NO174422B - Analogous methods for the preparation of therapeutically active chromane derivatives - Google Patents

Description

The invention relates to an analogue method for the production of therapeutically active, new chromane derivatives of formula I

where

R<1> and R<2> independently of each other are both A,

R<1> and R<2> together can also be alkylene with 3-6 C atoms,

R<3> is OH or 0-COA,

R<4> is H,

R<3> and R<4> together can also be a bond,

R<5> is unsubstituted or once with A or OH

substituted pyridyl, pyridazinyl, pyrazinyl, oxo-dihydro-pyridyl or oxo-dihydro-pyridazinyl radical,

R<6> is AOOC, NO2 or CN,

R<7> and R<8> are both H,

Z is 0 or S, and

A is alkyl with 1-4 C atoms,

as well as pharmaceutically acceptable acid addition salts thereof.

The invention was based on the task of finding new compounds with valuable properties, especially those that can be used in the manufacture of medicinal preparations.

The compounds of formula I and their pharmaceutically acceptable acid addition salts with good compatibility were found to have valuable pharmacological properties. Thus, they show effects on the cardiovascular system whereby a selective attack on the coronary system can usually be observed at lower doses and a blood pressure-lowering effect at higher doses. On the coronary system, e.g. resistance reduction and current increase, while the influence on the pulse is small. Furthermore, the compounds exhibit a relaxing effect on various smooth muscle organs (stomach and intestinal tract, respiratory system and uterus). The effect of the compounds can be determined with the help of methods known per se, such as e.g. is disclosed in EP-A1-76075, EP-A1-173848 or AU-A-45547/85 (Derwent Farmdoc No. 86081769), as well as by K.S. Meesmann et al., Arzneimittelforschung 25 (11), 1975, 1770-1776. As experimental animals, e.g. mice, rats, guinea pigs, dogs, cats, monkeys or pigs.

The compounds can thus be used as active drug compounds in human and veterinary medicine.

In given formulas, A means a preferably unbranched alkyl group with 1-4, especially 1, 2 or 3 C atoms, more specifically methyl, more preferably ethyl, propyl and isopropyl.

If R 1 and R 2 together mean alkylene, then the alkylene group is preferably unbranched, more specifically "(CH 2 )n~ is preferred, where n means 3,4,5 or 6.

R , and R _ are preferably both alkyl, especially methyl

1 2

or ethyl, preferably methyl, further R and R together are preferably - (CH^)^- or -(CI^)^-.

The residues R<5> which contain a hydroxy group next to a ring N atom can also be present in the tautomeric lactam form, as indicated in some cases above.

In R<6>, AOOC preferably means methoxycarbonyl, also ethoxycarbonyl.

The residue R6 is preferably in the 6-position in the chroman system. However, it can also be in the 5-, 7- and 8-position, and is preferably CN or NO2.

The object of the invention is correspondingly, in particular, the compounds of formula I where at least one of the mentioned residues has one of the above-mentioned preferred meanings. Some of the preferred groups of compounds can be expressed by the formulas Ia - li below, which correspond to formula I, and where the residues not further specified have the meaning indicated for formula I, where however

1 2

in Ia, R and R mean A,

1 2

in Ib, R and R mean CH.,,

in Ic, R 1 and R * together mean the alkylene with 3-6 C atoms,

in Id, R 5 means an unsubstituted or an OH group substituted pyridyl, pyridazinyl or pyrazinyl residue or an A substituted oxo-dihydro-pyridyl or oxo-dihydro-pyridazinyl residue.

in le means R<5> 2-hydroxy-4-pyridyl or 6-hydroxy-3-pyridazinyl,

in If R<5> means 6-hydroxy-3-pyridazinyl,

in lg, R<1> and R<2> mean CH3 or together -(CH2)4~ or -(<CH>2)5~, R<5> an unsubstituted or one substituted with an OH group pyridyl-, pyridazinyl - or pyrazinyl residue, or an A-substituted oxo-dihydro-pyridyl or oxo-dihydro-pyridazinyl residue,

in Ih, R<1> and R<2> mean CH-.,

R 2-hydroxy-4-pyridyl, 6-hydroxy-3-pyridazinyl or 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl and

Z 0,

in li R 1 and R 2 mean CH-,

R 6-hydroxy-3-pyridazinyl and

Z 0.

