WO1992020672A1

WO1992020672A1 - Isoindolyl and isochinolyl-substituted benzopyrane derivatives, intermediate products, and process for producing them

Info

Publication number: WO1992020672A1
Application number: PCT/DE1992/000357
Authority: WO
Inventors: Ben Armah; Dieter Muster; Gerd Rühter; Theo Schotten; Wolfgang Stenzel
Original assignee: Beiersdorf-Lilly Gmbh
Priority date: 1991-05-11
Filing date: 1992-05-06
Publication date: 1992-11-26
Also published as: PL297369A1; AU1692192A; DE4115521A1

Abstract

Benzopyrane derivatives of general formula (I), in which the substituents have the meanings given in the description and the tautomeric and isomeric forms of (I) and the salts and/or acid addition products.

Description

description

Isoindolyl and isoquinolyl substituted

Benzopyran derivatives, intermediates, and processes for their preparation

The present invention relates to new substituted benzopyran derivatives of the general formula I,

in the

R ₁ and R _{2 may be the} same or different and

Hydrogen, C _1-6 alkyl, C _3-6 branched alkyl,

Are C _3-7 cycloalkyl or, together with the carbon atom enclosed by them, mean C _3-7 spiroalkyl,

R ₃ hydroxy, C _1-8 alkoxy, formyloxy,

C _1-8 alkylcarbonyloxy, C _1-8 alkoxycarbonyloxy,

C _1-8 mono-alkylaminocarbonyloxy or

C _1-8 dialkylamino-carbonyloxy means, where the C _1-8 alkyl or alkoxy groups can be both linear and branched, and R _{4 represents} hydrogen or

R ₃ and R ₄ together form a bond, R ₅ forms a heterocycle of the formula A.

or formula B

means where

R _{7 represents} hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, nitro or mono- or disubstituted C _1-6 alkylamino,

R ₆ difluoromethoxy, difluoromethylthio,

Difluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylthio, trifluoromethylsulfinyl

Trifluoromethylsulfonyl, trifluoroethylthio,

Trifluoroethylsulfinyl or Trifluorethylsulfonyl means, with the heterocycle R ₅ preferably is in the trans position to the radical R ₃ if R ₃ and R ₄ do not together represent a bond, with the exception of compounds of the formula I in which

R _{5 is} a heterocycle A where R _{7 is} hydrogen, and R _{3 is} hydroxy and R _{4 is} hydrogen and R ₆

Trifluoromethylsulfonyl or trifluoromethylsulfinyl and R ₁ and R ₂ each denote methyl,

as well as their salts and acid addition salts, tautomers and optical isomers, processes for their preparation, their use and preparations containing them

Connections included.

A distinction is made below between compounds of the general formulas Ia and Ib. In Ia R _{3 has} the meaning given and R ₄ denotes hydrogen, in Ib R ₃ and R ₄ together represent a bond.

For the sake of simplicity, those according to the invention are

Compounds in only one through Formula I

reproduced tautomeric form defined. The

However, the invention extends to all tautomeric forms of the compounds.

Although pharmaceutically acceptable salts and

Acid addition salts of the new compounds of the formulas I and their tautomeric forms are preferred all salts within the scope of the invention. All

Salts are valuable for making the compounds, even if the special salt is only for the purpose of

Purification or identification is formed, or when used as an intermediate in the manufacture of a pharmaceutically acceptable salt, for example by ion exchange processes.

Compounds of general formula I and their salts and acid addition salts contain asymmetric

Carbon and sulfur atoms. Therefore, the various optical isomers and diastereomers are the subject of the invention. The racemates can be separated into the optical antipodes by methods known per se.

Those enantiomers or diastereomers which have an S configuration at the 3-position of the 3,4-dihydro-2H-benzo (b) pyran system and at the 4-position

R configuration are particularly preferred.

The invention also relates to the new compounds of the formulas II, III, IV, V and VI:

with the meanings given above for R ₁ , R ₂ and R ₆ and the process for their preparation. They serve as intermediate or intermediate products

Production of the end products according to the invention.

With the compounds of the present invention

structurally related connections are in the

European patent applications EP-0 158 923 and EP-0 314 446 as well as US 4,908,378 and WO 90/12 011

described. The connections of the registration

WO 90/12 011 were taken into account in the "disclaimer". However, the compounds of the present invention are neither specifically disclosed nor suggested.

The compounds of formula I according to the invention

are characterized in particular by a significantly higher potency with a significantly longer potency

compared to the known compounds.

Unless otherwise stated, the

alkyl groups and alkyl parts according to the invention

or alkylene parts of groups are straight-chain or branched, and they each preferably have 1-6 carbon atoms, preferably 1-4

Carbon atoms, particularly preferably 1 or 2

Carbon atoms. The branched alkyl groups have at least 3 carbon atoms. Preferred alkyl or alkylene parts are methyl, ethyl, n-propyl, isopropyl, Butyl or correspondingly methylene, ethylene, n-propylene, isopropylene and butylene.

Preferably have

Cycloalkyl groups and cycloalkyl parts such as

Cycloalkyl radicals of cycloalkylalkyl groups of 3 to 7 carbon atoms, in particular 3 to 6

Carbon atoms. Cyclopropyl and cyclohexyl are particularly preferred.

It should mean:

Formyl: H-CO-,

Formyloxy: H-CO-O-,

C _1-8 alkylcarbonyloxy: C _1-8 alkyl-CO-O-, C _1-8 alkoxycarbonyloxy: C _1-8 alkyl-O-CO-O-, C _1-8 monoalkylaminocarbonyloxy: C _{1- 8-} alkyl-NH-CO-0-, C _1-8 -dialkylaminocarbonyloxy: (C ₁ _ ₈ -alkyl) ₂ N-CO-0-, C _1-8 -alkyl carbonyl: C _1-8 -alkyl-CO -,

C _1-6 alkylcarbonyl: C _1-6 alkyl-CO-,

C _1-8 alkoxycarbonyl: C _1-8 alkoxy-CO.

Halogen: fluorine, chlorine, bromine, iodine

The trifluoroethyl group or trifluoroethyl as part of other radicals according to the invention such as trifluoroethylthio is preferably 2,2,2-trifluoroethyl.

Is C _3-7 cycloalkyl substituted C _1-9 alkyl

preferably cyclopropylmethyl.

R ₁ is preferably hydrogen, methyl or ethyl, particularly preferably methyl.

R ₂ is preferably hydrogen, methyl or ethyl, particularly preferably methyl. R ₁ and R ₂ are particularly preferably both at the same time

Methyl.

If R ₁ and R _{2 are} preferred branched alkyl or cycloalkyl, isopropyl or cyclopropyl are particularly preferred.

If R ₁ and R ₂ together with that of them

enclosed carbon atom form a spiroalkyl ring, spirocyclopentyl and spirocyclohexyl are preferred.

