CA1336891C - Use of substituted 3,4-dihydro-2h-benzopyrans as remedies for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages - Google Patents
Use of substituted 3,4-dihydro-2h-benzopyrans as remedies for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passagesInfo
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- CA1336891C CA1336891C CA000605990A CA605990A CA1336891C CA 1336891 C CA1336891 C CA 1336891C CA 000605990 A CA000605990 A CA 000605990A CA 605990 A CA605990 A CA 605990A CA 1336891 C CA1336891 C CA 1336891C
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The use of substituted 3,4-dihydro-2H-benzopyrans as remedies for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages The use of 3,4-dihydro-2H-benzo[b]pyrans of the formula I
I
in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy for obstructive func-tional disorders of the lungs and/or disorders of the efferent urinary passages, is described
I
in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy for obstructive func-tional disorders of the lungs and/or disorders of the efferent urinary passages, is described
Description
Description The use of substituted 3,4-dihydro-2H-benzopyrans as remedies for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages.
The invention relates to the use of 3,4-dihydro-2H-benzo-tb]pyrans of the formula I
rx~
~ - C=O
Ar-SOn ~ R~2 in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NOz, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom 0, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, ' _ - 2 - 1336891 for the preparation of a remedy for obstructive func-tional 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, and a 5- or 6-membered heteroaromatic system Ar is preferably a radical of a 5-or 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, prefer-ably F and Cl.
Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzotb]pyran 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 R1, ArSOn, R2 and/or R3 contains centersof 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, di-astereoisomers, racemates or mixtures thereof.
Preferably used are compounds of the formula I in ~hich R1 to R3 and ArSOn 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 represents a chain (CH2)r with r = 3 or 4.
t Especially preferably used are those compounds in which R1 denotes H, R2 and R3 represent (C1-C2)-alkyl, S Ar represents phenyl which is unsubstituted or substituted once by (C1-Cz)-alkyl, (C1-C2)-alkoxy or halogen, n represents 2, and X represents a chain (CH2)r with r =
3 or 4.
Likewise preferred are compounds with R1 equal to H, R2 and R3 equal to (C1-C2)-alkyl, X equal to (CH2)3r-Ar equal to C6H4Cl, and n equal to 2, as well as those with R1 equal to H, R2 and R3 equal to (C1-C2)-alkyl, Ar equal to phenyl, n equal to 2, and X equal to (CH2)3.
EP 0,176,689 describes the use of benzopyrans for res-piratory tract diseases and/or disorders of the gastro-intestinal 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. 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 investiga-tions that compounds I are likewise suitable for use as remedies for respiratory tract diseases and/or disorders of the efferent urinary passages.
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 dis-turbance of the smooth muscular contractions of the parti-cular organs, such as, for example, asthma, incontinence or renal colic. Particularly important in this connec-tion 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 dis-orders of the lungs, ~hich contains a compound I as active substance besides customary additives, as ~ell as S at a compound I for use for the treatment of obstructive functional disorders of the lungs and/or of the efferent ur1nary passages.
Very particularly preferred is the use of 3,4-dihydro-2,2-dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol for the preparation of a remedy for disorders of the efferent urinary pass-ages and the use of 3,4-dihydro-2,2-dimethyl-6-phenyl-sulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-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 com-pounds according to the invention for the preparation of pharmaceuticals ~hich are used for the treatment and prophylaxis of the abovementioned diseases.
The compounds I can be prepared by the follouing pro-cesses:
by a) reacting compounds of the formula II
O~ II
Ar-S ~ ~ ~r R1 ~ ~ R23 in ~hich R1 to R3 and ArSOn are as defined above, ~ith lactams of the formula III
- 1~36891 (N)~O I I I
b) reacting compounds of the formula IV
Ar-SOn ~ ~ IV
in ~hich R1 to R3 and ArSOn are as defined above, with the lactams of the formula III, c) acylating compounds of the formula V
AsSOn ~2R3 ( V ) in ~hich R1 to R3 and ArSOn are as defined above, to give the compounds VI
RN ~ X-Y
ArSOn ~ ~ R3 VI
in ~hich Y is a leaving group such as, for example, chlorine or bromine, and R1 to R3 and ArSOn are as defined above, and cyclizing the latter to give the compounds I, d) oxidizing compounds of the formula VII
( ~);H2 R ~O~R13i VI I
in which R1 to R3 and ArSOn are as defined above, to give the compounds I.
~here 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 sol-vents 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-alkylations. The temperature for this reaction can be varied ~ithin ~ide 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
o 1~ ~ R3 VIII
in ~hich R1, R2 and R3 are as defined above, are reacted with acid chlorides Ar-SOn-Cl in a type of Friedel-Crafts acylation in a manner known per se to give com-pounds of the formula IX
~ V ~ R2 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 NaBH4 in methanol, into the - 7 ~ 1336891 compounds X
- OH
Rl~RR3 X
~hich are then subjected to elimination of ~ater, for example by pyridine/phosphorus oxychloride, resulting in compounds of the formula XI:
~ R3 Compounds XI can no~ easily be converted by standard methods into the epoxides IV or the bromohydrins II.
If in this reaction sequence R means NH2 or OH, protec-tive groups may be necessary, such as, for example, thedimethylaminomethylene 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 kno~n per se by thermally induced cyclization of the corresponding propargyl ethers XII
ArSOn~@~ C~ X I I
. ~1 O~R3 These in turn can be prepared in a manner known per se from the phenols XIII and the propargyl chlorides XIV.
~ 8 -~ ~rSOn ~ HC - C - C - Cl XIII XIV
It is possible and particularly beneficial to use pro-cesses c) and d) ~hen 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 saltswith organic acids. It is possible, by crystallization ~ith a suitable optically pure acid such as, for example, (I)-mandelic acid or (~)-lactic acid, in a manner kno~n per se to obtain them as pure enantiomers, and convert them by processes c) and d) into final products I as pure enantiomers.
Ho~ever, 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 ~ith optically pure acid derivatives (ester formation via the 3-hydroxy group of the chroman system) or ~ith optically pure iso-cyanates (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 3-OH group.
Separation of the diastereomeric 3-menthoxyacetates has proven particularly advantageous in this connection.