Furthermore, preferred are compounds with the formulas I<1> and Ia<1> - li<1> which correspond to the formulas I and Ia - li, where, however, in addition R3 means OH or OCCH3, especially such compounds with the formulas I' and Ia' - li', where in addition R<3 >means OH.

Furthermore, there are preferred compounds with the formulas I'<1 >and Ia'' - li'<1> which correspond to the formulas I and Ia - li, where, however, in addition R3 and R<4> together mean a bond.

Moreover, compounds with the formulas I, I', I", Ia - li, Ia' - li' and Ia" - li'<1,> are preferred

where in addition

(a) R<6> means NO, or CN,

6

(b) R stands for N02 or CN and is in the 6-position,

(c) R<6> means CN,

(d) R stands for CN and is in the 6-position.

Otherwise, above and below have the residues R1 - R<8>

and A the meanings given for formula I when nothing else is expressly stated.

The object of the invention is thus an analogous method for the production of therapeutically active chroman derivatives of formula I, characterized in that a chroman of formula

II

where

0

X-Y means -CH-CR8- or -CHE-CR<3>R<8->, and

E means Cl, Br, J or a reactive esterified OH group, and

R 1 , R 2 , R 3 , R 6 , R 7 and R 8 have the meanings given for formula I,

is reacted with a compound of formula III

where R 5 and Z have the meanings given for formula I, or with one of its reactive derivatives,

and/or a compound of formula I where R3 is OH and R<4> is H, is dehydrated, and/or in a compound of formula I a hydroxy group is acylated, and/or an NH group is alkylated, and/or a basic compound of formula I is converted by treatment with an acid to one of its pharmaceutically acceptable acid addition salts.

The compounds of formula I are also prepared according to methods known per se as described in the literature (e.g. in standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc., New York, as well as in the above-mentioned patent applications), and then under reaction conditions which are known and suitable for the aforementioned conversions. Thereby, use can also be made of variants known in and of themselves which are not mentioned in detail here.

If desired, the starting compounds can also be formed in situ in that they are not isolated from the reaction mixture, but immediately converted further to the compounds of formula I. The compounds of formula I are prepared, as mentioned, by reaction between compounds of formula II and compounds of formula III, preferably in presence of an inert solvent at temperatures between approx. 0 and 150°C.

Starting compounds of formula II with X-Y =

(3,4-epoxy-chroman) is preferred.

The starting compounds II and III are usually known (cf. e.g. DE-OS 37 26 261). To the extent that they are not known, they can be produced according to methods known per se. Thus, the starting compounds of formula II

(-X-Y- =

obtained by reaction of 2-hydroxy-afocermtheol fenR o1 n-eCOr -mR e2 d tifol rmteil lsv2a-HreOn-dR e 6 R 74C-k6 ,Hro2 „m-CaOnConHe3-, r mmed ed kefotormneer l <m>IV< ed>a

if necessary by condensation with aldehydes of formula R<9->CHO (R<9> = alkyl with 1-5 C atoms) to 3-alkylidene-4-chromanones of formula IVb, reduction e.g. with NaBH^ to chromanols of formula IVc, dehydration e.g. with p-toluenesulfonic acid to chromenes of formula IVd and oxidation, e.g. with 3-chloroperbenzoic acid. The latter oxidation can also take place over several steps. Thus, e.g. with N-bromosuccinimide in aqueous solution, then the bromohydrin of formula IVe is prepared and HBr is then cleaved from this with a base, e.g. baking soda.

The chromenes of formula IVd can also be obtained by condensation of salicylaldehydes of formula 2-HO-R 6 R 7-C,H9-CH0 with

18

ketones with the formula R -CO-CH2-R to hydroxyketones with

6 7 file

formula 2-HO-R R CgH2-CH=CR -CO-R , reaction with organo-Li compounds of formula R<2->Li and subsequent hydrolysis to diols of formula 2-H0-R<6>R<7 >CgH2-CH=CR<8->CR<1>R<2->0H and ring closure during water splitting.

