)-3 4-dihydro-2,2-dimethyl-2H-benzoCb]pyran-4-ol.

White crystals of melting point: 234-235°C.

Preparation of the starting material: 3-Bromo-6-(4-cyanophenyLsuLfonyL)-3/.4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-4-ol is obtained as described in Example 3 from 6- ( -c anopheny s u I f ony I ) -2 , 2-d i me t hy I -3-chromene.

Melting point: 157- 158°C .

Example 13 3,4-Dihydro-2,2-dimethyl-6-(2-methoxyphenylsulfonyl)-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-b r omo-3 , 4-d i h y d r o-2 , 2-dimethyl-6-(2-methoxyphenylsulfonyl)-2H-benzoCb]pyran-4-ol. White crystals of melting point: 196-198°C.

Example 14 3,4-Dihydro-2.2-dimethyl-6-(2-methylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrol dinyl )-2H-benzoCb]pyran-3-ol In analogy to Example 1. White crystals of melting point 214-216°C.

Examp I e 15 3,4-Dihydro-2,2-dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol In analogy to Example 1. White crystals of melting point: 85-87°C Example 16 Preparation of 3, 4-d i hydr o-2,2-d i me t hy I -6-phen I s u I f ony I -trans-4-(2-oxo-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol (compound of Example 5 by process variant c) A solution of 3-b r omo-3 , 4-d i hyd r o-2 , 2-d i me t h y I -6-ph eny I -s u I f ony I -2H-benzo C b ] py r an-4-o I 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 rec rys taL I i zed from ethyl acetate. 4-Amino- 3,4-dihydro-2,.2-dimethyl-6-phenylsulfonyl-2H-benzo[b]-pyran-3-oL of melting point: 160-163°C is obtained and is immediately subjected to acylation with 4- c h I o r obu t y r-yl chloride. For this purpose, the substance is dissolved together with the acid chloride in C H2 L 2 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-di-hydro-2 2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol of melting point 155-157°C. Cyclization to give the title compound is carried out by dissolving the substance in tet rahydrof uran, 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-am i no-3, -d i h y d r o-2 , 2-d i e t h -6-phenylsulfonyl-2H-benzoCb]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-D ihydro-2,2-di methyl -6-pheny I su I foxy-trans-4-( 2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol analogy to Example 1. Melting point: 211 - 212 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 H2O 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 p r es s u re- re I i e f 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 H2O). The continuing inflow of air flows through the pressure-relief 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 /m i n .

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/phys iological saline solut ion has no action itself.

B ron c hoc ons t r i c t i on is induced by doses of histamine di- hydrochloride (6 - 12 μg / 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 br one hoc ons t r i c t i on . The histamine doses are given at intervals of 5 minutes. After at least 3 well-reproduced bronchoconstrictions, the test substances are administered as aerosol for 1 min and, after an action time of 2 min, the b r on c h o c on s t r i c t i on is induced anew and repeated at intervals of 5 minutes.

The degree of inhibition of the h i s t am i ne- i nduc ed broncho constriction after pretreatment with the test substance is regarded as a measure of the bronchod i I ator activity and is reported as % change from the control.

All results are subjected to linear regression, and the 105 o is determined.

Results: % inhibition of histamine-induced bronchoconstriction Compound Dose n % inhibition Example 5a 1 ug/kg 6 14 + 4 <+)-3,4-dihydro-2,2- 3 ug/kg 6 35 + 4 dimethyl-6-pheny l- 10 yg/kg 6 77 + 7 sulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb3pyran-3-ol ID5Q: 4.39 , ug/kg b) Efferent urinary passages Effect on the K C L - i ndu c ed rhythmic contractions of the guinea-pig ureter in vitro Method: Male guinea-pigs were sacrificed by a bLow to the back of the neck and exsanguinat ion from the carotids. The two ureters were immediately removed, avoiding the region near the renaL pelvis because of the pacemaker activity present there. Pieces 2 cm long were first freed of connective tissue in a Petri dish containing Tyrode solution and then suspended in a 25 ml organ bath (from Rhema Labo r t ec hn i k , Hofheim), in each case with a tension of 4.9 mN (= 0.5 p). The organ bath contained Tyrode solution of the following composition (mmol/l): NaCl 137, KCl 2.68, MgS0 1.05, CaCl2 1.8, NaHgPC^ 0.41, NaHC03 11.9, glucose 5.55, which was maintained at 37°C and through which carbogen (95% Oj, 5% 002) was bubbled.