As already mentioned, the compounds I can be used accord-ing 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, parenterally, intravenously, rectally or by inhalation, with the pre-ferred administration form being dependent on the disease which is to be treated. In this connection, the com-pounds I can be used alone or together with pharmaceuti-cal auxiliaries, specifically both in veterinary and in human medicine.
The expert is familiar, on the basis of his expert know-ledge, 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 cap-sules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium Z5 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 sub-stances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, into a solution, sus-pension or emulsion. Examples of suitable solvents are water, physiological saline or alcohols, for example o- 1336891 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 sub-stance 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, X by weight.
The dosage of the active substance of the formula I which is to be administered, and the frequency of administra-tion, 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 res-ponse 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 ~ith other compounds, for example when used for obstructive respiratory tract disorders with 32-agonists such as salbutamol, or with theo-phylline or with disodium cromoglycate.
~hen used for disorders of the efferent urinary passages, - examples of partners in the combination are those having antibacterial or analgesic activity.
The compounds of the formula I compiled in the table S which follows are particularly well suited:
1) 2,2-dimethyl-3,4-dihydro-7-methoxy-6-(p-chlorophenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]-pyran-3-ol, 2) 2,2-dimethyl-3,4-dihydro-6-(p-chlorophenylsulfonyl)-trans-4-(2-oxo-1-piperidinyl)-ZH-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)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 5) 2,2-dimethyl-3,4-dihydro-6-(p-methoxyphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 6) 2,2-dimethyl-3,4-dihydro-6-(p-trifluoromethylphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-pyran-3-ol, 7) 2,2-dimethyl-3,4-dihydro-6-(p-methylsulfonylphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-pyran-3-ol, 8) 2,2-dimethyl-3,4-dihydro-6-(p-acetylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 9) 2,2-dimethyl-3,4-dihydro-7-methylamino-6-phenylsulf-onyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-o~, ~ - 12 -10) 2,2-dimethyl-3,4-dihydro-7-fluoro-6-phenylsulfonyl-- trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]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-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 13) 2,2-dimethyl-3,4-dihydro-6-(4-chloro-3-methylphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-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-ol, 15) 2,2-dimethyl-3,4-dihydro-trans-4-(4-methyl-2-oxo-1-piperazinyl)-6-phenylsulfonyl-2H-benzoCb]pyran-3-ol, 16) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4-(2-oxo-1-morpholinyl)-2H-benzotb]pyran-3-ol, 17) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4-(5-oxo-3-oxazolinyl)-2H-benzotb]pyran-3-ol, 18) 3,4-dihydro-2,2-dimethyl-6-(p-fluorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 19) 3,4-dihydro-2,2-dimethyl-6-(o-fluorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 20) 3,4-dihydro-2,2-dimethyl-6-(3-pyridylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 21) 3,4-dihydro-2,2-dimethyl-6-(2-pyrimidinylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 22) 3,4-dihydro-2,2-dimethyl-6-(2-furylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-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 S 4.3 9 (0.0097 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-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 9 of sodium hydride (80% suspension in oil) tO.0325 mole) are added, and the mixture is stirred at 40C 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. ~hite crystals of me~ting point:
263 - 65C.
Preparation of the starting compound:
3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolyl-sulfonyl)-2H-benzo[b]pyran-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulf-oxide and H20. Melting point: 200-201C
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 with phosphorus oxychloride/pyridine in benzene. Melting point: 132 - 33C
2,2-Dimethyl-7-methoxy-6-(p-tolylsulfonyl)chroman-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulf-onyl)chroman-4-one with NaPH4 in ethanol.
Melting point: 196 - 97C
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 ~ - 14 - 1336891 chloride in methylene chloride.
Melting point: 221 - 23C.
Example 2 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-trans-4-(2-oxo-1-piperidinyl)-2H-benzo~b]pyran-3-ol 5 9 (0.011 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-benzo~b]pyran-4-ol are dissolved in 32 ml of dimethyl sulfoxide, and 4.9 9 of valerolactam (0.0526 mole) and 0.8 9 (0.033 mole) of NaH, 80~ suspension in oil, are added, and the mixture is stirred at 40C for 5 hours. It is poured into ice-water and filtered ~ith suction. The residue is extrac-ted by boiling several times ~ith methanol.
White crystals of melting point: 261 - 63C
Example 3 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]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-yl-2H-benzcrb]pyran-4-ol.
White crystals of melting point: 227 - 29C
Separation of the antipodes, Example 3a 1.075 9 (0.0025 mole) of (+)-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]pyran-3-ol are dissolved in 5 ml of 1,2-di-chlorobenzene, and 0.9 9 of S(-)-1-phenylethyl isocyanate is added, and the mixture is stirred at 140C for about 12 h. The complete mixture is subsequently chromato-graphed on silica gel with the solvent system toluene/
ethyl acetate 1:1. The diastereomeric carbamate ~hich ~ - 15 -migrates slo~er can be enriched and obtained pure by crystallization from toluene (melting point 243-245C).
Hydrolysis ~ith NaOH in EtOH at 80C results in (+)-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol of melting point: 209-211C and C~]D = + 109 (c = 0.28;
CHCl3) Preparation of the starting material:
3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenyl-sulfonyl-2H-benzo[b]pyran-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and H20. Melting point: 202 - 203C.
2,2-Dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene is obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenyl-sulfonylchromene ~ith pyridine/phosphorus oxychloride in benzene. Melting point: 140 - 41C.
2,2-Dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchroman is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonyl-chroman-4-one ~ith sodium borohydride in methanol.
Melting point: 146 - 147C.
2,2-Dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one is obtained from phenylsulfonyl chloride, 2,2-dimethyl-7-methoxychroman-4-one and aluminum chloride in methylene chloride.
Melting point: 223 - 25C
Example 4 3,4-Dihydro-2,2-dimethyl-6-(4-methylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol 0.75 9 (0.025 mole) of 80% NaH is introduced into 8.2 9 r--~
(0.02 mole) of 3-bromo-3,4-dihydro-2,Z-dimethyl-6-(4-methylphenylsulfonyl)-2H-benzoCb]pyran-4-ol in 30 ml of dimethyl sulfoxide. After stirring at 20 for one hour, a further 0.75 9 (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 - 243C.