R ₃ preferably represents hydroxyl or particularly preferably forms a bond with R. so that there is a between the C ₃ and C ₄ positions of the benzopyran skeleton

There is a double bond. The invention

Compounds with this C ₃ = C ₄ double bond are particularly preferred.

If R _{3 is} alkoxy, ethoxy and especially methoxy are preferred.

If R _{3 is} alkylcarbonyloxy, propionyloxy and especially acetoxy and formyloxy are preferred. R ₅ is preferably a heterocycle of the formula A.

R ₆ is preferably difluoromethoxy, difluoromethylthio, difluoromethylsulfonyl, difluoromethylsulfinyl,

Trifluoromethylthio, trifluoromethylsulfinyl and

Trifluoromethylsulfonyl, of which particularly preferred

Difluoromethoxy, trifluoromethylthio,

Trifluoromethylsulfinyl and trifluoromethylsulfonyl, especially difluoromethoxy, trifluoromethylthio and trifluoromethylsulfonyl. R ₇ is preferably hydrogen, methyl, ethyl, methoxy, ethoxy or halogen, is particularly preferred

Hydrogen. Chlorine is preferred among the halogens.

Benzopyran derivatives of the general formula I in which R _{1 is} selected from the group consisting of hydrogen, methyl, ethyl,

R _{2 is} selected from the group hydrogen, methyl, ethyl,

R ₃ either symbolizes a bond together with R ₄ or is selected from the group hydroxy, methoxy, ethoxy,

R _{6 is} selected from the group difluoromethoxy,

Trifluoromethylthio, trifluoromethylsulfonyl and

R _{7 is} selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy and chlorine.

Compounds of the formulas Ia1 and Ib1 are particularly preferred:

wherein R _{6 is} difluoromethoxy, trifluoromethylthio,

Trifluoromethylsulfinyl or trifluoromethylsulfonyl means and R _{7 represents} hydrogen.

In particular, compounds of the formula Ia which have a 3S, 4R configuration are preferred.

The following are very particularly preferred

Compounds, their tautomers and their optical

Isomers: a) trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy-6- (difluoromethoxy) -4H-1-benzopyran-4-yl) -2,3-dihydro-1H- isoindol-1-one b) trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy-6- (trifluoromethylthio) -4H-1-benzopyran-4-yl) -2,3-dihydro -1H-isoindol-1-one c) 2- (2,2-dimethyl-6- (difluoromethoxy) -2H-1-benzopyran- 4-yl) -2,3-dihydro-1H-isoindol-1-one d ) 2- (2,2-Dimethyl-6- (trifluoromethylthio) -2H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one e) 2- (2,2-dimethyl -6-trifluoromethylsulfinyl) -2H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one f) 2- (2,2-dimethyl-6- (trifluoromethylsulfonyl) -2H- 1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one The compounds of formula I according to the invention, their physiologically tolerable salts and

Acid addition products and their tautomeric and optical isomers are therapeutic agents, have high pharmacological activity and are

valuable medicines. In particular, they show

vasodilating, vasospasmolytic, especially broncholytic effect. The can

vasospasmolytic effect in the entire vascular system or more or less isolated in circumscribed vascular areas such as brain, coronary or

Develop peripheral areas.

The compounds according to the invention in particular have an antihypertensive effect and can therefore be used as

antihypertensive agents can be used.

The substances according to the invention are distinguished by a considerable reduction in arterial blood pressure. Doses of 0.01-10 mg / kg s.c. lead to a reduction in blood pressure of at least 20%

hypertensive rats.

The substances according to the invention are distinguished by a particular influence on the flow of potassium ions in the cells. In particular, they are

Potassium channel activators. They are suitable for the prophylaxis and treatment of the following diseases

Warm-blooded animals, especially humans:

1. Hypertension, especially arterial

High blood pressure,

2. Heart failure, coronary insufficiency, angina

Pectoris, 3. Arterial occlusive disease and peripheral

Circulatory disorders,

4. cerebral insufficiency, migraines, dizziness,

Diseases of the inner ear and hearing system,

5. increased intraocular pressure, glaucoma, poor eyesight

6. renal insufficiency, organic diseases of the urinary tract and the accessory glands of the urinary tract, erectile dysfunction,

7. organic disorders of the gastrointestinal tract as well as the pancreas and liver,

8. lack of blood circulation to the scalp, hair loss,

9. Airway disorders including bronchial asthma,

10. metabolic diseases,

11. spasmogenic diseases of the uterus,

12. Incontinence.

Furthermore, the compounds according to the invention promote blood circulation to the scalp and hair growth. They are also tocolytically effective.

The compounds according to the invention have a long duration of action with only low toxicity. Therefore, they are particularly suitable for the treatment of acute and chronic heart diseases, for the treatment of high blood pressure, heart failure and for the treatment of asthma and cerebral and peripheral circulatory disorders. The compounds of the present invention can be found in

Humans orally or parenterally in a dosage of

0.001 to 100 mg, preferably 0.01 to 50 mg,

particularly preferably 0.05 to 10 mg per day, are used, in particular also in divided doses, for

Example two to four times a day. These dosages are advantageous for the treatment of the diseases mentioned above, in particular of

Heart disease, hypertension, and asthma

Circulatory disorders.

In general, it has proven to be advantageous to administer amounts of about 0.001 to 10 mg, preferably about 0.05 to 5 mg, to humans per day for intravenous administration in order to achieve effective results. In the case of oral administration, the dosage is about 0.05 to 30 mg, preferably 0.1 to 10 mg, per day.

The above dosages are particularly preferred for the treatment of hypertension.

However, it may still be necessary to deviate from the quantities mentioned, namely in

Dependence on body weight or the type of application route, but also due to

individual behavior towards the drug or the type of its formulation and the time or the time interval at which the administration takes place. So it may be sufficient in some cases, with less than the aforementioned minimum amount

get along, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses throughout the day. The invention also relates to

Compounds according to the invention for the treatment of the above diseases and methods for the treatment of these diseases in which these compounds

be used and their use in the process for

Manufacture of means that these compounds

included to treat these diseases as well

Process for making the compounds.

According to the invention, pharmaceutical preparations or compositions are described, the one

compound of the invention or its pharmaceutically acceptable salt or acid addition salts together with a pharmaceutically acceptable

Contain diluents or carriers. The usual pharmaceutical additives can be used here.

The compounds according to the invention can with

usual pharmaceutically acceptable

Diluents or carriers and, if appropriate, mixed with other auxiliaries and administered, for example, orally or parenterally. You can

preferably orally in the form of granules, capsules, pills, tablets, film-coated tablets, dragees, syrups, emulsions, suspensions, dispersions, aerosols and solutions and liquids or parenterally in the form of solutions, emulsions or suspensions. Oral preparations can contain one or more additives such as sweeteners,

Flavoring agents, colorants and

Preservatives included. Tablets can contain the active ingredient mixed with customary pharmaceutically acceptable auxiliaries, for example inert diluents such as calcium carbonate,

Sodium carbonate, lactose and talc, granulating agents and agents which promote the disintegration of the tablets when administered orally, such as starch or alginic acid, Binders such as starch or gelatin, lubricants such as

Magnesium stearate, stearic acid and talc.