In compounds of formula II (-X-Y- = -CHE-CR<3>R<8->), the esters come in particular with alkylsulfonic acids (where the alkyl group contains 1-6 C atoms) or with arylsulfonic acids (where the aryl group contains 6- 10 C atoms) in consideration of "reactive esterified OH groups". These compounds can be obtained from 4-chromanols of formula IVc by reaction with an inorganic acid halide such as PC13, PBr3, SOCl2 or SOBr2, or with a sulphonic acid chloride such as methane or p-toluenesulphonic acid chloride.

The corresponding salts are suitable as reactive derivatives of III, e.g. The Na or K salts, which can also occur in situ.

It is appropriate to work in the presence of a base. Suitable bases are e.g. alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates, hydrides or also amides, such as NaOH, KOH, Ca(OH)2, Na2C03, K2C03, Na- or K-methylate, -ethylate or tert.-butylate , NaH, KH, CaH2, NaNH2, KNH2, also organic bases such as triethylamine or pyridine, which can also be used in excess and then simultaneously serve as a solvent.

Alcohols such as methanol, ethanol, isopropanol, n-butanol or tert.-butanol are particularly suitable as inert solvents; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; glycol ethers such as ethylene glycol monomethyl or -monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglym); ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or phosphoric acid hexamethyltriamide; sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Furthermore, mixtures of these solvents with each other are suitable.

The epoxide II (X-Y =

can also be produced in

situ, e.g. by the action of a base on the corresponding bromohydrin IVe.

A particularly preferred way of working consists in using an alcohol (e.g. ethanol) as a solvent and adding an organic base (e.g. pyridine), suitably boiling for approx. 0.5 - 20 hours.

3 4

A compound of formula I where R = OH and R = H can be converted by treatment with a dehydrating agent into

3 4

a compound of formula I where R and R together mean a bond. It succeeds, e.g. by impact of the indicated bases, e.g. NaH, in one of the stated solvents, e.g. DMSO, at temperatures between 0 and 150°C. Especially compounds where Z = S can be dehydrated in this way.

Furthermore, in a compound of formula I, an amino or hydroxy group can be alkylated or acylated respectively.

A primary or secondary amino group can be converted by treatment with alkylating agents to the corresponding secondary or tertiary amino group. As an alkylating agent, e.g. compounds with the formulas A-Cl, A-Br or A-J or corresponding sulfuric acid or sulphonic acid esters such as methyl chloride, -bromide, -iodide, dimethylsulphate, methyl-p-toluenesulphonate. The alkylation is conveniently carried out in the presence or absence of one of the aforementioned inert solvents, e.g. DMF, at temperatures between approx. 0 and approx. 120 °C, as a catalyst can also be added, preferably a base such as potassium tert.-butylate or NaH.

Suitable acylating agents for the acylation of hydroxy groups are the halides (e.g. the chlorides

or the bromides) or the anhydrides of carboxylic acids of the formula Ac-OH, e.g. acetic anhydride, propionyl chloride, isobutyryl bromide, formic/acetic anhydride, benzoyl chloride. The addition of a base such as pyridine or triethylamine, by acylation is possible.

One acylates appropriately in the presence or absence of an inert solvent, e.g. a hydrocarbon such as toluene, a nitrile such as acetonitrile, an amide such as DMF, or an excess of a tertiary base such as pyridine or triethylamine, at temperatures between approx. 0 and approx. 160 °C, preferably between 20 and 120 °C. A formylation is also successful with formic acid in the presence of pyridine.