Preparation of the starting material 3-Bromo-3,4-dihydro-2,2-dimethyl-6-(4-methylphenyl-sulfonyl)-2H-benzoCb]pyran-4-ol 14.2 9 (0.08 mole) of freshly recrystallized N-bromo-succinimide are introduced into 12.6 9 (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 15C. The temperature rises transiently to 27.
It is cooled to 20C and, after stirring for one hour, introduced into ice/ethyl acetate. The ethyl acetate phase is washed several times with water and dried over Na2S04. The bromohydrin deri~ative crystallizes on concentration. Crystals of melting point: 141 - 142C.
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 9 (0.02 mole) of 3,4-dihydro-2,2-di-methyl-3,4-epoxy-6-phenylsulfonyl-2H-benzotb]pyran in 20 ml of DMS0 is added dropwise, at 20, to a suspension of 0.6 9 (0.02 mole) of 80% NaH in 10 ml of DMS0. 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 ~~ - 17 - 1336891 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 S 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-2H-benzoCb]pyran is obtained from 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol with NaH
in DMS0.
Melting point: 103-105 3-Promo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol is obtained from 2,2-dimethyl-6-phenylsulfonyl-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and HzO.
Melting point: 126 2,2-Dimethyl-6-phenylsulfonyl-2H-chromene, with melting point 70-71, was prepared by known methods from 4-phenylsulfonylphenyl 1,1-dimethylpropargyl ether. This ether is obtained, likewise in a known manner, from 4-phenylsulfonylphenol and 3-methy!-3-c~orobutyne.
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol (Example Sa) (+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol is esterified with (-)-menthoxyacetyl chloride by standard methods. The diastereomeric esters are separated on a silica gel column with methylene chlor;de/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 ~ith ether.
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol Melting point: 122-123 ta]D = ~ 39.5 (c = 1, ethanol) Example 6 6-(4-Chlorophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]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-benzo~b]pyran-4-ol.
~hite crystals with melting point: 260-262C
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 ~ith melting point: 175-177C
6-(4-Chlorophenylsulfonyl)-2,2-dimethyl-7-methoxychromene ~ith melting point: 142-143C
Example 7 6-(4-Bromophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol In analogy to Example 1 from 3-bromo-6-(4-bromophenyl-sulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-2H-benzo[b]-pyran-4-ol.
White crystals of melting point: 281-282C.
Example 8 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-~4-methoxyphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-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-(4-methoxy-phenylsulfonyl)-2H-benzoCb]pyran-4-ol and has a melting point of 286-287C.
Example 9 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(2-thienylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(2-thienylsulfonyl)-2H-benzoCb]pyran-4-ol, melting point: 135-136C.
Example 10 3,4-Dihydro-2,2-dimethyl-7-ethoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-ethoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol, melting point: 197-198C.
Example 11 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzoCb]pyran-3-o-In analogy to Example 2 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol. ~hite crystals of melting point: 157-158C.
Example 12 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-benzotb]pyran-4-ol.
~hite crystals of melting point: 234-235C.
_ Preparation of the starting material:
3-Bromo-6-(4-cyanophenylsuLfonyl)-3,4-dihydro-2,2-dimethyl-2H-benzotb]pyran-4-ol is obtained as described in Example 3 from 6-(4-cyanophenylsulfonyl)-2,2-dimethyl-3-chromene.
Melting point: 157-158C.
Example 13 3,4-Dihydro-2,2-dimethyl-6-(2-methoxyphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-6-(2-methoxyphenylsulfonyl)-2H-benzoCb~pyran-4-ol. ~hite crystals of melting point: 196-198C.
Example 14 3,4-Dihydro-2,2-dimethyl-6-(2-methylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol In analogy to Example 1. ~hite crystals of melting point:
214-216C.
Example 15 3,4-Dihydro-2,2-dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol In analogy to Example 1. ~hite crystals of melting point: 85-87C
Example 16 Preparation of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-trans-4-(2-oxo-1-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-phenyl-sulfonyl-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-Amino-- 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]-pyran-3-ol of melting point: 160-163C is obtained and is immediately subjected to acylation with 4-chlorobutyr-yl chloride. For this purpose, the substance is dis-solved together with the acid chloride in CH2Cl2 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 155-157C. Cyclization to give the title compound is carried out by dissolving the substance in tetrahydrofuran, addition of a stoichiometric amount of 80Z 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: 200-201C. If 4-amino-3,4-dihydro-2,2-dimethyl-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-Dihydro-2,2-dimethyl-6-phenylsulfoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1. Melting point: 211 - 212C
Pharmacological data a) Effect on respiratory tract disorders Effect on histamine-induced bronchoconstriction in guinea-pigs Method:
Uhite guinea-pigs of both sexes and weighing bet~een 450 and 550 9 were anesthetized with 60 mg/kg pentobarbital i.p. After tracheotomy, they were ventilated with a Starling pump (from Braun, Melsungen). The tidal volume ~as selected for generous ventilation of the lungs. The ventilation pressure was adjusted to 80 mm H20 with the S aid of a water column (Rosenthal and Dervinis). The breathing rate was 30 breaths/min. An excess of avail-able respiratory air can pass through a bypass in the inhalation tube to a washbottle which is designed as a water pressure-relief valve. ~hen 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 flo~s 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 replacedby 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 ~ith 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 ~ - - Z3 - 1336891 propanediol/physiological saline solution has no action itself.
Eronchoconstriction is induced by doses of histamine di-hydrochloride (6 - 12 ~g/kg i.v.). Injection is through S 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 areadministered as aerosol for 1 min and, after an action time of 2 min, the bronchoconstriction is induced ane~
and repeated at intervals of S minutes.
The degree of inhibition of the histamine-induced broncho-constriction after pretreatment with the test substance is regarded as a measure of the bronchodilator activity and is reported as Z change from the control.
All results are subjected to linear regression, and the IDso is determined.
