DK171782B1 - Use of 3,4-dihydro-2H-benzo [b] pyrans for the manufacture of a drug against obstructive pulmonary dysfunction - Google Patents

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

DK 171782 Bl i

The present invention relates to the use of

3,4-dihydro-2H-benzo [b] pyrans of formula I

* U, c '° W> ** ° a CK (I) © Λ -, 1 wherein R 2 and R 3 are the same or different and mean alkyl of 1-4 carbon atoms,

Ph means phenyl, n is 1 or 2, and 15 X means a chain (CH 2) r, where r is 3 or 4, for the manufacture of a drug against obstructive functional disorders of the lungs.

The carbon nanotubes 3 and 4 of the 3,4-dihydro-2H-benzo [b] pyran system (hereinafter also briefly referred to as the "chromane system") of formula I are substituted asymmetrically. The object of the invention here is only those compounds which have opposite configurations at these centers, that is, a "trans" orientation of the substituents at these carbon atoms. If R2 and R3 are different (and consequently also provide an asymmetric carbon atom), compounds having both S- and R-configured centers are the subject of the invention.

The compounds may exist as optical isomers, as diastereoisomers, as racemates or as mixtures thereof.

Preferred are such compounds where R 2 and R 3 are (C 1 -C 2) alkyl, n is 2 and X and Ph have the meaning given above.

Also preferred are compounds wherein R 2 and R 3 are (¢ ^ -O 2) -alkyl, n is 2, X is (O 2) 3, and Ph 35 is as defined above.

DK 171782 B1 2 EP Publication No. 0.176,689 describes the use of benzopyrans in respiratory diseases and / or disorders of the gastrointestinal tract and / or uterus, in particular highlighting such disorders that occur in contractions of the smooth musculature.

EP Publication No. 207,614 describes the use of benzopyrans in incontinence. EP 277,611 describes the use of benzopyrans for the manufacture of a drug against disorders of the urinary tract.

10 Furthermore, it is from J. Med. Chem. 1986, 22, 2194-22201, known that such compounds may have blood pressure lowering properties.

Surprisingly, for the compounds of formula I, it has now been found in pharmacological studies that the 15 are also suitable as drugs against obstructive functional disorders of the lungs.

Accordingly, the present invention relates to the use of the compounds of formula I for the preparation of a medicament for the treatment and prophylaxis 20 of such disorders, in particular a disorder of the smooth muscle contractions in the lungs, e.g. asthma.

Of particular importance are such compounds of formula I, whose blood pressure lowering properties are less pronounced.

Particularly preferred is the use of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3- etc. for the manufacture of a drug against obstructive respiratory diseases.

The compounds of formula I can be prepared by the following methods.

(a) Compounds of formula II

OH

Ph “s9n * s ^ vAv ^ lr (ii) (Κλ * 3

Ir DK 171782 B1 where R2, R3, Ph and n have the meaning given above,

react with lactams of formula III

Cx (I11> 5 i

B

wherein X has the meaning given above,

(b) Compounds of Formula IV

Ph'son (IV) λ wherein R 2, R 3, Ph and n are as defined above are reacted with the lactams of formula III.

C) Compounds of Formula V

κή2

PhSO_ 0H (V) (¾¾3

Wherein R 2, R 3, Ph and n have the meaning given above, are acylated to compounds VI

BN

'@ 03.

wherein Y means an escape group, e.g. chlorine or bromine, and R 2, R 3, Ph, X and n are as defined above and are cyclized to the compounds of formula I.

D) Compounds of Formula VII

CX

Wherein R2, R3, X and n are as defined above, they are oxidized to the compounds of formula I.

If the compounds of formula I are prepared according to methods a) or b), this is done by reacting compounds II 5 or IV in a suitable solvent, preferably in dipolar aprotic solvents such as dimethylsulfoxide or THF, with the lactams III, preferably under the action of bases, e.g. sodium hydride or K-tert-butylate or similar bases, which are known to be suitable for lactam N-10 alkylations. Thus, the reaction temperature can be varied over a wide range, and preferably between 0 ° C and room temperature or at temperatures which may be slightly above room temperature.

The lactams of formula III are in many cases known or can be readily prepared by methods known in the literature. The compounds of formula II or IV are novel.

For example, they can is prepared by the following synthetic route. Compounds of Formula VIII

0 20 (VIII) ®Os * 23

wherein R 2 and R 3 are as defined above are reacted with acid chlorides Ph-SOn-Cl in known manner according to a Friedel-25 Crafts acylation for compounds of formula IX

"" " 'Λ.

R2, where R2, R3, Ph and n are as defined above.