Suitable carriers are, for example, milk sugar (lactose), gelatin, corn starch, stearic acid, ethanol, propylene glycol, ether of tetrahydrofuryl alcohol and water.

Examples of auxiliary substances are:

Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut or sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol,

Polyethylene glycol), solid carriers such as e.g.

natural stone flours (e.g. kaolins, clays,

Talc, chalk), synthetic stone powder (e.g.

finely divided silica, silicates), sugar (e.g.

Cane, milk and dextrose), emulsifiers (e.g. polyoxyethylene fatty acid esters,

Polyoxyethylene fatty alcohol esters, alkyl sulfonates and aryl sulfonates), dispersants (e.g. methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and

Sodium lauryl sulfate).

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, for example: if water is used as

Diluents, optionally organic

Solvents can be used as auxiliary solvents.

The application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral use

Tablets, of course, apart from the above

Carriers also additives such as sodium citrate,

Calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably

Contain potato starch, gelatin and the like.

Lubricants such as magnesium stearate,

Sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs which are intended for oral use, the active compounds can be used in addition to those mentioned above

Auxiliaries with different flavor enhancers or colorants are added.

In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials.

The tablets can be coated according to known procedures to delay the breakdown and absorption in the gastrointestinal tract, whereby the activity of the active ingredient can extend over a longer period of time. Likewise, the active ingredient can be mixed in the suspensions with auxiliaries which are customary for the preparation of such compositions, for example suspending agents such as methyl cellulose, tragacanth or sodium alginate, wetting agents such as lecithin,

Polyoxyethylene stearate and

Polyoxyethylene sorbitan monooleate and

Preservatives such as ethyl parahydroxybenzoate.

Capsules can contain the active ingredient as a single ingredient or mixed with a solid diluent such as calcium carbonate, calcium phosphate or kaolin. The injectable preparations are also formulated in a manner known per se. The pharmaceutical preparations can contain the active ingredient in an amount of 0.1 to 90 percent by weight,

contain in particular 1 to 90 percent by weight, i.e. in amounts sufficient to meet the stated

Achieve dosage scope, with the rest being a

Carrier or additive is. In terms of

Solid preparations such as tablets and capsules are preferred for preparation and administration. The preparations preferably contain the active ingredient in an amount of 0.05 to 10 mg.

The invention also relates to a process for the preparation of pharmaceutical preparations, characterized in that one or more compounds according to claim 1 or their physiologically tolerable salts and, if appropriate, customary carriers and / or diluents are mixed.

The compounds of the formula I are directly or indirectly accessible by nucleophilic ring opening of 2,2,6-substituted 3,4-dihydro-3,4-oxiranyl-2H-benzo (b) pyrans of the formula II:

The anions of the formulas A 'or B' and ammonia are preferably used as nucleophiles. The resulting compounds of the formulas I and IV are obtained as trans isomers and are practically free from cis isomers. The anions A 'and B' are from the compounds of

Formulas HA and HB accessible through the action of a strong base. R ₇ has the meaning given above. As

Base is preferably sodium hydride.

Below are some preferred ones

Manufacturing process for the invention

Connections shown.

1. Process for the preparation of compounds of

Formulas III and V

Compounds of the general formula III in which the bromine atom and hydroxyl group are trans to one another and compounds of the general formula V can be prepared by processes which are conventional per se. These processes correspond to scheme 1 below. They have been described several times, for example EP 0 076 075, J.Org.Chem. 38 (22), 3832 (1973), ibid. 39 (7), 881 (1974), ibid. 37 (6), 841 (1972): Scheme 1

The following conditions are preferred: i) eg K ₂ CO ₃ / acetone; Reflux

or K ₂ CO ₃ / butanone; Reflux

or K ₂ CO ₃ / dimethylformamide; 90 ° C

or NaOH / 40% triethylbenzylammonium hydroxide in

Methanol; Room temperature ii) e.g. 1,2-dichlorobenzene, 180 ° C

or N, N-diethylaniline, 200 ° C

or without solvent, 200 ° C iii) N-bromosuccinimide / dimethyl sulfoxide / water iv) bromine, carbon tetrachloride v) acetone / water

The 4-substituted phenols (VII) in which R _{6 has} the meaning given above are known or can be prepared by known processes, for example by reducing the corresponding 4-substituted

Nitro aromatics, for example with hydrogen and

Raney nickel as a catalyst or by nascent hydrogen to the corresponding 4-substituted anilines and diazotization and boiling to the

corresponding phenols.

In cases where R _{6 is} difluoromethylthio, difluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylthio, trifluoromethylsulfinyl,

Trifluoromethylsulfonyl, 2,2,2-trifluoroethylthio,

2,2,2-trifluoroethylsulfinyl and

2,2,2-trifluoroethylsulfonyl, the radicals mentioned can be obtained more advantageously by chemical transformation of intermediates in which R _{6 is} different from that above has the above-mentioned meaning.

For example, 2H-benzopyrans are the general

Formula V in which R _{6 has} the meaning

Difluoromethylsulfonyl, trifluoromethylsulfonyl and

Has 2,2,2-trifluoroethylsulfonyl, by reacting the corresponding fluoroalkylsulfonyl fluorides with

2H-Benzo (b) pyrans of the general formula V, in which R _{6 has} the meaning MgHal, are obtained. Here shark has the

Meaning chlorine, iodine and especially bromine.

It is also possible to use the ones described above

Grignard compounds of 2H-benzo (b) pyrans with

Disulfides of the general formula R-S-S-R, in which R is trifluoromethyl, difluoromethyl and

2,2,2-trifluoroethyl has, to 2H-benzo (b) pyrans, in which R _{6 is} difluoromethylthio,

Trifluoromethylthio and 2,2,2-trifluoroethylthio has to implement.

It is also possible, starting from intermediate or end products in which R ₆ contains a sulfur atom, by methods known per se by reduction or, in particular, oxidation to give intermediate or end products in which the sulfur atom referred to is another

Has oxidation level to arrive.

Examples of possible oxidizing agents are: potassium permanganate, sodium periodate,

Chlorine trioxide or preferably oxone (potassium persulfate) and hydrogen peroxide / glacial acetic acid.

For example, 4. difluoromethylsulfonylphenol,

4-trifluoromethylsulfonylphenol or

4- (2,2,2-trifluoroethylsulfonyl) phenol cheaper than by known methods by oxidation of the

corresponding fluoroalkylthiophenols with Oxone ^R in methanol-water mixtures at temperatures between -10 ° C and the reflux temperature of the reaction mixture, preferably at temperatures between 0 ° C and 25 ° C, are obtained.