Results:
% inhibition of histamine-induced bronchoconstriction Compound Dose n % inhibition Example Sa 1 ~g/kg 6 14 + 4 (+)-3,4-dihydro-2,2- 3 ~g/kg 6 35 ~ 4 25 dimethyl-6-phenyl- 10 ~g/kg 6 77 + 7 sulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol IDso: 4-39 ~g/kg ~ - 24 - 1336891 b) Efferent urinary passages Effect on the KCl-induced 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 exsanguination 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 solu-tion and then suspended in a 25 ml organ bath (from Rhema Labortechnik, Hofheim), in each case with a tension of 4.9 mN (= 0.5 p). The organ bath contained Tyrode solu-tion of the following composition (mmol/l): NaCl 137, KCl 2.68, MgS04 1.05, CaCl2 1.8, NaH2P04 0.41, NaHC03 11.9, glucose 5.55, which was maintained at 37C and through which carbogen (95% 2~ 5% C02) was bubbled.
The contractions were measured isometrically using Gould/
Statham UC2 pickups. After an equilibration time of at least 15 minutes, KCl was added to the organ bath to reach a concentration of 4 x 10 2 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 rhythmiccontractions ceasing immediately. After a second run with addition of agonist and the rinsing procedure, the test substance (benzopyran derivative) ~as added to the organ bath (in the form of a solution in 0.1 ml of ethanol; the final concentration was 10 7 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 agonist/rinsing procedures.
` 1336891 _ Z5 The following parameters were determined in each of the two-minute periods during which KCl acted: 1. mean force of contraction, 2. frequency of contractions and 3. pro-duct of mean force and frequency of contractions.
The criteria for exclusion were mean forces of contrac-tion below 4 mN or frequencies of below 2/min in more than one of the four periods in ~hich only the agonist KCl was present in the bath. Evaluation was of the per-centage 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 (SEM) was calculated.
Results:
n = number of ureters Mean force Frequency v k . v n Compound of con- (%) (%) traction k (%) 3,4-Dihydro-2,2- 68 + 11 67 ~ 1485 1 7 4 dimethyl-6-(2-chloro-~enylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol Example 15 Reference: R. Schiantarelli and ~. Murmann, Arznei-mittel-Forschung/Drug Research 30, 1102 -1109 (1980)
The invention relates to the use of 3,4-dihydro-2H-benzo-tb]pyrans of the formula I
rx~
~ - C=O
Ar-SOn ~ R~2 in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NOz, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom 0, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, ' _ - 2 - 1336891 for the preparation of a remedy for obstructive func-tional 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, and a 5- or 6-membered heteroaromatic system Ar is preferably a radical of a 5-or 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, prefer-ably F and Cl.
Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzotb]pyran 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 R1, ArSOn, R2 and/or R3 contains centersof 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, di-astereoisomers, racemates or mixtures thereof.
Preferably used are compounds of the formula I in ~hich R1 to R3 and ArSOn 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 represents a chain (CH2)r with r = 3 or 4.
t Especially preferably used are those compounds in which R1 denotes H, R2 and R3 represent (C1-C2)-alkyl, S Ar represents phenyl which is unsubstituted or substituted once by (C1-Cz)-alkyl, (C1-C2)-alkoxy or halogen, n represents 2, and X represents a chain (CH2)r with r =
3 or 4.
Likewise preferred are compounds with R1 equal to H, R2 and R3 equal to (C1-C2)-alkyl, X equal to (CH2)3r-Ar equal to C6H4Cl, and n equal to 2, as well as those with R1 equal to H, R2 and R3 equal to (C1-C2)-alkyl, Ar equal to phenyl, n equal to 2, and X equal to (CH2)3.
EP 0,176,689 describes the use of benzopyrans for res-piratory tract diseases and/or disorders of the gastro-intestinal 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. 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 investiga-tions that compounds I are likewise suitable for use as remedies for respiratory tract diseases and/or disorders of the efferent urinary passages.
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 dis-turbance of the smooth muscular contractions of the parti-cular organs, such as, for example, asthma, incontinence or renal colic. Particularly important in this connec-tion 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 dis-orders of the lungs, ~hich contains a compound I as active substance besides customary additives, as ~ell as S at a compound I for use for the treatment of obstructive functional disorders of the lungs and/or of the efferent ur1nary passages.
Very particularly preferred is the use of 3,4-dihydro-2,2-dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol for the preparation of a remedy for disorders of the efferent urinary pass-ages and the use of 3,4-dihydro-2,2-dimethyl-6-phenyl-sulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-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 com-pounds according to the invention for the preparation of pharmaceuticals ~hich are used for the treatment and prophylaxis of the abovementioned diseases.
The compounds I can be prepared by the follouing pro-cesses:
by a) reacting compounds of the formula II
O~ II
Ar-S ~ ~ ~r R1 ~ ~ R23 in ~hich R1 to R3 and ArSOn are as defined above, ~ith lactams of the formula III
- 1~36891 (N)~O I I I
b) reacting compounds of the formula IV
Ar-SOn ~ ~ IV
in ~hich R1 to R3 and ArSOn are as defined above, with the lactams of the formula III, c) acylating compounds of the formula V
AsSOn ~2R3 ( V ) in ~hich R1 to R3 and ArSOn are as defined above, to give the compounds VI
RN ~ X-Y
ArSOn ~ ~ R3 VI
in ~hich Y is a leaving group such as, for example, chlorine or bromine, and R1 to R3 and ArSOn are as defined above, and cyclizing the latter to give the compounds I, d) oxidizing compounds of the formula VII
( ~);H2 R ~O~R13i VI I
in which R1 to R3 and ArSOn are as defined above, to give the compounds I.
~here 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 sol-vents 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-alkylations. The temperature for this reaction can be varied ~ithin ~ide 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
o 1~ ~ R3 VIII
in ~hich R1, R2 and R3 are as defined above, are reacted with acid chlorides Ar-SOn-Cl in a type of Friedel-Crafts acylation in a manner known per se to give com-pounds of the formula IX
~ V ~ R2 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 NaBH4 in methanol, into the - 7 ~ 1336891 compounds X
- OH
Rl~RR3 X
~hich are then subjected to elimination of ~ater, for example by pyridine/phosphorus oxychloride, resulting in compounds of the formula XI:
~ R3 Compounds XI can no~ easily be converted by standard methods into the epoxides IV or the bromohydrins II.
If in this reaction sequence R means NH2 or OH, protec-tive groups may be necessary, such as, for example, thedimethylaminomethylene 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 kno~n per se by thermally induced cyclization of the corresponding propargyl ethers XII
ArSOn~@~ C~ X I I
. ~1 O~R3 These in turn can be prepared in a manner known per se from the phenols XIII and the propargyl chlorides XIV.