These are reacted by reactions under standard conditions, e.g. NaBH 4 in methanol, for the compounds of formula X

DK 171782 B1 5

OH

"Τοώτ / wherein r2, r3, Ph and n have the meanings set forth above and are then subjected to a water decomposition, for example, with pyridine / phosphorus oxychloride to form compounds

of formula XI

wherein R2, R3, Ph and "have the meanings set forth above.

The compounds of formula XI are now readily converted to the epoxides of formula IV and the bromohydrin of formula II by standard methods.

Chromas of formula XI are in some cases known in the known manner by thermally induced cyclization of the corresponding propargyl ethers of formula XII

PhS ° n 'ΤηΊ C ^' H

R1 * 25 wherein R2, R3, Ph and n have the meanings set forth above.

These may again be prepared in known manner from the phenols of formula XIII and the propargyl chlorides of formula XIV

PhSO __

pftSOn I

in O I HCeC-C-Cl

L

R3 (XIII) (XIV) wherein Ph, n, R2 and R3 have the meanings set forth above.

DK 171782 B1 6

Methods c) and d) can be used particularly favorably when enantiomerically pure final products of formula I. are desired. Compounds of formula V and formula VII are in contrast to compounds of formula I basic and thus capable of salt formation with organic acids. By crystallization with a suitable optically uniform acid, e.g. (+) - mandelic or (+) lactic acid, they can be obtained enantiomerically pure in known manner and converted to enantiomerically pure final products of formula I by methods c) and d).

However, enantiomerically pure final products of formula I may also be obtained by conventional racemate cleavage methods, e.g. the chromatographic separation using chiral phases or derivatization of the racemic products with optically uniform acid derivatives (ester formation via the 3-hydroxy group of the chromane system) or with optically uniform isocyanates (carbamate formation via the 3-hydroxy group). The resulting diastereoisomeric isocyanates or esters can be cleaved by conventional methods (crystallization or chromatograph i) and converted to the optically uniform final compounds of formula I while cleavage of the optically active auxiliary group by the 3-OH function. Particularly advantageous here is the separation of the diastereomeric 3-methoxyacetates.

The compounds of formula I, as already mentioned above, can be used as agents for the treatment of obstructive airway diseases. Thus, drugs containing a compound of formula I may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred mode of administration being dependent on the disease to be treated. The compounds of formula I can be used for this alone or together with galenic adjuvants, both in veterinary medicine and in human medicine.

The adjuvants suitable for the desired drug formulation are known to those skilled in the art on the basis of his professional knowledge. In addition to solvents, gels, suppository bases, tablet adjuvants and other carriers for active substances, e.g. antioxidants, dispersants, emulsifiers, antifoams, flavor correction agents, preservatives, solvents or colorants are used.

For an oral use, the active compounds are blended with the therefore suitable additives, such as carriers, stabilizers or inert diluents, and are brought by conventional methods to suitable administration forms such as tablets, dragees, sachets, aqueous, alcoholic or oil-based suspensions or aqueous alcoholic or oil-based solutions. As inert carriers, e.g. gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, are used. The preparation can be done both as dry and as a moist granule. As oil-based carriers or solvents, e.g. vegetable or animal oils considered, such as sunflower oil or liver oil.

For subcutaneous or intravenous administration, the 20 active compounds are brought into solution, suspension or emulsion, if desired with the usual substances, such as solvents, emulsifiers or additional excipients. Given as a solvent, e.g. water, physiological saline or alcohols, e.g. ethanol, propanol or glycerol, in addition, sugar solutions such as glucose or mannitol solutions as well as a mixture of the various solvents mentioned.

Suitable as pharmaceutical compositions for administration in the form of aerosols or sprays are e.g. solutions, suspensions or emulsions of the active substance of formula I in a pharmaceutically harmless solvent, especially ethanol or water, or a mixture of such solvents. The formulation may additionally contain other pharmaceutical excipients, such as surfactants, emulsifiers and stabilizers, as well as a propellant. Such a preparation usually contains the active ingredient at a concentration of from about

0.1 to approx. 10% by weight, especially from approx. 0.3 to approx. 3% by weight.

The dosage of the active substance of formula I to be administered and the frequency of administration depend on the potency and duration of the compound used, in addition to the nature and severity of the disease to be treated, and on gender, age, weight and individual susceptibility of the mammal to be treated. On average, the recommended daily dose of a compound of formula I 10 is in a patient of approx. 75 kg 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 case of an acute outbreak of the disease, e.g. in cases of asthma, more may be needed, e.g. up to four single doses per day. per day, while prophylaxis may also be sufficient for one dose.

The compounds of formula I may be administered alone or in combination with other compounds, e.g. the use against obstructive airway disorders together with S2 agonists, such as salbutamol, or with theophylline or di-Na-20-chromium glycate.