Especially in cases where R _{6 is} difluoromethylsulfinyl, trifluoromethylsulfinyl or 2,2,2-trifluoroethylsulfinyl, it is more favorable to start with the corresponding ones starting from the 4-fluoroalkylthiophenols (VII) according to Scheme 1

6-Fluoroalkylthio-2H-benzo (b) pyrans V, in which R ₁ and R _{2 have} the meaning given above, and then the desired oxidation to the respective 6-fluoroalkylsulfinyl-2H-benzo (b) pyrans of the general formula V to make, in which R _{6 has} the meaning given above. Surprisingly, the selectivity is this

Response very high for the named connection classes.

The starting materials used are known or can be prepared by processes known per se or analogously to the processes described here or analogously to processes known per se.

2. Process for the preparation of compounds

Formula II

To make compounds of general formula II

the following manufacturing process is advantageous:

2.1 From compounds of the formula III (bromohydrin) with bases (for example sodium hydride) in a solvent such as DMSO or tetrahydrofuran (THF) at temperatures between 10 ° C. and 80 ° C., preferably room temperature. The oxirane (compound

II) can be further implemented in situ, but it can also be isolated, as shown below.

The compounds of the formulas H-A and H-B in the

The meanings mentioned above are known or can be represented in analogy to known processes.

2.2 Oxiranes of the formula II are according to the in 2.1

described method accessible from the bromohydrins according to formula III. If it is desired to isolate the oxiranes, it is advantageous to bromohydrins of the formula III in an ether, for example diethyl ether, dioxane or THF with a base, for example

Potassium hydroxide, but preferably sodium hydride in THF to implement.

2.3 It is also possible to use benzopyrans of the formula V by oxidation, advantageously with peracids

Convert compounds according to formula II. The implementation with is particularly advantageous

m-chloro-perbenzoic acid, especially when an oxidation of sulfur-containing radicals R _{6 is} also desirable.

3. Process for the preparation of compounds of

Formula IV

Compounds of the general formula IV are advantageously obtained by using oxiranes of the formula II

Reacts ammonia, preferably in solvents such as

Chloroform, methylene chloride or lower alcohols, for example methanol, ethanol, propanol or

isopropanol. Ethanol or aqueous solutions of such alcohols are preferred. Are advantageous

Reaction temperatures between 0º C and the boiling point of the respective solvent, preferably

Room temperature.

4. Process for the preparation of compounds of

Formula VI

The compounds of general formula VI can by reacting oxiranes of formula II with

Alkali metal azides such as sodium azide.

This reaction advantageously takes place in solvents such as dimethylformamide at temperatures between 20 ° C and 120 ° C, preferably at 60 ° C to 100 ° C. From the 2,2,6-substituted

trans-4-azido-2H-benzo (b) pyran-3-ols of the formula VI, the corresponding compounds IV can be prepared by reduction, preferably by hydrogen over 10% palladium / carbon.

5. Process for the preparation of compounds

Formula I.

5.1 Oxiranes of the general formula II are with

Compounds of the formula H-A or H-B in one

Solvents such as e.g. Dimethyl sulfoxide (DMS0) in

Presence of a base such as sodium hydride

Temperatures between 10 ° C and 80 ° C, preferably room temperature, implemented. This creates compounds of formula Ia with R ₃ = OH and R ₄ = H.

5.2 Compounds of the formula IV can be alkylated with compounds of the formula C. In the compounds C, n can be 1 or 2, X is a halogen,

preferably chlorine or bromine, and R _{8 is} one C _1-6 alkyl radical, preferably methyl or ethyl,

represent.

In situ reaction can be carried out in this reaction mixture

intramolecular cyclization take place, wherein

Compounds of formula Ia can be obtained. Preferred solvents are, for example, lower alcohols such as methanol and ethanol, or nitromethane or acetonitrile. The alkylation is carried out in the presence of organic or inorganic bases, for example tertiary amines such as triethylamine or alkali metal carbonates such as K ₂ CO ₃ .

It is advantageous to carry out the reaction as a one-pot reaction. For this purpose, reaction temperatures between 0 ° C and the boiling point of the respective

Solvent chosen. Preferably that is

The reaction mixture was initially kept at room temperature until the alkylation reaction had ended, and

then the cyclization at a higher temperature, preferably the boiling point of the particular

Solvent, carried out in situ.

Compounds of the formula C are known or can be prepared analogously to known processes.

5.3 Compounds of the formula IV can be reductively alkylated with compounds of the formula D.

In the formula D, m is 0 or 1, R ₈ is a C _1-6 -alkyl radical, preferably methyl or ethyl. A suitable reducing agent is in particular

Sodium cyanoborohydride / zinc chloride. If desired, the alkylation products can be isolated, but it is also advantageous to use the intramolecular ones

To perform cyclization in situ. Toluene is particularly suitable as a solvent for these reactions. It is favorable to choose the reaction temperature between 10 ° C and the boiling point of the respective solvent. The reaction mixture is preferably first kept at room temperature until the reductive alkylation has ended, and then the cyclization is carried out in situ at a higher temperature, preferably the boiling point of the particular solvent.

Compounds of the formula D are known or can be prepared analogously to known processes.

5.4 The compounds of the formula Ia obtainable by the processes described above contain the free hydroxyl group R ₃ . They can be converted by O-alkylation or O-acylation into other compounds of the formula Ia in which R _{3 is} C _1-8 alkoxy or C _1-8 alkylcarbonyloxy, C _1-8 alkoxycarbonyloxy, formyloxy, C _{1 -8} -monoalkylaminocarbonyloxy or

C _1-8 dialkylaminocarbonyloxy, R ₁ , R ₂ , R ₆ and R _{6 have} the have the meaning given and R _{4 represents} hydrogen.

Alkylation can e.g. by using a

C _1-8 alkyl iodide can be carried out in an inert solvent such as toluene or dimethylformamide in the presence of a base such as potassium hydroxide or barium hydroxide.

Esterification can be accomplished by using a

C _1-8 acyl chloride or acyl anhydride or another activated derivative of the alkanoic acid in question, optionally in the presence of an organic base such as pyridine or triethylamine or an inorganic base such as potassium carbonate, optionally under

Participation of catalysts such as

4- (N, N-dimethylamino) pyridine or

Condensation reagents such as dicyclohexylcarbodiimide are carried out in an inert solvent, if appropriate at elevated temperature.

A conversion to carbonates is carried out analogously

Reaction with chloroformic acid C _1-8 alkyl esters under the conditions specified above.

The conversion to carbamates takes place either in

Analogous to the processes described above, by reaction with mono- or dialkylaminocarbamoyl chlorides or by reaction with C _1-8 -alkyl isocyanates in an inert solvent, for example toluene, at temperatures between 0 ° C. and the boiling point of the reaction mixture.