~ 8 -~ ~rSOn ~ HC - C - C - Cl XIII XIV
It is possible and particularly beneficial to use pro-cesses c) and d) ~hen 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 saltswith organic acids. It is possible, by crystallization ~ith a suitable optically pure acid such as, for example, (I)-mandelic acid or (~)-lactic acid, in a manner kno~n per se to obtain them as pure enantiomers, and convert them by processes c) and d) into final products I as pure enantiomers.
Ho~ever, 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 ~ith optically pure acid derivatives (ester formation via the 3-hydroxy group of the chroman system) or ~ith optically pure iso-cyanates (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 3-OH group.
Separation of the diastereomeric 3-menthoxyacetates has proven particularly advantageous in this connection.
As already mentioned, the compounds I can be used accord-ing 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, parenterally, intravenously, rectally or by inhalation, with the pre-ferred administration form being dependent on the disease which is to be treated. In this connection, the com-pounds I can be used alone or together with pharmaceuti-cal auxiliaries, specifically both in veterinary and in human medicine.
The expert is familiar, on the basis of his expert know-ledge, 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 cap-sules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium Z5 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 sub-stances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, into a solution, sus-pension or emulsion. Examples of suitable solvents are water, physiological saline or alcohols, for example o- 1336891 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 sub-stance 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, X by weight.
The dosage of the active substance of the formula I which is to be administered, and the frequency of administra-tion, 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 res-ponse 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 ~ith other compounds, for example when used for obstructive respiratory tract disorders with 32-agonists such as salbutamol, or with theo-phylline or with disodium cromoglycate.
~hen used for disorders of the efferent urinary passages, - examples of partners in the combination are those having antibacterial or analgesic activity.
The compounds of the formula I compiled in the table S which follows are particularly well suited:
1) 2,2-dimethyl-3,4-dihydro-7-methoxy-6-(p-chlorophenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]-pyran-3-ol, 2) 2,2-dimethyl-3,4-dihydro-6-(p-chlorophenylsulfonyl)-trans-4-(2-oxo-1-piperidinyl)-ZH-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)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 5) 2,2-dimethyl-3,4-dihydro-6-(p-methoxyphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 6) 2,2-dimethyl-3,4-dihydro-6-(p-trifluoromethylphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-pyran-3-ol, 7) 2,2-dimethyl-3,4-dihydro-6-(p-methylsulfonylphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-pyran-3-ol, 8) 2,2-dimethyl-3,4-dihydro-6-(p-acetylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 9) 2,2-dimethyl-3,4-dihydro-7-methylamino-6-phenylsulf-onyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-o~, ~ - 12 -10) 2,2-dimethyl-3,4-dihydro-7-fluoro-6-phenylsulfonyl-- trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]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-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 13) 2,2-dimethyl-3,4-dihydro-6-(4-chloro-3-methylphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-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-ol, 15) 2,2-dimethyl-3,4-dihydro-trans-4-(4-methyl-2-oxo-1-piperazinyl)-6-phenylsulfonyl-2H-benzoCb]pyran-3-ol, 16) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4-(2-oxo-1-morpholinyl)-2H-benzotb]pyran-3-ol, 17) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4-(5-oxo-3-oxazolinyl)-2H-benzotb]pyran-3-ol, 18) 3,4-dihydro-2,2-dimethyl-6-(p-fluorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 19) 3,4-dihydro-2,2-dimethyl-6-(o-fluorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 20) 3,4-dihydro-2,2-dimethyl-6-(3-pyridylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 21) 3,4-dihydro-2,2-dimethyl-6-(2-pyrimidinylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol, 22) 3,4-dihydro-2,2-dimethyl-6-(2-furylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-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 S 4.3 9 (0.0097 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-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 9 of sodium hydride (80% suspension in oil) tO.0325 mole) are added, and the mixture is stirred at 40C 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. ~hite crystals of me~ting point:
263 - 65C.
Preparation of the starting compound:
3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolyl-sulfonyl)-2H-benzo[b]pyran-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulf-oxide and H20. Melting point: 200-201C
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 with phosphorus oxychloride/pyridine in benzene. Melting point: 132 - 33C
2,2-Dimethyl-7-methoxy-6-(p-tolylsulfonyl)chroman-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulf-onyl)chroman-4-one with NaPH4 in ethanol.
Melting point: 196 - 97C
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 ~ - 14 - 1336891 chloride in methylene chloride.
Melting point: 221 - 23C.
Example 2 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-trans-4-(2-oxo-1-piperidinyl)-2H-benzo~b]pyran-3-ol 5 9 (0.011 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-benzo~b]pyran-4-ol are dissolved in 32 ml of dimethyl sulfoxide, and 4.9 9 of valerolactam (0.0526 mole) and 0.8 9 (0.033 mole) of NaH, 80~ suspension in oil, are added, and the mixture is stirred at 40C for 5 hours. It is poured into ice-water and filtered ~ith suction. The residue is extrac-ted by boiling several times ~ith methanol.
White crystals of melting point: 261 - 63C
Example 3 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]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-yl-2H-benzcrb]pyran-4-ol.
White crystals of melting point: 227 - 29C
Separation of the antipodes, Example 3a 1.075 9 (0.0025 mole) of (+)-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]pyran-3-ol are dissolved in 5 ml of 1,2-di-chlorobenzene, and 0.9 9 of S(-)-1-phenylethyl isocyanate is added, and the mixture is stirred at 140C for about 12 h. The complete mixture is subsequently chromato-graphed on silica gel with the solvent system toluene/
ethyl acetate 1:1. The diastereomeric carbamate ~hich ~ - 15 -migrates slo~er can be enriched and obtained pure by crystallization from toluene (melting point 243-245C).
Hydrolysis ~ith NaOH in EtOH at 80C results in (+)-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol of melting point: 209-211C and C~]D = + 109 (c = 0.28;
CHCl3) Preparation of the starting material:
3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenyl-sulfonyl-2H-benzo[b]pyran-4-ol is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and H20. Melting point: 202 - 203C.
2,2-Dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene is obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenyl-sulfonylchromene ~ith pyridine/phosphorus oxychloride in benzene. Melting point: 140 - 41C.
2,2-Dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchroman is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonyl-chroman-4-one ~ith sodium borohydride in methanol.