The contractions were measured i some t r i c a 11 y using Gould/ Statham UC2 pickups. After an equilibration time of at least 15 minutes, KCl was added to the organ bath to _2 reach a concentration of 4 x 10 mol/l. The agonist was left in the bath for 2 minutes, during which phasic contractions occurred without bringing about any note-worthy increase in the basic line tension.

Rinsing was then carried out for 1 minute, the rhythmic contractions ceasing immediately. After a second run with addition of agonist and the rinsing procedure, the test substance (benzopyran derivative) was added to the organ bath (in the form of a solution in 0.1 ml of ethanol; the final concentration was 10~^ mol/l in all cases) and was allowed to act for one minute before KCl was added. The subsequent rinsing procedure was followed by two final additions of agon i s t / r i ns i ng procedures.

The foLLowing parameters were determined in each of the two-minute periods during which CL acted: 1. mean force of contraction, 2. frequency of contractions and 3. product of mean force and frequency of contractions.

The criteria for exclusion were mean forces of contraction below 4 mN or frequencies of below 2/min in more than one of the four periods in which only the agonist Cl was present in the bath. Evaluation was of the percentage inhibition with the test substance compared with the mean value from the two initial runs.

Besides the arithmetic mean ( x ) , the standard error of the mean (SE ) was calculated.

Resul ts : n = number of ureters Mean force Frequency v k . v n Compound of con- (%) (%) traction k (%) 3,4-Dihydro-2,2- 68 + 11 67 + U 85 + 7 4 dimethyl-6-(2-chloro-phenylsulf onyl )-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb p ran-3-ol Example 15 Reference: R. S c h i an t a r e 11 i and W. Murmann, Arznei- mi ttel-Forschung/Drug Research 30, 1102 - 1109 (1980)

Claims

91015/2 Claims :

1. The use of a compound I in which R represents H, OH, (C^ -C^ )-alkoxy, (C -Cj )-alkyl or NR R , where R and R are identical or different and represent H, (C^ -C^ )-alkyl or (C^ -C^ )-alkyl- carbonyl , ^ and R are identical or different and represent alkyl having 1-4 carbon atoms, Ar represents phenyl system which is unsubstituted or substituted by 1 to 3 identical or different radicals (C; -Cjj ) -alkyl , (C< -C^ )-alkoxy, halogen, trifluoromethyl, CN, O^ , CO-(C -C^ ) -alkyl or SOw - (Cy -C^ ) -alkyl with m = 1 or 2 , n represents 1 or 2, X represents a chain (CH^ )y which can be interrupted by a heteroatom 0, S or NR6 , where R6 denotes H or (Cj -C^ ) -alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages, substantially as described. 91015/2 - 27 -

2. A pharmaceutical product for the treatment of obstructive functional disorders of the lungs, which contains a compound I as active substance besides customary additives .

3. A composition as claimed in claim 2, in which R to R and ArSO*, are as defined in claim 1, and x denotes (CH^ )f. with r = 3 or 4.

4. A composition as claimed in claim 2, wherein R to R have the abovementioned meanings, A represents phenyl which is unsubstituted or substituted as in claim 1, and x denotes (CH^ )Y with r = 3 or 4.

5. A composition as claimed in claim 2, wherein R^ denotes hydrogen, R* and R represent (C./ -Ca )-alkyl, Ar denotes phenyl which is unsubstituted or substituted once by (C^ -C^ )-alkyl, (C. -C ^ )-alkoxy or halogen, n denotes 2 , and x denotes (CH^ )γ with r = 3 or 4.

6. A composition as claimed in claim 2, wherein R'' denotes hydrogen, R and R represent (C^ -CA )-alkyl, X denotes (CH^ ) Ar denotes CI and n denotes 2 , for the preparation of a remedy for disorders of the efferent urinary passages.

7. A composition in claim 2, wherein R^ denotes hydrogen, R and R represent (C -C^ )-alkyl, Ar denotes phenyl, n denotes 2, and x denotes (CH^ )^ . 91015/2

8. . The use of 3 , 4-dihydro-2 , 2-dimethyl-6- ( 2-chloro- phenylsulfony ) -trans-4- ( 2-bxo-l-pyrrolidinyl ) -2H- benzo[b]pyran-3-ol for the preparation of a remedy for disorders of the efferent urinary passages, substantially as described in the specification.

9. The use of 3 , 4-dihydro-2 , 2-dimethyl-6-phenylsulfonyl trans-4- ( 2 -oxo-1 -pyrrolidinyl ) -2H-benzo[b]pyran-3- ol for the preparation of a remedy for obstructive respiratory tract diseases, substantially as described in the specification. COHEN ZEDEK & RAPAPOR1