Formyloxy can be introduced by reaction with formic acid in the presence of pyridine.

5.5 The compounds of the formula I which can be obtained by the processes described above and which contain the free hydroxyl group R ₃ (compounds Ia) can be converted by dehydration into other compounds of the general formula I, the one

Double bond (compounds Ib) included.

The dehydration is caused by reagents such as

Sodium hydride in an inert solvent such as THF, preferably at the reflux temperature of

Reaction mixture carried out.

Compounds of the general formula Ib can

optionally also be obtained as by-products in the reaction of oxiranes of the formula II with heterocycles of the formulas H-A or H-B by the process described under 5.1. The intermediate hydroxy compounds react further with elimination of water to give products of type Ib.

In particular, the compounds of the formula Ib can be used under the conditions described in 5.1

Main products are obtained when the reaction of the oxiranes II with the heterocycles H-A or H-B at elevated temperature, preferably 40 ° C, longer

Response times and excess base, e.g.

Sodium hydride takes place.

Any resulting mixtures of compounds of types Ia and Ib can be separated by conventional methods such as chromatography or fractional crystallization.

5.6 Compounds of formula I in which R _{6 is} the

Difluoromethylthio, trifluoromethylthio or 2,2,2-trifluoroethylthio can have meaning by suitable oxidizing agents such as e.g. Hydrogen peroxide in

Glacial acetic acid or Oxone ^R in methanol-water mixtures at temperatures between 0 ° C and the reflux temperature of the reaction mixture, preferably at temperatures between 20 ° C and 60 ° C, are converted into compounds of formula I in which R _{6 has} the meaning

Difluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylsulfinyl, trifluoromethylsulfonyl,

2,2,2-trifluoroethylsulfinyl or

2,2,2-trifluoroethylsulfonyl.

Mixtures of sulfinyl and

Sulfonyl compounds can be separated into the pure components by conventional methods such as chromatography or fractional crystallization.

The compounds of formula I can be basic

Have properties and are therefore isolated in the form of their salts or acid addition salts from the reaction mixtures. As bases with suitable inorganic or organic acids, they can be converted into salts by known processes.

In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g.

Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore

organic acids, especially aliphatic,

alicyclic, araliphatic, aromatic or

heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid,

Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,

Benzoic acid, salicylic acid, 2- or

3-phenylpropionic acid, citric acid, gluconic acid,

Ascorbic acid, nicotinic acid, sonic acid, methane or ethanesulfonic acid, ethanedisulfonic acid,

2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and

-disulfonic acids, lauryl sulfuric acids. For the preparation, the hot alcoholic solution of the base is mixed with the alcoholic solution of a suitable acid, and the salt is obtained, if appropriate after adding ether.

Salts with physiologically unacceptable acids, e.g. Picrates can be used to purify the compounds. Compounds of formula I can have one or more chiral centers due to asymmetric sulfur or carbon atoms. They can therefore be prepared as racemates, diastereomeric mixtures of racemates, or, if optically active starting materials are used, also in optically active form as enantiomers or mixtures of

Diastereomers can be obtained.

If the connections e.g. two or more chiral centers, then they can be synthesized as

Mixtures of racemates are obtained, from which the individual racemates, for example, by

Recrystallization from inert solvents, can isolate in pure form. For example, compounds of the formula I in which R ₁ = R ₂ , R ₃ = OH and R ₄ = H have two chiral centers on C (3) and C (4) des

3,4Dihydro-2H-benzopyran skeleton. In the preparation by reaction of compounds of formula II with

Nucleophiles, especially the anions A 'and B' or ammonia, however, predominantly result in a racemate with the trans position of the substituents R ₃ = OH and R ₅ .

If desired, the racemates can be separated mechanically or chemically into their enantiomers by methods known per se. Thus, diastereomers can be formed by reaction with a chiral separating agent. As a release agent for basic compounds of Formula I are suitable, for example, chiral acids such as D- and

L forms of tartaric acid, dibenzoyl tartaric acid,

Diacetyltartaric acid, camphorsulfonic acids, mandelic acid,

Malic acid or lactic acid. Carbinols, i.e.

Compounds of formula Ia with R ₃ = OH, can

especially with S- or R-a-methylbenzyl isocyanate or

R- or S-1- (1-naphthyl) ethyl isocyanate are esterified and then separated (cf. EP-A2-0 314 446). The various forms of the enantiomers of the formula I can be obtained in a manner known per se from the

Diastereomers are released.

Enantiomer separations also succeed

Chromatography on chiral support materials. According to the invention, however, it is also possible to use the pure

Obtain enantiomers by asymmetric synthesis.

The invention also relates to a process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I and / or one of its physiologically acceptable salts is combined with at least one solid, liquid or semi-liquid carrier or auxiliary and

if appropriate in combination with one or more further auxiliaries in a suitable dosage form.

The following examples are intended to explain the present invention in more detail, without any intention of restricting the invention to these examples.

example 1

Formula Ia, R ₁ = R ₂ = CH ₃ , R ₃ = OH, R ₆ = CF ₃ S-, R ₇ = H trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy- 6- (trifluoromethyl-thio) -4H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one

A solution of 0.9 g trans-2,2-dimethyl-3-hydroxy-6- (trifluoromethylthio) -2H-1-benzopyran-4-amine (formula IV; R ₁ = R ₂ = CH ₃ , R ₆ = CF ₃ -S-) in 20 ml absolute

Acetonitrile together with 0.3 g of potassium iodide, 1.52 g of K ₂ CO ₃ and 0.9 g of ethyl 2- (bromomethyl) -benzoate are stirred for one hour at room temperature, then for 16 hours at 75 ° C - 80 ° C. After cooling, the mixture is filtered, the residue is washed with ethyl acetate and the organic phase is concentrated. The remaining oil is purified by HPLC (silica gel, methylene chloride / ethanol 98: 2). 0.9 g of the compound given in the title (60% of theory) are obtained as colorless crystals.

Melting point: 216 - 217 ° C.

Example 1a

Formula Ia, R ₁ - R ₂ = CH ₃ , R ₃ = OH, R ₆ = CHF ₂ S-, R ₇ = H trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy- 6- (difluoromethylthio) -4H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one.

The connection is analogous to Example 1

trans-2,2-dimethyl-3-hydroxy-6-difluoromethylthio) -2H-1-benzopyran-4-amine (formula IV; R ₁ = R ₂ = CH ₃ , R ₆ =

CHF ₂ S-) in 55%

Yield accessible.