Melting point: 146 - 147C.
2,2-Dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one is obtained from phenylsulfonyl chloride, 2,2-dimethyl-7-methoxychroman-4-one and aluminum chloride in methylene chloride.
Melting point: 223 - 25C
Example 4 3,4-Dihydro-2,2-dimethyl-6-(4-methylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol 0.75 9 (0.025 mole) of 80% NaH is introduced into 8.2 9 r--~
(0.02 mole) of 3-bromo-3,4-dihydro-2,Z-dimethyl-6-(4-methylphenylsulfonyl)-2H-benzoCb]pyran-4-ol in 30 ml of dimethyl sulfoxide. After stirring at 20 for one hour, a further 0.75 9 (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 - 243C.
Preparation of the starting material 3-Bromo-3,4-dihydro-2,2-dimethyl-6-(4-methylphenyl-sulfonyl)-2H-benzoCb]pyran-4-ol 14.2 9 (0.08 mole) of freshly recrystallized N-bromo-succinimide are introduced into 12.6 9 (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 15C. The temperature rises transiently to 27.
It is cooled to 20C and, after stirring for one hour, introduced into ice/ethyl acetate. The ethyl acetate phase is washed several times with water and dried over Na2S04. The bromohydrin deri~ative crystallizes on concentration. Crystals of melting point: 141 - 142C.
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 9 (0.02 mole) of 3,4-dihydro-2,2-di-methyl-3,4-epoxy-6-phenylsulfonyl-2H-benzotb]pyran in 20 ml of DMS0 is added dropwise, at 20, to a suspension of 0.6 9 (0.02 mole) of 80% NaH in 10 ml of DMS0. 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 ~~ - 17 - 1336891 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 S 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-2H-benzoCb]pyran is obtained from 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol with NaH
in DMS0.
Melting point: 103-105 3-Promo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol is obtained from 2,2-dimethyl-6-phenylsulfonyl-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide and HzO.
Melting point: 126 2,2-Dimethyl-6-phenylsulfonyl-2H-chromene, with melting point 70-71, was prepared by known methods from 4-phenylsulfonylphenyl 1,1-dimethylpropargyl ether. This ether is obtained, likewise in a known manner, from 4-phenylsulfonylphenol and 3-methy!-3-c~orobutyne.
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol (Example Sa) (+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol is esterified with (-)-menthoxyacetyl chloride by standard methods. The diastereomeric esters are separated on a silica gel column with methylene chlor;de/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 ~ith ether.
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol Melting point: 122-123 ta]D = ~ 39.5 (c = 1, ethanol) Example 6 6-(4-Chlorophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]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-benzo~b]pyran-4-ol.
~hite crystals with melting point: 260-262C
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 ~ith melting point: 175-177C
6-(4-Chlorophenylsulfonyl)-2,2-dimethyl-7-methoxychromene ~ith melting point: 142-143C
Example 7 6-(4-Bromophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol In analogy to Example 1 from 3-bromo-6-(4-bromophenyl-sulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-2H-benzo[b]-pyran-4-ol.
White crystals of melting point: 281-282C.
Example 8 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-~4-methoxyphenyl-sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-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-(4-methoxy-phenylsulfonyl)-2H-benzoCb]pyran-4-ol and has a melting point of 286-287C.
Example 9 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(2-thienylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(2-thienylsulfonyl)-2H-benzoCb]pyran-4-ol, melting point: 135-136C.
Example 10 3,4-Dihydro-2,2-dimethyl-7-ethoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-ethoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol, melting point: 197-198C.
Example 11 3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzoCb]pyran-3-o-In analogy to Example 2 from 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol. ~hite crystals of melting point: 157-158C.
Example 12 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-benzotb]pyran-4-ol.
~hite crystals of melting point: 234-235C.
_ Preparation of the starting material:
3-Bromo-6-(4-cyanophenylsuLfonyl)-3,4-dihydro-2,2-dimethyl-2H-benzotb]pyran-4-ol is obtained as described in Example 3 from 6-(4-cyanophenylsulfonyl)-2,2-dimethyl-3-chromene.
Melting point: 157-158C.
Example 13 3,4-Dihydro-2,2-dimethyl-6-(2-methoxyphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-dimethyl-6-(2-methoxyphenylsulfonyl)-2H-benzoCb~pyran-4-ol. ~hite crystals of melting point: 196-198C.
Example 14 3,4-Dihydro-2,2-dimethyl-6-(2-methylphenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol In analogy to Example 1. ~hite crystals of melting point:
214-216C.
Example 15 3,4-Dihydro-2,2-dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol In analogy to Example 1. ~hite crystals of melting point: 85-87C
Example 16 Preparation of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-trans-4-(2-oxo-1-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-phenyl-sulfonyl-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-Amino-- 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]-pyran-3-ol of melting point: 160-163C is obtained and is immediately subjected to acylation with 4-chlorobutyr-yl chloride. For this purpose, the substance is dis-solved together with the acid chloride in CH2Cl2 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 155-157C. Cyclization to give the title compound is carried out by dissolving the substance in tetrahydrofuran, addition of a stoichiometric amount of 80Z 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: 200-201C. If 4-amino-3,4-dihydro-2,2-dimethyl-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-Dihydro-2,2-dimethyl-6-phenylsulfoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol In analogy to Example 1. Melting point: 211 - 212C
Pharmacological data a) Effect on respiratory tract disorders Effect on histamine-induced bronchoconstriction in guinea-pigs Method:
Uhite guinea-pigs of both sexes and weighing bet~een 450 and 550 9 were anesthetized with 60 mg/kg pentobarbital i.p. After tracheotomy, they were ventilated with a Starling pump (from Braun, Melsungen). The tidal volume ~as selected for generous ventilation of the lungs. The ventilation pressure was adjusted to 80 mm H20 with the S aid of a water column (Rosenthal and Dervinis). The breathing rate was 30 breaths/min. An excess of avail-able respiratory air can pass through a bypass in the inhalation tube to a washbottle which is designed as a water pressure-relief valve. ~hen 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 flo~s 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 replacedby 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 ~ith 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 ~ - - Z3 - 1336891 propanediol/physiological saline solution has no action itself.
Eronchoconstriction is induced by doses of histamine di-hydrochloride (6 - 12 ~g/kg i.v.). Injection is through S 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 areadministered as aerosol for 1 min and, after an action time of 2 min, the bronchoconstriction is induced ane~
and repeated at intervals of S minutes.
The degree of inhibition of the histamine-induced broncho-constriction after pretreatment with the test substance is regarded as a measure of the bronchodilator activity and is reported as Z change from the control.
All results are subjected to linear regression, and the IDso is determined.
Results:
% inhibition of histamine-induced bronchoconstriction Compound Dose n % inhibition Example Sa 1 ~g/kg 6 14 + 4 (+)-3,4-dihydro-2,2- 3 ~g/kg 6 35 ~ 4 25 dimethyl-6-phenyl- 10 ~g/kg 6 77 + 7 sulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol IDso: 4-39 ~g/kg ~ - 24 - 1336891 b) Efferent urinary passages Effect on the KCl-induced 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 exsanguination 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 solu-tion and then suspended in a 25 ml organ bath (from Rhema Labortechnik, Hofheim), in each case with a tension of 4.9 mN (= 0.5 p). The organ bath contained Tyrode solu-tion of the following composition (mmol/l): NaCl 137, KCl 2.68, MgS04 1.05, CaCl2 1.8, NaH2P04 0.41, NaHC03 11.9, glucose 5.55, which was maintained at 37C and through which carbogen (95% 2~ 5% C02) was bubbled.
The contractions were measured isometrically using Gould/
Statham UC2 pickups. After an equilibration time of at least 15 minutes, KCl was added to the organ bath to reach a concentration of 4 x 10 2 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 rhythmiccontractions ceasing immediately. After a second run with addition of agonist and the rinsing procedure, the test substance (benzopyran derivative) ~as added to the organ bath (in the form of a solution in 0.1 ml of ethanol; the final concentration was 10 7 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 agonist/rinsing procedures.
` 1336891 _ Z5 The following parameters were determined in each of the two-minute periods during which KCl acted: 1. mean force of contraction, 2. frequency of contractions and 3. pro-duct of mean force and frequency of contractions.
The criteria for exclusion were mean forces of contrac-tion below 4 mN or frequencies of below 2/min in more than one of the four periods in ~hich only the agonist KCl was present in the bath. Evaluation was of the per-centage 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 (SEM) was calculated.
Results:
n = number of ureters Mean force Frequency v k . v n Compound of con- (%) (%) traction k (%) 3,4-Dihydro-2,2- 68 + 11 67 ~ 1485 1 7 4 dimethyl-6-(2-chloro-~enylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol Example 15 Reference: R. Schiantarelli and ~. Murmann, Arznei-mittel-Forschung/Drug Research 30, 1102 -1109 (1980)
Claims (11)
1. The use of a compound I
(I) in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, vhere R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy for obstructive func-tional disorders of the lungs and/or disorders of the efferent urinary passages.
(I) in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, vhere R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, for the preparation of a remedy for obstructive func-tional disorders of the lungs and/or disorders of the efferent urinary passages.
2. A pharmaceutical product for the treatment of obstruc-tive functional disorders of the lungs, which contains a compound I
(I) in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, as active substance besides customary additives.
(I) in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, where R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3, 4 or 5, as active substance besides customary additives.
3. A compound I
(I) in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, vhere R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3,
(I) in which R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl or NR4R5, where R4 and R5 are identical or different and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-carbonyl, R2 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, (C1-C2)-alkoxy, halogen, trifluoromethyl, CN, NO2, CO-(C1-C2)-alkyl or SOm-(C1-C2)-alkyl with m = 1 or 2, n represents 1 or 2, X represents a chain (CH2)r which can be interrupted by a heteroatom O, S or NR6, vhere R6 denotes H or (C1-C4)-alkyl, and r represents the numbers 2, 3,
4 or 5, for use for the treatment of obstructive functional disorders of the lungs and/or of the efferent urinary passages.
4. The use of a compound I as claimed in claim 1, in which R1 to R3 and ArSOn are as defined in claim 1, and X denotes (CH2)r with r = 3 or 4.
4. The use of a compound I as claimed in claim 1, in which R1 to R3 and ArSOn are as defined in claim 1, and X denotes (CH2)r with r = 3 or 4.
5. The use as claimed in claim 1, wherein R1 to R3 have the abovementioned meanings, Ar represents phenyl which is unsubstituted or substi-tuted as in claim 1, and X denotes (CH2)r with r = 3 or 4.
6. The use as claimed in claim 1, wherein R1 denotes hydrogen, R2 and R3 represent (C1-C2)-alkyl, Ar denotes phenyl which is unsubstituted or substitu-ted once by (C1-C2)-alkyl, (C1-C2)-alkoxy or halogen, n denotes 2, and X denotes (CH2)r with r = 3 or 4.
7. The use of a compound I as claimed in claim 1, wherein R1 denotes hydrogen, R2 and R3 represent (C1-C2)-alkyl, X denotes (CH2)3, Ar denotes C6H4Cl and n denotes 2, for the preparation of a remedy for disorders of the efferent urinary passages.
8. The use as claimed in claim 1, wherein R1 denotes hydrogen, R2 and R3 represent (C1-C2)-alkyl, Ar denotes phenyl, n denotes 2, and X denotes (CH2)3
9. The use of 3,4-dihydro-2,2-dimethyl-6-(2-chloro-phenylsulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol for the preparation of a remedy for disorders of the efferent urinary passages.
10. The use of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzot[b]pyran-3-ol for the preparation of a remedy for obstructive respiratory tract diseases.