Reference Example 1 3,4-Dihydro-2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) -trans-4- (2-oxo-1-pyrrolidinyl) -2H-25-benzo [b] pyran-3-ol (not according to the invention).

4.3 g (0.0097 mol) of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) -2H-benzo [b] pyran-4-ol dissolve in 28 ml of dimethyl sulfoxide, mix with 3.5 ml (0.0465 mol) of 2-pyrrolidinone and 0.78 g (0.0325 mol) of sodium hydride (80% suspension in oil) and stir for 3 hours. at 40 ° C. After standing overnight, pour the mixture into ice water and suction. The precipitate is recrystallized from isopropanol. White crystals, m.p. 263-265 ° C.

35 DK 171782 B1 9

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, 2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) -2H-chromene and N-bromosuccinimide 5 in a 9: 1 mixture of dimethylsulfoxide and H2 O, m.p. 200-201 ° C.

2,2-Dimethyl-7-methoxy-6- (p-tolylsulfonyl) -2H-chromene is obtained from 2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) -chro-man-4-ol with phosphorus oxychloride / pyridine in benzene, m.p. 132--133 ° C.

2,2-Dimethyl-7-methoxy-6- (p-tolylsulfonyl) -chroman--4-ol is obtained from 2,2-dimethyl-7-methoxy-6- (p-tolylsulfonyl) - chroman-4 -one with NaBH 4 in ethanol, m.p. 196-197 ° C.

2,2-Dimethyl-7-methoxy-6- (p-tolylsulfonyl) -chroman-4-one is obtained from 2,2-dimethyl-7-methoxy-chroman-4-one and 15-p-toluenesulfonic acid chloride in the presence of aluminum chloride in methylene chloride, m.p. 221-223 ° C.

Example 1 3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-20-trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol.

To a suspension of 0.6 g (0.02 mol) of 80% NaH in 10 ml of DMSO, drop at 20 ° C a solution of 6.3 g (0.02 mol) of 3,4-dihydro-2.2 -dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-benzo [b] pyran in 20 ml of DMSO. Then 2.3 ml (0.03 mole) of 2-pyrrolidinone is added and stirred at 45 ° C for 1 hour. After standing overnight at 20 ° C, pour into ice water. The precipitate is aspirated, washed neutral, dried and chromatographed on silica gel with methylene chloride / methanol 19: 1. 30 fractions of 30 ml are collected. Fractions 12-25 are concentrated and the residue is recrystallized from acetonitrile, m.p. 201-202 ° C.

Preparation of the starting material: 3,4-Dihydro-2,2-dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-benzo [b] pyran is obtained from 3-bromo-3,4-dihydro-2, 2-dimethyl-1- 10 -6-phenylsulfonyl-2H-benzo [b] pyran-4-ol with NaH in DMSO. Mp. 103-105 ° C.

3-Bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo [b] pyran-4-ol is obtained from 2,2-dimethyl-6-phenylsulfonyl-2H chromium and N-bromosuccinimide in a 9: 1 mixture of dimethyl sulfoxide and water, m.p. 126 ° C.

2,2-Dimethyl-6-phenylsulfonyl-2H-chromene, m.p. 70-71 ° C, is prepared by known methods from 4-phenylsulfonylphenyl-1,1-dimethylpropargyl ether. This ether is obtained in 10 similarly known ways from 4-phenylsulfonylphenyl and 3-methyl-3-chlorobutyne.

(+) -3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2-oxo-1-pyrrolidinyl) -2H-benzotheb] -15-pyran-3-ol (Example 1a).

(±) -3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol is esterified by standard methods with (- ) -menthoxyeddikesyrechlorid. The diastereomeric ester is separated on a silica gel column with methylene-20 chloride / ethyl acetate (9: 1) and saponified with alcoholic sodium-ethylate solution with stirring at 20 ° C. After dilution with cold water, the precipitate is aspirated, washed neutrally and triturated with ether.

(+) -3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol m.p. 122-123 ° C, [α] D = + 39.5 ° (c = 1, ethanol).

Example 2

Preparation of 3,4-dihydro-2,2-dimethyl-6-30-phenylsulfonyl-trans-4- (2-oxo-1-pyrrolidine)

nyl) -2H-benzo [tb] pyran-3-oL

(Compound of Example 1 of 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 for 8 hours at 50 ° C in an autoclave. at a pressure of 8 atmospheres. After cooling, concentrate to dryness and recrystallize from ethyl acetate. 4-amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo [b] pyran-3-ol is obtained, m.p. 160--163 ° C, which is immediately subjected to an acylation with 4-chloro-butyric acid chloride. To this, the compound and the acid chloride are stirred in CH 2 Cl 2 and in a biphasic mixture with 2 N sodium hydroxide solution for 24 hours at room temperature. After the usual work-up, 4- (4-chlorobutyrylamino) -3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo [b] pyran-4-ol, m.p. 155-157 ° C.

The cyclization of the title compound occurs by dissolving the compound in tetrahydrofuran, adding 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), m.p. 200-201 ° C. If 4-amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzotheb] pyran-3-ol is subjected to a racemate cleavage, it can be obtained from its (+) enantiomers. pure (+) enantiomers from Example 1a with the data provided there.

Example 3 3,4-Dihydro-2,2-dimethyl-6-phenylsulfinyl - trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol.

Prepared analogously to Reference Example 1, m.p.

211-212 ° C.

Pharmacological data.

a) Influence on respiratory disorders.

Influence of histamine-induced bronchoconstriction on guinea pigs.

Method:

Albino guinea pigs of both sexes weighing between 450 and 550 g are anesthetized with 60 mg / kg pentobarbital intraperitone total. After tracheotomy, they are given artificial respiration with a 35 Starling pump (Company Braun, Melsungen). The respiratory volume is chosen so that the lungs are thoroughly vented. Respiratory pressure is adjusted using a water column of 80 mm H2O (Rosenthai and Dervinis). The respiratory rate is 30 breaths / minute. An excess of available respiratory air can reach a wash bottle through a side path in the inhalation hose. If air from the Starling pump is blown into the lung through the inhalation hose, it is filled until the pressure in the system has reached the value set at the height of the water column (80 mm H2O). The additional flowing air flows through the pressure valve into the wash bottle. This excess air, which, after exceeding the set pressure, escapes into the bottle, is measured by means of a piston recorder and is used as a measure of a change in respiratory resistance. This measurement is carried out in a slightly modified way from the original Konzett-Rossler method, since the piston recorder has been replaced with a tuning pressure tube according to Fleisch (type 0000). The appearing pressure differential has been recorded with a differential pressure converter Statham PM 97 TC. To record the measurement values has earned a multichannel printer from the company Holy.

The test substances are administered as an aerosol by means of an ultrasonic atomizer (Monaghan M 650). The nebulizer chamber is inserted into the inhalation tube of the respiratory pump and the animals are allowed to inhale the aerosol for 1 minute. The volume to be atomized is 0.02 ml / minute.

25 A physiological saline solution is atomized to which the substance to be tested is added in the form of a solution in propanediol.

In a control experiment, it is determined that the solvent propanediol / physiological saline solution has no intrinsic effect.

A bronchoconstriction is induced by administration of histamine dihydrochloride (6-12 Mg / kg intravenously). The injection is done through a catheter inserted into V. jugularis. The dosage is selected so that during the histamine-induced broncho-constriction, a respiratory "flood" of 60% of the offered volume of breathing occurs. The histamine administration DK 171782 B1 13 occurs at intervals of 5 minutes. After at least 3 well reproducible bronchoconstrictions, the test substances are administered as aerosol for 1 minute, and after a duration of 2 minutes the bronchoconstriction is induced again and repeated 5 at 5 minute intervals.

The degree of inhibition of the histamine-induced broncho-constriction after pretreatment with the test substance is considered a measure of the bronchodilatory effect and is indicated as a percentage change compared to the control.

10 All results are subjected to linear regression and ID50 is measured.

Results:% Inhibition of the histamine-induced bronchoconstriction.

Compound Dose n% Inhibition

Example 1a µg / kg 6 14 ± 4 20 (+) - 3,4-Dihydro-2,2-di-3 µg / kg 6 35 ± 4 methyl-6-phenylsulfonyl-10 µg / kg 6 77 ± 7 -trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol ID50: 4.39 µg / kg

Claims (4)

14 DK 171782 B1 Patent claims. Use of 3,4-dihydro-2H-benzo [b] pyranes of the formula I m 10 wherein R 2 and R 2 are the same or different and represent alkyl of 1-4 carbon atoms, Ph means phenyl, 15. is 1 or 2, and X is a chain (CH 2) r, where r is 3 or 4, to produce a drug against obstructive functional disorders of the lungs. Use according to claim 1, characterized in that R 2 and R 2 are (C 1 -C 2) -alkyl, n is 2, and X and Ph are as defined in claim 1. Use according to claim 1, characterized in that R 2 and R 2 are (¢ 2 -O 2) -alkyl, n is 2, X means (CH 2) 3 and Ph has the meaning given in claim 1. Use of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol to prepare a drug against obstructive airway diseases. 30 35