REPLACEMENT LEAF Examples 2 and 3

Formula Ia, R ₁ = R ₂ = CH ₃ , R ₃ = OH, R ₆ = CHF ₂ SO or R ₆ = CHF ₂ SO ₂ , R ₇ = H

To a solution of 0.41 g of that according to Example 1

Compound obtained in 14 ml of methanol, 1.9 g of oxone in 10 ml of water are added and stirred at room temperature. After 5 days, a further 1.2 g of Oxone ^R in 5 ml of water are added and another 2 days

Room temperature stirred. It is filtered, the filtrate is concentrated, taken up in methylene chloride, washed with water, dried (over Na ₂ SO ₄ ) and evaporated. After cleaning twice using HPLC (silica gel,

Hexane / acetone 7: 3, then methylene chloride / ethyl acetate 8: 2) gives 30 mg (6.8% of theory) of trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy-6- (difluoromethyl-sulfonyl) -4H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one and 80 mg (18.7% of theory) trans-2- (2,3- Dihydro-2,2-dimethyl-3-hydroxy-6- (difluoromethylsulfinyl) -4H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one.

Example 4

Formula Ia, R ₁ = R ₁ = CH ₃ , R ₃ = OH, R ₆ = CHF ₂ O-, R ₇ = H trans-2- (2, 3-dihydro-2, 2-dimethyl-3-hydroxy- 6- (difluoromethoxy) -4H- 1 -benzopyran-4-yl) -2, 3-dihydro-1H-isoindol-1-one. The compound is accessible analogously to Example 1 from trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy-6- (difluoromethoxy) -2H-1-benzopyran-4-amine and 2- ( Bromomethyl) benzoic acid ethyl ester.

Crystals of the compound are obtained (melting point 198-201 ° C.).

Example 5

Formula Ib, R ₁ = R ₂ = CH ₃ , R ₃ + R ₄ = bond, R ₆ = CF ₃ S-, R ₇ = H

2- (2,2-Dimethyl-6- (trifluoromethylthio) -2H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one

200 mg of the compound obtained analogously to Example 1 are dissolved in 5 ml of absolute THF and mixed with

excess sodium hydride heated under reflux for 3 days. The reaction product is purified by chromatography (silica gel, methylene chloride / ethanol 98: 2). 160 mg of the compound given in the title (40% of theory) are obtained as a colorless oil.

Example 1 '

4-trifluoromethylsulfonyl phenol

Method A ':

1 g (5.2 mMoL) of 4-trifluoromethylethiophenol is dissolved in 20 ml of methanol and at 0 ° C a suspension of 9.6 g of Oxone ^R in 20 ml of water is added with stirring.

After 5 days of stirring at room temperature, 50 ml

Diluted water and extracted with chloroform (3 × 50 ml). After drying and evaporation, 1.1 g of colorless crystals of 4-trifluoromethyIsulfonylphenol (94% of theory) remain M ⁺ = 226 (8)

Method B ':

1 g (5.2 mmol) of 4-trifluoromethylthiophenol

together with 4 ml of glacial acetic acid and 4 ml of 30%

Hydrogen peroxide stirred at 50 ° C for 20 hours,

then another 2 ml of 30%

Hydrogen peroxide added and after another 2

Hours at 50 ° C are worked up as for A '. After chromatography on silica gel, 230 mg of colorless crystals of 4-trifluoromethylsulfonylphenol (20% of theory) are obtained, mp. 123 ° C. (lit .: 119-120 ° C.)

Example 2 '

4-difluoromethylsulfonylphenol

The connection is accessible analogously to the process described under 1 ', A' or 1 ', B'. Example 3 '

4- (2,2,2-trifluoromethylsulfonyl) phenol

The compound is available analogously to method V, A 'or 1', B '.

Example 4 '6-Trifluoromethylthio-2,2-dimethyl-2H-benzo (b) pyran a) 3- (4- (Trifluoromethylthio) phenoxy) -3-methyl-1-butyne

In a solution of 19.4 g (0.1 mol)

4- (trifluoromethylthio) phenol in 250 ml dry

13.8 g (0.1 mol) of butanone are dried

Potassium carbonate and 1.6 g (0.01 mol) of potassium iodide

suspended and 15.4 g (0.15 mol)

3-Chloro-3-methyl-1-butine was added dropwise. The mixture is then heated under reflux for 20 hours, again 15.4 g of 3-chloro-3-methyl-1-butyne and 13.8 g

Potassium carbonate is added and the mixture is further heated under reflux for 40 hours. Inorganic constituents are filtered off, the solution is concentrated, the residue is taken up in 200 ml of methylene chloride and extracted with 1N

NaOH solution extracted. The organic phase is washed with water, dried and concentrated, the

The residue is filtered through silica gel.

Yield: 22 g (85% of theory) b) 6-trifluoromethylthio-2,2-dimethyl-2H-benzo (b) pyran

22 g (0.085 mol) of the compound (4'a) described above are dissolved in 50 ml of 1,2-dichlorobenzene Argon heated to 180 ° C for 2 hours and then in

Vacuum fractionated.

Yield: 13 g of colorless oil (59.1% of theory) bp 55 ° C / 2 Pa

Example 5 '

6-trifluoromethylsulfonyl-2,2-dimethyl-2H-benzo (b) pyran

1 g (4.4 mmol) of 4-trifluoromethylsulfonylphenol are combined with 0.66 g of potassium carbonate, 80 mg of potassium iodide and 2 g of 3-chloro-3-methyl-1-butyne in 13 ml of dry butanone for 20 hours under argon at 80 - stirred at 90 ° C. Then another 0.33 g of potassium carbonate, 40 mg

Potassium iodide and 1 g of 3-chloro-3-methyl-1-butyne are added and stirring is continued at 80-90 ° C for 20 hours. The mixture is allowed to cool, filtered and the filtrate is evaporated. The residue is dissolved in 20 ml of methylene chloride

taken up, washed with water (2 × 20 ml),

dried and evaporated. The remaining oil (1.3 g) is heated in o-dichlorobenzene (3 ml) at 180 ° C. for 3 hours under argon. After distilling off the

The solvent is chromatographed on silica gel. 0.5 g of colorless oil (50% of theory) is obtained. M ⁺ = 292 (5).

Example 6 '

6-trifluoromethoxy-2,2-dimethyl-2H-benzo (b) pyran

In a solution of 90 g (0.5 mol)

4-trifluoromethoxyphenol in 900 ml of dry acetone, 69.2 g (0.5 mol) of dried potassium carbonate and 8.3 g (0.05 mol) of potassium iodide are suspended and 70 g (0.68 mol) of 3-chloro-3 - Methy1-1-butin added dropwise. After 36 hours of stirring at the reflux temperature, another 35 g (0.34 g mol) of 3-chloro-3-methyl-1-butyne are added and the mixture is stirred for a further 36 hours

Reflux temperature stirred. The cooled suspension is filtered, washed with acetone, the filtrate is concentrated, the residue is taken up in methylene chloride and extracted with 1N NaOH solution. The methylene chloride phase is washed neutral, dried and evaporated.