11. Use of a compound of the formula I, as defined in any one of claims 1 and 4 to 10 for treating obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3824446A DE3824446A1 (en) | 1988-07-19 | 1988-07-19 | USE OF SUBSTITUTED 3,4-DIHYDRO-2H-BENZOPYRANE AS A MEDICINE AGAINST OBSTRUCTIVE FUNCTIONAL DISORDERS OF THE LUNG AND / OR DISORDERS OF THE LEADING URINE PATHS |
| DEP3824446.2 | 1988-07-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1336891C true CA1336891C (en) | 1995-09-05 |
Family
ID=6359009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000605990A Expired - Fee Related CA1336891C (en) | 1988-07-19 | 1989-07-18 | Use of substituted 3,4-dihydro-2h-benzopyrans as remedies for obstructive functional disorders of the lungs and/or disorders of the efferent urinary passages |
Country Status (18)
| Country | Link |
|---|---|
| EP (2) | EP0351720B1 (en) |
| JP (1) | JPH0273015A (en) |
| KR (1) | KR900001367A (en) |
| AT (1) | ATE110270T1 (en) |
| AU (1) | AU621388B2 (en) |
| CA (1) | CA1336891C (en) |
| CZ (1) | CZ417091A3 (en) |
| DE (2) | DE3824446A1 (en) |
| DK (1) | DK171782B1 (en) |
| ES (1) | ES2061816T3 (en) |
| FI (1) | FI893460A (en) |
| HU (1) | HU210149B (en) |
| IE (1) | IE63872B1 (en) |
| IL (1) | IL91015A (en) |
| NZ (1) | NZ229961A (en) |
| PH (1) | PH26696A (en) |
| PT (1) | PT91197B (en) |
| ZA (1) | ZA895459B (en) |
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|---|---|---|---|---|
| TW244350B (en) * | 1991-12-14 | 1995-04-01 | Hoechst Ag | |
| TW316850B (en) * | 1992-02-28 | 1997-10-01 | Takeda Pharm Industry Co Ltd | |
| HUT72741A (en) * | 1992-12-19 | 1996-05-28 | Alkaloida Vegyeszeti Gyar | Method for producing benzopyrane derivatives and pharmaceutical compositions containing them |
| GB9316111D0 (en) * | 1993-08-04 | 1993-09-22 | Pfizer Ltd | Benzopyrans |
| WO2001047491A1 (en) | 1999-12-23 | 2001-07-05 | Coifman Robert E | Methods and formulations for the efficient delivery of water-insoluble drugs by nebulizer |
| KR100475147B1 (en) * | 2002-09-09 | 2005-03-10 | 정의상 | Remove noxious gas deodorant composite of alumina dust |
| US7306789B2 (en) | 2002-11-12 | 2007-12-11 | Warner-Lambert Company, Llc | Method of stimulating hair growth using benzopyrans |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3364734D1 (en) * | 1982-10-19 | 1986-08-28 | Beecham Group Plc | Novel chromans and chromenes |
| GB8419515D0 (en) * | 1984-07-31 | 1984-09-05 | Beecham Group Plc | Treatment |
| GB8513369D0 (en) * | 1985-05-28 | 1985-07-03 | Beecham Group Plc | Treatment |
| DE3881714D1 (en) * | 1987-02-04 | 1993-07-22 | Hoechst Ag | ALKYL-SUBSTITUTED N-BENZOPYRANYLLACTAME, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS. |
| DE3703227A1 (en) * | 1987-02-04 | 1988-08-18 | Hoechst Ag | SUBSTITUTED 3,4-DIHYDRO-2H-BENZOPYRANES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
-
1988
- 1988-07-19 DE DE3824446A patent/DE3824446A1/en not_active Withdrawn
-
1989
- 1989-07-14 ES ES89112897T patent/ES2061816T3/en not_active Expired - Lifetime
- 1989-07-14 AT AT89112897T patent/ATE110270T1/en not_active IP Right Cessation
- 1989-07-14 EP EP89112897A patent/EP0351720B1/en not_active Expired - Lifetime
- 1989-07-14 DE DE58908228T patent/DE58908228D1/en not_active Expired - Fee Related
- 1989-07-17 FI FI893460A patent/FI893460A/en not_active IP Right Cessation
- 1989-07-17 EP EP93105146A patent/EP0560399A1/en not_active Withdrawn
- 1989-07-17 NZ NZ229961A patent/NZ229961A/en unknown
- 1989-07-17 HU HU893591A patent/HU210149B/en not_active IP Right Cessation
- 1989-07-17 PH PH38951A patent/PH26696A/en unknown
- 1989-07-18 PT PT91197A patent/PT91197B/en not_active IP Right Cessation
- 1989-07-18 CA CA000605990A patent/CA1336891C/en not_active Expired - Fee Related
- 1989-07-18 IL IL9101589A patent/IL91015A/en not_active IP Right Cessation
- 1989-07-18 AU AU38189/89A patent/AU621388B2/en not_active Ceased
- 1989-07-18 IE IE232389A patent/IE63872B1/en not_active IP Right Cessation
- 1989-07-18 KR KR1019890010129A patent/KR900001367A/en not_active Application Discontinuation
- 1989-07-18 DK DK355489A patent/DK171782B1/en not_active IP Right Cessation
- 1989-07-18 ZA ZA895459A patent/ZA895459B/en unknown
- 1989-07-18 JP JP1183848A patent/JPH0273015A/en active Pending
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1991
- 1991-12-30 CZ CS914170A patent/CZ417091A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUT55988A (en) | 1991-07-29 |
| ES2061816T3 (en) | 1994-12-16 |
| JPH0273015A (en) | 1990-03-13 |
| AU3818989A (en) | 1990-01-25 |
| ZA895459B (en) | 1990-03-28 |
| NZ229961A (en) | 1991-11-26 |
| IE892323L (en) | 1990-01-19 |
| ATE110270T1 (en) | 1994-09-15 |
| DK171782B1 (en) | 1997-05-26 |
| PT91197B (en) | 1995-07-18 |
| IL91015A (en) | 1994-11-28 |
| EP0351720B1 (en) | 1994-08-24 |
| CZ417091A3 (en) | 1993-02-17 |
| DK355489D0 (en) | 1989-07-18 |
| PH26696A (en) | 1992-09-15 |
| AU621388B2 (en) | 1992-03-12 |
| FI893460A0 (en) | 1989-07-17 |
| EP0351720A3 (en) | 1992-01-02 |
| IE63872B1 (en) | 1995-06-14 |
| FI893460A (en) | 1990-01-20 |
| PT91197A (en) | 1990-02-08 |
| EP0560399A1 (en) | 1993-09-15 |
| DK355489A (en) | 1990-01-20 |
| KR900001367A (en) | 1990-02-27 |
| DE58908228D1 (en) | 1994-09-29 |
| HU210149B (en) | 1995-02-28 |
| EP0351720A2 (en) | 1990-01-24 |
| DE3824446A1 (en) | 1990-01-25 |
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