A base of formula I can be transferred with an additional acid

the corresponding acid addition salt. For this turnover, only acids that give physiologically acceptable salts are involved. Thus, inorganic acids such as e.g. sulfuric acid, nitric acid, hydrogen halide acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho-phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or multi-basic carbon, sulfone or sulphur- acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic 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, isonicotinic acid, methane - or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and

-disulfonic acids, laurylsulphuric acid. Salts with physiologically unacceptable acids, e.g. picrate, can be used for the purification of the compounds of formula I. The compounds of formula I can have one or more chiral centers. They can thus be obtained during production as racemates or, if optically active starting compounds are used, also in optically active form. If the compounds have two or more chiral centers, they may precipitate during the synthesis as mixtures of racemates, from which the individual racemates can be isolated in pure form, e.g. by recrystallization from inert solvents. Thus, e.g. compounds 12 3 4 of formula I where R = R , R = OH and R = H, two chiral centers; however, when prepared by reacting II with III, only a racemate with trans-3 5 is obtained

position of the substituents R = OH and R -Z. Obtained racemates can, if desired, be resolved mechanically, chemically or biochemically into their enantiomers according to methods known per se. Thus, diastereomers can be formed from the racemate by reaction with an optically active solvent. As a solvent for basic compounds of formula I suitable as e.g. optically active acids, such as the D and L forms of

tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphoric acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. Carbmols (I, R = OH) can also be esterified using chiral acylation reagents, e.g. the specified acids, in particular (+)- or (-)-camphanic acid or (+)- or (-)-camphor-10-sulphonic acid, or with D- or L-oc-methylbenzyl isocyanate,

and then dissolved (cf. EP-A1-120428). The different forms of the diastereomers can be dissolved on. in and of itself known way, e.g. by fractional crystallization, and the enantiomers of formula I can be liberated in a manner known per se from the diastereomers. Enantiomer solutions also occur by chromatography on optically active carrier materials.

The compounds of formula I and their physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular in a non-chemical way. Thus, they can be brought in a suitable dosage form together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance,

and optionally in combination with one or more additional active compounds.

These preparations can be used as medicines in human or veterinary medicine. Carriers include organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and which do not react with the new compounds, e.g. water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrate such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly. For oral use tablets, dragees, capsules, syrups, juices or drops are particularly useful, for rectal use suppositories, for parenteral use solutions, preferably oil or water solutions, further suspensions, emulsions or implants, for topical use ointments, creams, pastes , lotions, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof and/or with water) or powders. The new compounds can also be lyophilized, and the lyophilisates obtained can be used, e.g. for the production of injection preparations. Especially for topical application, liposomal preparations also come into consideration. The stated preparations may be sterilized and/or contain auxiliary substances such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colouring, flavoring and/or aroma substances. If desired, they can also contain one or more additional active compounds, e.g. one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as monkeys, dogs, cats, rats or mice,

and is used in the therapeutic treatment of the human or animal body, as well as in the fight against diseases, in particular in therapy and/or prophylaxis of disorders in the cardiovascular system, in particular decompensated heart failure, angina pectoris, arrhythmia, peripheral or cerebral vascular diseases, as well as disease states which is associated with blood pressure, also in diseases associated with changes in the non-vascular musculature, e.g. asthma, urinary bladder incontinence.

Thereby, the compounds according to the invention are usually administered analogously to known anti-anginosis or blood-pressure-lowering agents, e.g. nicorandil or kromakalim, preferably in doses between 0.01 and 5 mg, especially between 0.02 and 0.5 mg, per dosage unit. The daily dosage is preferably between approx. 0.0001 and 0.1, especially between 0.0003

and 0.01 mg/kg body weight. However, the particular dose for each particular patient depends on various factors, e.g.

of the effect of the particular compound used, of age, body weight, general state of health, heredity,

of the diet, the time and method of administration, the excretion rate, the drug combination and the severity of the individual disease to which the treatment applies. The oral application is preferred.

The compounds of formula I and their salts are also suitable, especially for topical application, for the treatment of Alopecia areata. For this, in particular, pharmaceutical preparations are used which are suitable for topical treatment of the scalp and which are mentioned above. They contain approx. 0.005 - 10, preferably 0.5 - 3, % by weight of at least one compound of formula I and/or at least one of its salts. Furthermore, these compounds can be used against alopecia analogously to what is stated in WO 88/00822.

In the following examples, "usual preparation" means: If necessary, water is added, it is extracted with an organic solvent such as ethyl acetate, separated, the organic phase is dried over sodium sulfate, it is filtered, evaporated and purified by chromatography and/or crystallization .

Above and below, all temperatures are given in °C. [a] = [a3p° in methanol.

Trial report

Mean arterial blood pressure was measured directly before and up to 120 minutes after oral administration of 1 mg/kg of the test compound to spontaneously hypertensive rats. The test compounds were applied through tubing, suspended in 5% aqueous gum arabic.

Compounds of formula I

(R<1> = R<2>= methyl; R4 = R7 = R<8> = H)

Example 1

A mixture of 20.1 g of 2,2-dimethyl-3,4-epoxy-6-cyanochromane ("Ila"), 14 g of 2-hydroxypyridine (1H-2-pyridone), 7 ml of pyridine and 70 ml of ethanol was boiled for 2 hours. It was cooled, filtered off, the filtrate concentrated and the residue chromatographed on silica gel. With diethyl ether/ethyl acetate (1:1) 2,2-dimethyl-4-(2-pyridyl-oxy)-6-cyano-3-chromanol was obtained, m.p. 102-103°C.

Analogously (boiling time up to 15 hours) one got: 2,2,3-trimethyl-4-(2-pyridyl-oxy)-6-cyan-3-chromanol,

sm.p. 105-107°C,

2,2-tetramethylene-4-(2-pyridyl-oxy)-6-cyano-3-chromanol,

sm.p. 126-127°C,

2,2-pentamethylene-4-(2-pyridyl-oxy)-6-cyano-3-chromanol,

sm.p. 108-110°C,

2,2-dimethyl-4-(3-pyridyl-oxy)-6-cyano-3-chromanol,

sm.p. 202-204°C,

2,2-dimethyl-4-(4-pyridyl-oxy)-6-cyano-3-chromanol,

sm.p. 193-196°C,

2,2-dimethyl-4-(4-pyrimidinyl-oxy)-6-cyano-3-chromanol,

sm.p. 93-105°C, and

2,2-dimethyl-4-(2-pyrazinyl-oxy)-6-cyano-3-chromanol,

sm.p. 103-105°C

Example 2

A mixture of 20.1 g of IIa, 11.1 g of 2,4-dihydroxypyridine, 8 ml of pyridine and 400 ml of ethanol was boiled for 15 hours. It was evaporated, extracted with ethyl acetate, the organic phase washed with dilute hydrochloric acid and then with water, dried, evaporated, and there was obtained 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6- cyan-3-chromanol ("A"), m.p. 249-249.5° (from ethanol).

Analogously you got

with 2,4-dihydroxypyridine:

2,2,3-trimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyano-3-chromanol, m.p. 198-200°C, 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-nitro-3-chromanol, m.p. 224-226°C, 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-methoxycarbonyl-3-chromanol, m.p. 251-252°C, with 2,3-dihydroxypyridine: 2,2-dimethyl-4-(2-hydroxy-3-pyridyl-oxy)-6-cyano-3-chromanol, m.p. 262-265°C, with 2,5-dihydroxypyridine: 2,2-dimethyl-4-(2-hydroxy-5-pyridyl-oxy)-6-cyano-3-chromanol, m.p. 256-258°C, with 4,6-dihydroxypyrimidine: 2,2-dimethyl-4-(6-hydroxy-4-pyrimidinyl-oxy)-6-cyano-3-chromanol, m.p. 235-237°C, with 3,6-dihydroxypyridazine: 2,2-dimethyl-4-(6-hydroxy-3-pyridaZinyloxy)-6-cyano-3-chromanol ("B"), m.p. 255-256°C,

2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-3-chromanol, m.p. 236-239°C,

2,2-pentamethylene-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-3-chromanol, no m.p. below 275°C,

2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-nitro-3-chromanol, no m.p. below 260°C,

2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-nitro-3-chromanol, m.p. 223-225°C,

2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-bromo-3-chromanol, m.p. 257-259°C, and

2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-methoxycarbonyl-3-chromanol, m.p. 242°C.

Example 3

A mixture of 20.1 g of IIa, 11.1 g of 2-mercaptopyridine, 6.6 ml of pyridine and 265 ml of ethanol was boiled for 3 hours. It was concentrated, and the 2,2-dimethyl-4-(2-pyridyl-thio)-6-cyano-3-chromanol obtained was crystallized from diisopropyl ether, m.p. 101-103°C.

Example 4

A mixture of 2 g of Ila, 1.11 g of 2-mercaptopyridine,

60 ml of DMSO and 0.3 g of NaH (80% strength) were stirred for 6 hours at 20°C and worked up in the usual way. 2,2-dimethyl-4-(2-pyridyl-thio)-6-cyano-3-chromene was obtained, m.p. 110-112°C.

Example 5

A solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochromane (m.p. 89-92°C, which can be obtained by reduction of 2,2-dimethyl-6-cyano-4- chromanone with NaBH^ in CH 3 OH to oily 2,2-dimethyl-6-cyano-4-chromanol and reaction with PBr 3 in toluene at 20°C) and 2.5 g of pyridazine-3,6-diol in 70 ml of DMSO were added 1.2 g of 80% NaH and stirred for 3 days at 20°C. After the usual work-up, 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyanochromane was obtained, m.p. 221-224°C.

Example 6

A mixture of 10 g of 2,2-dimethyl-4-(2-pyridyl-thio)-6-cyano-3-chromanol, 3 g of sodium hydroxide and 350 ml of dioxane was boiled for 20 minutes. It was cooled, filtered, the filtrate evaporated, and 2,2-dimethyl-4-(2-pyridylthio)-6-cyano-3-chromene was obtained, m.p. 110-112°C.

Example 7

A mixture of 1 g of "B" (see Example 2) and 5 ml of acetic anhydride was boiled for 1 hour. It was cooled, worked up in the usual way, and 2,2-dimethyl-3-acetoxy-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyanochromane was obtained, m.p. 210-212 °C.

Example 8

A mixture of 312 mg "A", 20 ml acetone, 400 mg K 2 CO 3 and 0.2 ml dimethyl sulfate was boiled for 2 hours. It was filtered, evaporated and chromatographed over silica gel. With ethyl acetate/methanol (9:1) 2,2-dimethyl-4-(1,2-dihydro-1-methyl-2-oxo-4-pyridyl-oxy)-6-cyano-3-chromanol was obtained, sm .p. 202-203°C.

Analogously, the following was obtained: 2,2-dimethyl-4-(16-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromanol, m.p. 206-208°C, and 2,2-dimethyl-4-(1,2-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromanol, m.p. 164-167°C

Example 9

Analogously to example 8, one obtained from "B" and 2-bromo-propane 2,2-dimethyl-4-(1,6-dihydro-1-isopropyl-6-oxo-3-pyridazinyloxy)-6-cyano- 3-chromanol, m.p. 20l-203°C.

Example 10

a) A mixture of 5 g of "B", 5 g of (+)-camphor-10-sulfonic acid chloride and 50 ml of pyridine was heated at 70°C for 5 hours.

It was worked up with dilute hydrochloric acid and ethyl acetate as usual, separated chromatographically on silica gel with dichloromethane/ethyl acetate mixtures, and two epimers of the "B"-(+)-camphor-10-sulphonic acid ester were obtained, m.p. 223-224°C and m.p. 127-150°C. b) A mixture of 2 g of the "non-polar" epimer (m.p. 223-224°C), 16 g of "sodium hydroxide on carrier" (E. Merck, catalog "Reagenzien, Diagnostica, Chemikalien", 1987/88, page 587, no. 1567) and 80 ml of methanol were stirred for 20 hours at 20 °C. It was evaporated, dissolved in water,

added HCl until pH 8, and the obtained 2,2-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-cyano-3-chrome was

filtered off (m.p. 226-228°C). Work-up of the filtrate with hydrochloric acid/ethyl acetate at pH 4 and chromatography on silica gel with dichloromethane/ethyl acetate/methanol gave (-)-2,2-dimethyl-4-(1,6-dihydro-6-oxo-pyridazinyl-oxy) -6-cyano-3-chromanol, m.p. 229°; [a] -168.5°C. c) Analogously, (+)-2,2-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy) was obtained from the "polar" epimer (m.p. 127-150°C) )-6-cyano-3-chromanol, m.p. 232-233°C; [a] +170.0°C.

Analogously, one obtained from "A" over the appropriate (+)-camphor sulphonic acid ester 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyano-3-chromene (m.p. 263 -264°C) as well as (-)- and (+)-2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyan-3-chromanol.

Analogously, one obtained from 2,2-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromanol over the appropriate (+)-camphor sulfonic acid esters 2 ,2-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromene (m.p. 144-146°C) as well as (- )-2,2-dimethyl-4R-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3S-chromanol (m.p. 164°C, [a ] -165.1°C) and (+)-2,2-dimethyl-4S-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3R-chromanol (m.p. 161-162°C, [a] +171.8°C).

Analogously, one obtained from 2,2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyan-3-chromanol over the appropriate (+)-camphor sulfonic acid esters 2,2 ,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromene and (-)-2,2,3-trimethyl-4-(1, 6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromanol (m.p. 131-134°C, [a] -222.2°C) and (+)-2, 2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-3-chromanol (m.p. 131-134°C, [a] +222, 2°C).

The examples below relate to pharmaceutical preparations containing the compounds of formula I or their physiologically acceptable salts:

Example A Tablets

A mixture of 1 g of 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-3-chromanol, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0 .1 kg of magnesium stearate was pressed into tablets in the usual way so that each tablet contained 0.1 mg of active compound.

Example B Dragons

Analogously to example A, tablets were pressed which were then coated with a coating of sucrose, potato starch, talc, tragacanth and colouring.

Example C Capsules

1 kg of 2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyan-3-chromanol was filled in the usual way into hard gelatin capsules so that each capsule contained 0.5 mg of active connection.

Example D Ampoules

A solution of 10 g of 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-3-chromanol in 70 l of 1,2-propanediol was filled with twice-distilled water up to 100 l, sterile-filtered, filled into ampoules, and it was closed sterile. Each ampoule contained 0.1 mg of active compound.

Analogously, tablets, dragees, capsules or ampoules can be obtained which contain one or more of the other active compounds of formula I and/or their physiologically acceptable salts.

Claims (2)

1. Analogy method for the preparation of therapeutically active chromane derivatives of the general formula where R<1> and R<2> independently of each other are both A, R<1> and R<2> together can also be alkylene with 3-6 C atoms, R<3> is OH or 0-COA, R<4> is H, R<3> and R<4> together can also be a bond, R<5> is unsubstituted or once with A or OH substituted pyridyl, pyridazinyl, pyrazinyl, oxo-dihydro-pyridyl or oxo-dihydro-pyridazinyl radical, R<6> is AOOC, NO2 or CN, R<7> and R<8> are both H, Z is 0 or S, and A is alkyl with 1-4 C atoms, as well as pharmaceutically acceptable acid addition salts thereof, characterized in that a chroman of formula II where X-Y means or -CHE-CR<3>R<8->, and E means Cl, Br, J or a reactive esterified OH group, and R<1>, R<2>, R<3>, R<6>, R7 and R<8> have the meanings indicated for formula I, are reacted with a compound of formula III where R<5> and Z have the meanings given for formula I, or are reacted with one of its reactive derivatives, and/or a compound of formula I where R<3> is OH and R4 is H, is dehydrated, and/or in a compound of formula I a hydroxy group is acylated, and/or an NH group is alkylated, and/or a basic compound of formula I is converted by treatment with an acid into one of its pharmaceutically acceptable acid addition salts. 2. Analogous method according to claim 1 for the production of a) 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyan-3-chromanol, b) 2,2-dimethyl-4-( 6-hydroxy-3-pyridazinyl-oxy)-6-cyano-3-chromanol, or c) 2,2-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy )-6-cyano-3-chromanol, characterized in that corresponding output connections are used.