Yield: 67 g (54.9% of theory)

67 g of the above compound are in 380 ml

1,2-dichlorobenzo heated to 180 ° C. for 4 hours.

Fractionation in vacuo gives the desired product. Yield: 45 g (67.2% of theory) bp: 75 - 80 ° C / 1.3 Pa

Example 7 '

6-trifluoromethylsulfinyl-2,2-dimethyl-2H-benzo (b) pyran a) 2 g (7.7 mmol)

6-Trifluoromethylthio-2,2-dimethyl-2H-benzo (b) pyran (example 4 ') are dissolved in 40 ml of methanol and at 0 ° C a suspension of 14.2 g (23.1 mmol) of Oxone ^R in 40 ml Water added. After 2 days of stirring at room temperature, the mixture is diluted with 50 ml of water, extracted with chloroform (3 × 100 ml) and the residue which remains after drying and evaporation is chromatographed on silica gel. 1 g of colorless oil (47% of theory) M ⁺ = 276 (9) b) 6-trifluoromethylsulfonyl-2,2-dimethyl-2H-benzo (b) pyran is obtained

2 g (7.7 mmol) of 6-trifluoromethyIthio-2,2-dimethyl-2H-benzo (b) pyran are mixed with 6 ml of glacial acetic acid and 6 ml of 30% hydrogen peroxide is stirred for 6 days at room temperature, then the mixture is diluted with 100 ml of water and extracted with chloroform (30 × 70 ml). To

Drying and evaporation leave 2 g of colorless oil. HPLC (mobile solvent 98: 2 chloroform: methanol) gives 0.3 g of colorless oil

6-trifluoromethylsulfinyl-2,2-dimethyl-2H-benzo (b) pyran (14% of theory;) and 0.2 g of colorless oil

8-trifluoromethylsulfonyl-2,2-dimethyl-2H-benzo (b) pyran (9% of theory).

Analogously:

Example 8 '

6-difluoromethylsulfinyl-2,2-dimethyl-2H-benzo (b) pyran and

Example 9 '

Obtained 6- (2,2,2-trifluoroethylsulfinyl) -2,2-dimethyl-2H-benzo (b) pyran.

Further 6-substituted 2H-benzo (b) pyrans

general formula V are prepared analogously.

Example 10 '

6-T rifl uo rme thylth io-3,4-dihydro-3-bromo-2,2-dimethyl-2H-benzo (b) pyran4-ol A solution of 7 g (0.027 mol) of the above

described benzopyran (Example 4'b) in 60 ml DMSO and 1 ml water are 7.7 g (0.043 mol) at 20 - 25 ° C

N-3romsuccinimide added. After stirring for one hour, the mixture was poured onto ice and extracted with ethyl acetate (3rd

× 100 ml). The combined organic phases were washed with water (3 × 50 ml), dried and concentrated, the product crystallizing out.

Yield: 8 g (83% of theory) of slightly brownish crystals.

Example 11 '

6-trifluoromethylthio-3,4-dihydro-3, A-oxirany1-2,2-dimethyl-2H-benzo (b) pyran

To a solution of 32 g (0.09 mol) of the bromohydrin described above in 500 ml of ro e k e ne m

Tetrahydrofuran were deoiled under nitrogen

Sodium hydride (3.5 g, 80%, in paraffin δl) was added in portions. After stirring for one hour at room temperature, another 1 g of sodium hydride is added. After a further hour, the mixture is filtered through silica gel and the solution is evaporated.

Yield: 26 g (100% of theory)

Example 12 '

6-trifluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-3-bromo-2H-benzo (b) pyran-4-ol

To a solution of 5 g (18 mmol)

6-Trifluoromethylsulfiny1-2,2-dimethyl-2H-benzo (b) pyran in 45 ml DMSO and 0.7 ml water are at 20 - 25 ° C 51 g (28.6 mmol) of N-bromosuccinimide were added. After a

Hour stirring was added to ice and extracted with ethyl acetate (3 x 100ml). The united organic

Phases are washed with water (3 × 50 ml),

dried and concentrated, taking the product

fully installed.

Yield 6.1 g (90% of theory) of light brown crystals.

Example 13 '

6-trifluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-3,4-oxiranyl-2H-benzo (b) pyran

To a solution of 5.6 g (15 mmol) of the bromohydrin described above in 80 ml of dry

Tet rahydrof uran is de-oiled under nitrogen

Sodium hydride (0.58 g, 80%, in paraffin oil)

added in portions. After stirring for one hour at room temperature, another 0.2 g of sodium hydride is added. After another hour, over

Filtered silica gel and evaporated the solution.

Yield: 4.3 g (100% of theory)

Example 14 '

Formula IV, R ₁ = R ₂ = CH ₃ , R ₆ = CF ₃ S-trans-2,3-dimethyl-3-hydroxy-6- (trifluoromethylthio) -2H-1-benzopyran-4-amine

1 g of the oxirane obtained in Example 11 'is dissolved in 5 ml of ethanol and 8 ml of a 25% strength aqueous ammonia solution are added at 0 ° C. After stirring for three days at room temperature, the mixture is concentrated in

Methylene chloride taken up, dried (over Na ₂ SO ₄ ) and the residue which remains after further concentration is purified by chromatography (silica gel,

Methylene chloride / ethanol 98: 2). 1 g of colorless crystals (95% of theory, melting point 86-88 ° C.) is obtained.

Example 6

Manufacture of tablets and capsules

Tablets and capsules, the following

contain specified components, are after

known working methods. These are suitable for the treatment of the abovementioned diseases, in particular hypertension, in dosage amounts of one tablet or capsule once a day.

Ingredients weight (mg)

Tablet capsule

trans-2- (2,3-dihydro-0,5 0,2 2,2-dimethyl-3-hydroxy-6- (trifluoromethylthio) -4H-1-benzopyran-4-yl-2,3-dihydro-1H -isoindol-1-one

Tragacanth 10.0 -

Lactose 247.5 300

Corn starch 25.0 -

Talk 15.0 -

Magnesium stearate 2.5 -

Example 7

Manufacture of ampoules

Ampoules containing the components mentioned below can be produced in a known manner. The active ingredient is dissolved in water and 1,2-propanediol and filled into glass ampoules under nitrogen.

2- (2,2-dimethyl-6- (trifluoromethylsulfonyl) 0.05 mg

-2H-1-benzopyran-4-yl-2,3-dihydro-1H-isoindol-1-one

1,2-propanediol 0.8 ml dist. Water ad 2.0 ml

Claims

1. Benzopyran derivatives of the general formula I

in the

R ₁ and R _{2 may be the} same or different and

Hydrogen, C _1-6 alkyl, C _3-6 branched alkyl,

Are C _3-7 cycloalkyl or, together with the carbon atom they contain, C ₃ _ ₇ -spiroalkyl,

R ₃ hydroxy, C _1-8 alkoxy, formyloxy,

C _1-8 alkylcarbonyloxy, C _1-8 alkoxycarbonyloxy,

C _1-8 mono-alkylaminocarbonyloxy or

C _1-8 dialkylamino-carbonyloxy means, where the C _1-8 alkyl or alkoxy groups can be both linear and branched, and

R _{4 represents} hydrogen or

REPLACEMENT LEAF

or formula B

means where

R _{7 is} hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, or nitro or mono- or disubstituted

C _1-6 alkylamino, R ₆ difluoromethoxy, difluoromethylthio,

Difluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylthio, trifluoromethylsulfinyl

Trifluoromethylsulfonyl, trifluoroethylthio,

Means trifluoroethylsulfinyl or trifluoroethylsulfonyl, where the heterocycle R _{6 is} preferably in the trans position to the radical R ₃ if R ₃ and R _{4 are} not together a bond, except compounds of formula I, in which at the same time

Trifluoromethylsulfonyl or trifluoromethylsulfinyl and

R ₁ and R ₂ each denote methyl, and the tautomeric and isomeric forms of I and the salts and / or acid addition products.

2. Benzopyran derivatives according to claim 1, characterized in that

R. is selected from the group hydrogen, methyl, ethyl,

R _{2 is} selected from the group hydrogen, methyl, ethyl,

R ₃ either symbolizes a bond together with R ₄ or is selected from the group hydroxy, methoxy, ethoxy, R _{6 is} selected from the group difluoromethoxy,

Trifluoromethylthio, trifluoromethylsulfonyl and

3. Benzopyran derivatives according to claim 1, by the structural formula

characterized in which R ₆ difluoromethoxy, trifluoromethylthio,

Trifluoromethylsulfinyl or trifluoromethylsulfonyl means.

4. Benzopyran derivatives, according to claim 1, by the structural formula

featured in which

R ₆ difluoromethoxy, trifluoromethylthio,

Trifluoromethylsulfinyl or trifluoromethylsulfonyl means.

5. Benzopyrane according to claim 2 or 3, characterized

characterized in that R ₁ and R _{2 are} both methyl.

6. Benzopyrans according to any one of claims 1-4, characterized in that they have a 3S, 4R configuration.

7. Benzopyrans according to any one of claims 1-5, characterized in that they are selected from group a) trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy-6- (difluoromethoxy) - 4H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one b) trans-2- (2,3-dihydro-2,2-dimethyl-3-hydroxy-6- ( trifluoromethylthio) -4H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one c) 2- (2,2-dimethyl-6- (difluoromethoxy-2H-1-benzopyran-4) -yl) -2,3-dihydro-1H-isoindol-1-one d) 2- (2,2-dimethyl-6- (trifluoromethylthio) -2H-1-benzopyran-4-yl) -2,3-dihydro -1H-isoindol-1-one e) 2- (2,2-dimethyl-6- (trifluoromethylsulfinyl) -2H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one f ) 2- (2,2-Dimethyl-6- (trifluoromethylsulfonyl) -2H-1-benzopyran-4-yl) -2,3-dihydro-1H-isoindol-1-one

8. A process for the preparation of benzopyran derivatives according to any one of claims 1-7, characterized in that a) Oxiranes of the general formula II

where R ₁ , R ₂ , R ₃ , R ₄ , and R _{6 have} the meaning given,

with compounds of the formula H-A or H-B

implemented, wherein R _{7 has} the meaning given, or b) compounds of the general formula IV

in which R ₁ , R ₂ , R ₃ , R ₄ and R _{5 have} the meaning given, with compounds of the formula

in which n can be 1 or 2, X is a halogen, and R _{8 is} a C _1-6 alkyl radical, alkylated and carried out an intramolecular cyclization, or c) compounds of the general formula IV

in which R ₁ , R ₂ , R ₃ , R ₄ , and R _{6 have} the meaning given, with compounds of the formula

in which m is 0 or 1, R _{8 is} one

C _1-6 alkyl group, alkylated and with a suitable

Reducing agent reduced, or d) those benzopyran derivatives according to claims 1-7, which contain the free hydroxyl group R ₃ , are converted by O-alkylation or O-acylation into other compounds according to claims 1- 7, in which R _{3 is} the Meaning C _1-8 alkoxy or

C _1-8 alkylcarbonyloxy, C _1-8 alkoxycarbonyloxy,

Formyloxy, C _1-8 monoalkylaminocarbonyloxy or

C _1-8 dialkylaminocarbonyloxy, where da) alkylation in an inert solvent in

Presence of a base can be carried out, db) esterification using a

C _1-8 acyl chloride or acyl anhydride or another activated derivative of the alkanoic acid in question, de) a reaction to carbonates can be carried out by reaction with chloroformic acid C _1-8 alkyl esters, dd) a reaction to carbamates by reaction with mono- or Dialkylaminocarbamoylchloriden or by reaction with C _1-8 alkyl isocyanates, de) a reaction to formyloxy compounds by reaction with formic acid in the presence of a base can take place, or e) those benzopyran derivatives according to any one of claims 1-7, which contain free hydroxyl group R ₃ , by dehydration in such benzopyran derivatives transferred, in which R ₃ and R ₄ together symbolize a bond, or ea) oxiranes of the formula

with compounds of the formula

or

at higher temperatures, in the presence of excess base,

f) benzopyran derivatives according to any one of claims 1-7 in which R _{6 is} difluoromethylthio, Trifluoromethylthio or 2,2,2-trifluoroethylthio has, by means of suitable oxidizing agents, been converted into compounds in which R _{6 has} the meaning

Difluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylsulfinyl, trifluoromethylsulfonyl,

2,2,2-trifluoroethylsulfinyl or

2,2,2-trifluoroethylsulfonyl, and g) any resulting mixtures of compounds in which R ₃ and R ₄ symbolize a bond, unresolve those in which R ₃ and R _{4 have} a different meaning, if desired, and / or possibly mixtures of sulfinyl and

If desired, sulfonyl compounds are separated into the pure components, and / or if appropriate mixtures of isomers are separated into the pure isomers if desired, and / or the benzopyran derivatives obtained in this way are, if desired, into their salts or

Acid addition products transferred.

9. Pharmaceutical compositions, characterized in that they have one or more benzopyran derivatives according to one of claims 1-7 as an active ingredient or ingredients

contain, optionally together with one or more auxiliaries or additives.

10. Use of one or more compounds according to claim 1 or their physiologically tolerable salts for the preparation of an agent for prophylaxis and Treatment of high blood pressure, heart failure, angina pectoris, peripheral circulatory disorders, cerebral

Insufficiency, asthma and acute and chronic

Heart disease.

11. Compounds of formulas II, III, IV, V and VI with the meaning given in claim 1

Substituents: