NZ231000A

NZ231000A - Heterocyclically substituted chroman derivatives and pharmaceutical compositions thereof

Info

Publication number: NZ231000A
Application number: NZ231000A
Authority: NZ
Inventors: Rolf Gericke; Manfred Baumgarth; Ingeborg Lues; Peyer Jacques De; Rolf Bergmann
Original assignee: Merck Patent Gmbh
Priority date: 1988-10-14
Filing date: 1989-10-12
Publication date: 1992-02-25
Also published as: DK511089D0; NO174422B; HU217812B; HUT58082A; IL91967A0; DE3835011A1; HU895311D0; PT91979B; NO894103L; AU4256589A; JPH02145584A; JP2874912B2; ZA897783B; FI92825C; KR900006326A; NO174422C; KR0150780B1; FI92825B; AU628395B2; DK511089A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £31 000 231000 Priority Deie(s):... AU-..IQ... Saaciftaation Filed: C-i (ts&: i j )• • T7X Cii t l-TX* f ^a^^AL/aa+C^^Li^XplH, - ubiicfttton D??s: P.O. Jc-Vi.'.iai, fo: Class Cont: JCC>rn.Q>3L"2577.^Ll+r.j. j *»-f?r?£i>.i-3Sr|i I «\2>.L^, ^ ,££)TXS;iM-.|..//.t% ND « NEW ZEALAND Patents Act 1953 A, COMPLETE SPECIFICATION CHROMAN DERIVATIVES We, MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, of Frankfurter Strasse 250, D-6100 Darmstadt, Federal Republic of Germany, a German Company do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) fW - lfl- Margie Patau* Caaati—k*6L ttifc bffloahe8.il]!Lei IMfLmuj ■fllOO D a if Chroman derivatives 5 The invention relates to novel chroman deriv atives of the formula I c in which Rl is A, R2 and Ra are each H or A, 10 or R1 and R2 together are an alkylene having 3-6 C atoms, R3 is H, OH, OA or QAc, R4 is H, or r3 and R4 together are a bond, Rs is a pyridyl, pyridazinyl, pyrimidinyl, pyraz- 15 inyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrixoidinyl or oxodihydropyrazinyl radical which is unsubstituted, monosubstituted or disubstituted by A, F, CI, Br, I, OH, OA, QAc, SH, N02, NHz, AcNH, HOOC and/or AOOC, 20 R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, N02, NH2, MHA, NAz, CN, F, CI, Br, I, CF3, ASO, ASOz, AO-SO, A0-S02, AcNH, AO-CO-NH, H2NSO, 25 HANSO, A2NS0, H2NS02, HANS02, AjNSOZ, H2NCO, HANCO, AjNCO, H2NCS, HANCS, AzNCS, ASONH, ASOzNH, AOSONH, A0S02NH, ACO-alkyl y^affitroalkyL,, _cyano-alkyl, A-C(=N0H) or A-C(=NNH2) HAT TQf? Iff 071099 - 2 - j j. Ij vJ U Z is O, S, or NH, A is alkyl having 1-6 C atoms, alkyl is alkylene having 1-6 C atoms and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms and their salts. The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the preparation of medicaments. It has been found that the compounds of the formula I and their physiologically acceptable salts, which if R8 is methyl are partly described and claimed in New Zealand Patent Specification No. 228991, possess, combined with good tolerability, useful pharmacological properties. Thus, they show effects on Jthe cardiovascular system, it usually being possible to observe a selective effect on the coronary system at lower doses and a hypotensive effect at higher doses. In the coronary system, for example, decreases in resistance and increases in flow occur, the influence on the heart rate remaining low. Furthermore, the compounds show a relaxant effect on various smooth muscle organs (gastrointestinal tract, respiratory system and uterus). The effects of the compounds can be determined with the aid of methods which are known per se, as are given, for example, in EP-Al-76,075, EP-A1-173,848 or AU-A-45,547/85 (Derwent Farmdoc No. 86081769) and by K.S. Meesmann et al., Arzneimittelforschung 25 (11), 1975, 1770-1776. Suitable experimental animals are, for example, mice, rats, guineapigs, dogs, cats, apes or pigs. The compounds can therefore be used as active medicament compounds in human and veterinary medicine. In addition, they can be used as intermediates for the preparation of further active medicament compounds. In the formulae given, A is a preferably un-branched alkyl group having 1-6, prefe^ably_ 1-4, in particular 1, 2 or 3 C atoms, in detail preferably, methyl, in addition preferably ethyl, propyl^MS<5 (y r"rrnr 1f nunm |'28jUiV,9j/^ v' 7 i - 3 - 23 10 butyl, isobutyl, and furthermore preferably sec.-butyl, 4 tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4 -methylpentyl). If R1 and R2 together are alkylene, the alkylene O 5 group is preferably unbranched, In detail preferably -(CH2)n-, where n is 3, 4, 5 or 6. The' group "alkyl" preferably stands for -CHZ- or -CH2CH2-. Ac is preferably alkanoyl having 1-6, in par-10 ticular 1, 2, 3 or 4 C atoms, in detail preferably foray 1 or acetyl, furthermore preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and in addition ( preferably benzoyl, o-, m- or p-toluyl, 1- or 2-naph- thoyl. 15 R1 and R2 are preferably each alkyl, in particular each methyl or ethyl, preferably each methyl; R1 and R2 together are furthermore preferably -(CHZ) 4- or -(CH2) 5-. If R* is H, R3 is preferably OH, and in addition preferably O-CHO or 0-C0CHa. 20 R5 is preferably 6-hydroxy-3-pyridazinyl (= 1,6- dihydro-6-oxo-3-pyr.idazi.nyl) or 2-hydroxy-4-pyridyl ( = l,2-dihydro-2-oxo-4-pyridyl), and in addition preferably unsubstituted 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidin-yl, 3-, 4- or 5-pyridazinyl or pyrazinyl, 25 hydroxypyridyl such as 3-, 4-, 5- or 6-hydroxy- ( 2-pyridyl, 2-, 4- or 5-hydroxy-4-pyridyl, 3-hydroxy-5- pyridyl, 2-hydroxy-5-pyridyl; hydroxypyridazinyl such as 4- or 5-hydroxy-3-pyridazinyl, 3-, 5- or 6-hydroxy-4-pyr idaz inyl; hydroxypyrimidinyl such as 4- or 5-hydro xy-30 2-pyrimidinyl, 2-, 5- or 6-hydroxy-4-pyrimidinyl, 2- or 4-hydroxy-5-pyrimidinyl; hydroxypyrazinyl such as 3-, 5-or 6-hydroxy-2-pyrazinyl; dihydroalkyloxopyridyl such as l,2-dihydro-l-methyl-2-oxo-3-, -4-, -5- or -6.-pyridyl, l,2-dihydro-l-ethyl-2-oxo-3-, -4-, -5- or -6-pyridyl; 35 dihydroalkyloxopyridazinyl such as 1,6-dihydro-l-methyl- 6-oxo-3-, -4- or -5-pyridazinyl, l,6-dihydro-l-ethyl-6-oxo-3-, -4- or -5-pyridazinyl; - 4 - 23 10 00 alkoxypyridyl such as 3-, 4-, 5- or 6-methoxy-2-pyridyl, 2-, 4- or 5-methoxy-3-pyridyl, 2- or 3-methoxy-4-pyridyl/ 2-methoxy-5-pyridyl, 2- or 3-ethoxy-4-pyridyl; alkoxy-pyridazinyl such as 4-, 5- or 6-me thoxy-3-pyr idaz inyl, 4-, 5- or 6-ethoxypyridazinyl, 3-, 5- or 6-methoxy-4-pyridazinyl, 3-, 5- or 6-ethoxy-4-pyridazinyl; alkoxy-pyrimidinyl* such as 4- or 5-methoxy-2-pyr imidinyl, 2-, 5-or 6-me thoxy-4-pyr imidinyl, 2- or 4-methoxy-5-pyrimid-inyl; alkoxypyrazinyl such as 3-, 5- or 6-methoxy-2-pyrazinyl; aminopyridyl such as 3-, 4-, 5- or 6-amino-pyr idyl, 2-, 4- or 5-amino-3-pyridyl, 2- or 3-amino-4-pyridyl, 2-amino-5-pyr idyl; aminopyr idaz inyl such as 4-, 5- or 6-amino-3-pyridazinyl, 3-, 5- or 6-amino-4 -pyr idaz -inyl; aminopyr imidinyl such as 4- or 5-amino-2-pyrimid-inyl, 2-, 5- or 6-amino-4-pyrimidinyl, 2- or 4-amino-5-pyrimidinyl; aminopyrazinyl such as 3-, 5- or 6-amino-2-pyrazinyl; mercaptopyridyl such as 3-, 4-, 5- or 6-mercapto-2-pyridyl, 2-, 4- or 5-mercapto-3-pyridyl, 2- ( = 1,2 -dihydro-2 -thioxo-4 -pyridyl) or 3 -mercapto-4 -pyridyl, 2-mercapto-5-pyridyl; mercaptopyridazinyl such as 4-, 5-or 6-mercapto-3-pyridazinyl (= 1,6-dihydro-6-thioxo-3-pyridazinyl), 3-, 5- or 6-mercapto-4-pyridazinyl; mercap-topyrimidinyl such as 4- or 5-mercapto-2-pyrimidinyl, 2-, 5- or 6 -mercapto-4-pyrimidinyl, 2- or 4-mercapto-5-pyrimidinyl; mercaptopyrazinyl such as 3-, 5- or 6-mercapto-2-pyrazinyl. Radicals of the type R5 which contain a hydroxyl or mercapto group adjacent to a ring N atom may also exist in the tautomeric lactam or thiolactam form, as indicated above in individual cases. In R6 and R7, the following are preferably: A: methyl, and in addition ethyl; AO: methoxy, and in addition ethoxy; ACO: acetyl, and in addition propionyl; ACS: thioacetyl, and in addition thiopropionyl; AOOC: methoxycarbonyl, and in addition ethoxy- carbonyl; - 5 - 231000 o 10 o 15 20 25 30 AO-CS: ACOO: ACSO: hydroxyalkyl: mercaptoalkyl: NHA: NA2: ASO: AS02: AO-SO: A0-S02: Ac-NH: AO-CO-NH: HANSO: AjNSO: HANS02: A2NS02: HANCO: AjNOC: methoxy-thiocarbonyl, and in addition ethoxythiocarbonyl; acetoxy, and in addition propionoxy; thio(no)acetoxy, and in addition thio(no)- propionoxy; hydroxymethyl or 1- or 2-hydroxysthy1; mere aptomethy1 or 1- or 2-mercaptoethyl; methylamino, and in addition ethylamino; dimethylamino, and in addition diethyl-amino; methylsulfinyl, and in addition ethyl-sulfinyl; methylsulfonyl, and in addition ethyl-sulfonyl; methoxy-sulfinyl, and in addition ethoxy-sulfinyl; methoxy-sulfonyl, and in addition ethoxy-sulfonyl; acetamido, and in addition formamido, propionamido or benzamido; methoxycarbonylamino, and in addition ethoxycarbonylamino; methylaminosulfinyl, and in addition ethylaminosul£inyl; dimethylaminosulfinyl, and in addition diethylaminosulf inyl; methylaminosulfonyl, and in addition ethylaminosul f onyl; dime thylaminosulf onyl, and in addition diethylaminosulf onyl; N-methylcarbamoyl, and in addition N-ethylcarbamoyl; N, N-dimethylcarbamoyl, and in - addition N, N-diethylcarbamoyl; 35 HANCS: N-methylthiocarbamoyl, and in addition N-ethylthiocarbamoyl; fiAS. ■ifi mmtt - 6 - 310 0 10 15 20 { 25 o 30 35 ASONH: AS02NH: AOSONH: AOSOjNH: ACO-alkyl: Nitroalkyl: Cyanoalkyl: A-C (■= NOH): A-C (= NNH2): addition and in addition and in addition and in addition AjNCS : N, N-dimethylthiocarbamoyl, and in addition N,N-diethylthiocarbamoyl; methylsulfinylamino, and in ethy1sulfinylamino; methylsulfonylamino, ethylsulfonylamino; methoxysulfinylamino, ethoxysulfinylamino; methoxysulfonylamino, ethoxysulfonylamino; 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl; nitromethyl, 1- or 2-nitroethyl; cyanomethyl, 1- or 2-cyanoethyl; 1-oximinoethyl, and in addition 1-oximino-propyl; 1-hydrazinoethyl, and in addition 1-hydrazinopropyl. The radicals R6 and R7 are preferably in the 6-and 7-position of the chroman system. However, they may also be in the 5- and 6-, 5- and 1-, 5- and 8-, 6- and 8-and 7- and 8-position. ' One of the radicals R6 and R7 is preferably H, whereas the other is different from H. This other radical is preferably in the 6-positionr but also in the 5-, 7-or 8-position, and is preferably CN or N02* in addition preferably CHO, ACO (in particular acetyl), AOOC (in particular methoxycarbonyl or ethoxycarbonyl), ACOO (in particular acetoxy), and furthermore preferably F, CI, Br, I, CF3, H2NC0, H2NCS or NH2. The radical Re is preferably H, and furthermore preferably methyl or ethyl. Accordingly, the invention in particular relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the previously mentioned preferred meanings. Some preferred groups of compounds can be expressed by the formulae la to Ii - 7 - 310 0 0 below, which correspond to the formula I and in which the radicals not designated in more detail have the meaning indicated in the formula I, in which however in la R1 and R2 are each A; in lb R1 and R2 are each CH3; in Ic R1 and R2 together are alkylene having 3-6 C atoms; in Id R5 is a pyridyl, pyr idaz inyl, pyr imidinyl or pyrazinyl radical which is unsub-stituted or substituted by an OH group or an oxodihydropyridyl or oxodihydro-pyridaz inyl radical which is substituted by A; in Ie R5 is 2-hydroxy-4-pyr idyl or 6-hydroxy- 3-pyridazinyl; in If R5 is 6-hydroxy-3-pyridazinyl; in Ig R1 and R2 are each CH3 or together are -(CH2)«- or -(CH2)s-; R5 is a pyridyl, pyr idaz inyl, pyrimidinyl or pyrazinyl radical which is unsubstituted or substituted by an OH group or an oxodihydropyridyl or oxodihydropyrida- zinyl radical which is substituted by A; R8 is H or CH3 and Z is 0, S or NH; in Ih R1 and R2 are each CH3; R5 is 2-hydroxy-4-pyridyl, 6-hydroxy-3- pyrida zinyl or 1,6-dihydro-l-methyl-6-oxo-3-pyrida^zinyl and Z is °; in Ii R1 and R2 are each CH3; R5 is 6-hydroxy-3-pyridazinyl and Z is 0. Compounds of the formulae I' and la' to Ii' are furthermore preferred which correspond to the formulae I 23 10 00 - 8 - and la to Ii, but in which in each case additionally R3 is H, OH, OCHO or OCOCH3 and R* is H, in particular those compounds of the formulae I' and la' to Ii' in which in each case additionally R3 is OH and R* is H. 5 Compounds of the formulae I" and la" to Ii" are furthermore preferred which correspond to the formulae I, and la to Ii, but in which in each case R3 and R4 together are additionally a bond. Compounds of the formulae I, I', I", la to Ii, > 10 la' to Ii' and la" to Ii" are in addition preferred, in which in each case additionally (a) R6 is different from H and R7 is H; (b) R6 is different from H and is in the 6-position 15 and R7 is H; (c) R6 is N02, CN, CHO, ACO, HOOC, AOOC, ACOO, F, CI, Br, I, CF3, HzNCO, H2NCS or NH2 and R7 is H; 20 (d) R6 is N02, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF3, H2NC0, H2NCS or NH2 and is in the 6-position and R7 is H; (e) R6 is N02, CN, CHO, CH3C0, CH3OOC, C2H5OOC or CH3COO O 25 and R7 is H; (f) R6 is N02, CN, CHO, CH3CO, CH3OOC, C2H3OOC or CH3COO and is in the 6-position and R7 is H; 30 (g) R6 is N02 or CN and R7 is H; (h) R6 is N02 or CN and is in the 6-position and R7 is H; (i) R6 is CN and 35 R7 is H; (j) R6 is CN and is in the 6-position and R7 is H. PAU LOO 10 071000 o Q - 9 - 3 10 00 Compounds of the formulae I, i»f i ", la to Ii, la' to Ii', la" to ii" and the remaining groups of compounds previously indicated as preferred are particularly preferred, in which R8 is additionally ch3. 5 Otherwise, the radicals Rl to R8, A, "alkyl" and Ac above and below have the meanings given in formula I, if not expressly stated otherwise. The invention in addition relates to a process for the preparation of chroman derivatives of the formula 10 I, characterized in that a chroman of the formula II IX in which ,8 X-Y is -CH-CR - or -CHE-CR3RB- and E is CI, Br, I or a reactively esterified OH group and R1, R2, R3, R6, R7 and R8 have the meanings given in formula 15 I is reacted with a compound of the formula III RS-ZH III in which Rs and Z have the meanings indicated in formula 20 I, or with one of its reactive derivatives and/or in that a compound of the formula I, in which R3 is OH and R* is H, is dehydrated and/or in that one or more of the radicals R3, Rs, R6 and/or R7 are converted into 25 other radicals R3, Rs, R6 and/or R7 in a compound of the formula I and/or in that a basic compound of the formula I is converted into one of its acid addition salts by treating with an acid. The compounds of the formula I are otherwise 30 prepared by methods which are known per se, as are PMi LOO 1G 07100& - 10 - 231000 described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organise hen Chemie (Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, 5 Inc., New York; and in the abovementioned patent applications ), in particular under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but which are not mentioned in more detail here. 10 The starting materials may also be formed, if - desired, in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I. Preferably, the compounds of the formula I are 15 prepared by reacting compounds of the formula II with compounds of the formula III, preferably in the presence of an inert solvent at temperatures between about 0 and 150°. Starting materials of the formula II with X-Y = 20 o ' X 8 -ch-cr - (3,4-epoxychromans) are preferred. The starting materials II and III are usually known (compare, for example, DE-OS 3,726,261). If they are not known, they can be prepared by methods which are 3 25 known per se. Thus, the starting materials of the formula o II (-X-Y- = -dH-CR8- ) are obtainable by reacting 2-hydroxyacetophenones of the formula 2-HO-R6R7C6H2-COCH3 with ketones of the formula R1-CO-R2 to give corresponding 4-chromanones of the formula IVa R6 IVa -X-Y- = -CO-CH2- x \ IVb -X-Y- = -CO-C (=CH-R9 ) - | | R2 IVC -X-Y- = -CHOH-CHR8- i IVd -X-Y- = -CH=CR8- r7 ' ive -X-Y- = -CHBr-CR8OH- 30 if desired condensing with aldehydes of the formula Rg-CHO (R9 = alkyl having 1-5 C atoms) to give 3-alkylidene-4- LOG 1C 0? 1Q9B - 11 - 231000 chromanones of the formula IVb, reducing, for example with NaBH*, to give chromanols of the formula IVc, dehydrating, for example with p-toluenesulfonic acid, to give chromenes of the formula IVd and oxidizing, for example with 3-chloroperbenzoic acid. The last-mentioned oxidation can also be carried out in a number of steps. Thus, for example, the bromohydrins of the formula IVe can initially be prepared using N-bromosucciniraide in aqueous solution and HBr can subsequently be eliminated from these using a base, for example sodium hydroxide solution. The chromenes of the formula IVd can also be obtained by condensation of salicylaldehydes of the formula 2-HO-R®R7C6H2-CHO with ketones of the formula R1-CO-CH2-R8 to give hydroxyketones of the formula 2-HO-R6R7C6H2-CH=CR8-CO-R1, reaction with organolithium compounds of the formula R2-Li and subsquent hydrolysis to give diols of the formula 2-HO-R6R7C6H2-CH=CR8-CR1R2-OH, and cyclization with elimination of water. In compounds of the formula II (-X-Y- --CHE-CR3R8-), possible "reactively esterified OH groups" are in particular esters with alkylsulfonic acids (in which the alkyl group contains 1-6 C atoms) or with arylsulfonic acids (in which the aryl group contains 6-10 C atoms). These compounds are obtainable from the 4-chromanols of the formula IVc by reacting with an inorganic acid halide such as PC13, PBr3, S0C12 or SOBr2 or with a sulfonyl chloride such as methanesulfonyl or p-toluenesulfonyl chloride. Reactive derivatives of III which are suitable are the corresponding salts, for example the Na or K salts, which can also be formed in situ. It is expedient to work in the presence of a base. Suitable bases are, for example, hydroxides, carbonates, alkoxides, hydrides and also amides of alkali metals or alkaline earth metals, such as NaOH, KOH, Ca(OH)2, Na2C03, K2C03, Na methoxide or K methoxide, Na - 12 - 23 10 00 ethoxide or K ethoxide or Na tert.-butoxide or K tert.-*■ butoxide, NaH, KH, CaH2, NaNH2, KNH2, and in addition organic bases such as triethylamine or pyridine, which can also be used in excess and then at the same time ^ 5 serve as solvent. Suitable inert solvents are, in particular, alcohols such as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; glycol 10 ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); (, ketones such as acetone or butanone; nitriles such as acetonltrile; nitro compounds such as nitromethane or 15 nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or hexa-methylphosphoramide; sulfoxides such as dimethyl sulfoxide (DKSO); chlorinated hydrocarbons such as dichloro-methane, chloroform, trichloroethylene, 1,2-dichloro-20 ethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are furthermore suitable. A 3 The epoxide II (X-Y = -CH-CR - ) can also be prepared in situ, for example by the action of a base on ^ 25 the corresponding bromohydrin IVe. A particularly preferred procedure consists in using an alcohol (for example ethanol) as a solvent and adding an organic base (for example pyridine), the reaction mixture expediently being boiled for about 0.5 30 to 20 hours. A compound of the formula I in which R3 = OH and R* = H can be converted into a compound of the formula I in which R3 and R* together are a bond by treating with a dehydrating agent. This is carried out, for example by 35 the action of one of the bases mentioned, for example NaH, in one of the solvents mentioned, for example DMSO, o 231000 at temperatures between 0 and 150°. In particular, compounds in which Z = S can be dehydrated in this manner. Furthermore, one or more of the radicals R3, R5, R6 and/or R7 can be converted into other radicals R3, Rs, R6 and/or R7 in a compound of the formula I. For example, it is possible to replace an H atom by a halogen atom by means of a halogenation or by a nitro group by means of a nitration and/or to reduce a nitro group to an amino group and/or to alkylate or acylate an amino or hydroxyl group and/or to convert a cyano group (for example with HC1 in water/methanol at 20-100°) into a carboxyl group or (for example with Raney nickel in water/acetic acid/pyridine in the presence of sodium phosphate) into a formyl group or (for example with KOH in tert.-butanol) into a carbamoyl group or (for example with HZS in pyridine/triethylamine) into a thio-carbamoyl group and/or to convert a -CO-NH- group ( for example with P2Ss or with Lawesson reagent in toluene) into a -CS-NH- or -C(SH)=N- group. Nitration is carried out under customary conditions, for example using a mixture of concentrated HNOa and concentrated H2S0< at temperatures between 0 and 30°. If at least one of the substituents R6 and R7 is an electronegative group such as CN or N02# the nitration predominantly takes place at the radical Rs; otherwise mixtures are usually obtained in which the nitro groups are on the radical R5 or on the chroman ring. This applies analogously to the halogenation which can be carried out, for example, using elemental chlorine or bromine in one of the customary inert solvents at temperatures between about 0 and 30°. A primary or secondary amino group and/or an OH group can be converted into the corresponding. secondary or tertiary amino group and/or alkoxy group by treating with alkylating agents. Suitable alkylating agents are, for example, compounds of the formulae A-Cl, A-Br or A-I or corresponding sulfuric acid or sulfonic acid esters, - 14 - 23 10 00 such as methyl chloride, bromide or iodide, dimethyl sulfate or methyl p-toluenesulfonate. In addition, for example, one or two methyl groups can be introduced with formaldehyde in the presence of formic acid. The alkyla-tion is preferably carried out in the presence or absence of one of the inert solvents mentioned, for example DMF, at temperatures between about 0° and about 120°, in which case a catalyst can also be present, preferably a base such as potassium tert.-butoxide or NaH. Suitable acylating agents for the acylation of amino or hydroxyl groups are preferably the halides (for example chlorides or bromides) or anhydrides of car-boxylic acids of the formula Ac-OH, for example acetic anhydride, propionyl chloride, isobutyryl bromide, formic acid/acetic anhydride and benzoyl chloride. The addition of a base such as pyridine or triethylamine during the acylation is possible. The acylation is preferably carried out in the presence or absence of an inert solvent, for example 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 about 0° and about 160°, preferably between 20° and 120°. Fonnylation is also carried out using formic acid in the presence of pyridine. A base of the formula I can be converted into the respective acid addition salt using an acid. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic 23 10 00 - 15 - 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 ^ 5 acid, isonicotinic acid, methanesulfonic or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesu1fonic acid, p-toluenesulfonic acid, naphthalenemonosul fonic and -di sul fonic acids, and laurylsulfuric acid. Salts with physiologically unaccept-""" 10 able acids, for example picrates, can be used for purifying the compounds of the formula I. The compounds of the formula I may possess one or ( more chiral centres. They can therefore be obtained during their preparation as racemates or also, if opti-15 cally active starting materials are used, in optically active form. If the compounds have two or more chiral centres, they may be obtained during synthesis as mixtures of racemates from which the individual racemates can be isolated in pure form, for example by recrystal-20 lizing from inert solvents. Thus, for example, compounds of the formula I in which Rl = R2, R3 = OH and R* = H have two chiral centres; during preparation by reaction of II with III, however, very predominantly only one racemate a having the trans-position of the substituents R3 = OH and 7* 25 R5-Z is formed. Racemates obtained can, if desired, ^ be separated mechanically, chemically or biochemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction Owith an optically active resolving agent. Suitable 30 resolving agents for basic compounds of the formula I are, for example, optically active acids, such as the D-and L-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphanic acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. 35 Carbinols (I, R3 = OH) can in addition be esterified and then resolved with the aid of chiral acylating reagents, for example the cited acids, particularly (+)- or (-)-camphanic acid or (+)- or (-)-camphor-lO-sulfonic acid or with D-or L-<t-methylbenzyl isocyanate (cf. - 16 - 23 10 00 EP-A1-120,428). The different forms of the diastereomers «. can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated in a manner known per se from ^ 5 the diastereomers. Resolution of enantiomers is in J addition carried out by chromatography on optically active support materials. The compounds of the formula I and their physiologically acceptable salts can be used for the production ^ 10 of pharmaceutical preparations, in particular in non-chemical ways. In this connection, they can be brought into a suitable form for administration together with at f least one solid, liquid and/or semi-liquid excipient or auxiliary and, if desired, in combination with one or 15 more further active compound(s). The invention in addition relates to agents, in particular pharmaceutical preparations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts. 20 These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical ad-ministration and which do not react with the novel 25 compounds, for example water, vegetable oils, benzyl f alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs or O 30 drops are used in particular for oral administration, suppositories are used in particular for rectal administration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used in particular for parenteral administration, and 35 ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, FA(D LOG 1G 971000' 23 1000 - 17 - dimethylacetamide, 1,2-propanediol or their mixtures with each other and/or with water) or powders are used in particular for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained 5 used, for example, for the production of injection preparations. Liposomal preparations are in particular also suitable for topical application. The preparations mentioned can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, • ' 10 stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colourants and flavourings and/or aromatizers. They can, C if desired, also contain one or more further active compounds, for example one or more vitamins. 15 The compounds of the formula I and their physio logically acceptable salts can be administered to humans or animals, in particular mammals such as apes, dogs, cats, rats or mice and can be used in the therapeutic treatment of the human or animal body and also in the 20 control of diseases, in particular in the therapy and/or prophylaxis of disturbances of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, arrhythmia, peripheral or cerebral vessel disorders, and disease conditions which are connected 25 with high blood pressure, and in addition disorders which are connected with changes in the non-vascular musculature, for example asthma or urinary incontinence. In this connection, the substances according to the invention are usually administered analogously to 30 known antianginals or hypotensives, for example nicoran-dil or cromakalim, preferably in doses between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dose unit. The daily dose is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg/kg of 35 body weight. The specific dose for each particular patient depends, however, on a variety of factors, for example on the efficacy of the specific compound 18 - 23 1000 employed, on the age, body weight, the general state of health, sex, on the food, on the time and route of administration, on the excretion rate, medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred. The compounds of the formula I and their salts are in adclition suitable, in particular on topical application, for the treatment of alopecia areata. For this purpose, in particular, pharmaceutical preparations are used which are suitable for the topical treatment of the scalp and which are mentioned above. They contain about 0.005 to 10, preferably 0.5 to 3, % by weight of at least one compound of the formula I and/or at least one of its salts. Otherwise, these compounds can be used against alopecia in analogy to the statements in WO 88/00822. In the following examples "customary working up" means: water is added, if necessary; the mixture is extracted using an organic solvent such as ethyl acetate, the organic phase is separated off, dried over sodium sulfate, filtered and evaporated, and the residue is purified by chromatography and/or crystallization. All temperatures indicated above and below are in •C. C<C1 = C&J™ in methanol, c = 1. Example 1 A mixture of 20.1 g of 2,2-dimethyl-S^-epoxy-S-cyanochroman ("Ila"), 14 g of 2-hydroxypyridine (1H-2-pyridone), 7 ml of pyridine and 70 ml of ethanol is boiled for 2 hours. The mixture is cooled, the precipitate is filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel. Using diethyl ether/ethyl acetate (1:1), 2,2-dimethyl-4-(2-pyridyloxy)-6-cyano-3-chromanol is obtained, m.p. 102-103°. - 19 - 231000 The following are obtained analogously (boiling tines up to 15 hours): 2,2,3-Trimethyl-4-(2-pyridyloxy)-6-cyano-3-chromanol,m.p.105-1 2,2-Tetramethylene-4-(2-pyridyloxy)-6-cyano-3-chromanol m.p. 126-127° 2 , 2-Pentamethylene-4- (2-pyridyloxy) - 6 -cyano - 3 -c hromano 1, m.p. 108-110° 2,2-Dimethyl-4-(2-pyridyloxy)-6-nitro-3-chromanol 2,2-Dimethyl-4-(2-pyridyloxy)-6-bromo-3-chromanol 2 , 2-Dimethyl-4- ( 2-pyridyloxy) -6-methoxycarbonyl-3-chromanol 2,2-Dimethyl-4-(3-pyridyloxy)-6-cyano-3-chromanol, m.p. 202-204° 2,2,3-Trimethyl-4-(3-pyridyloxy)-6-cyano-3-chromanol 2 , 2-Dimethyl-4- (4-pyridyloxy) -6-cyano-3-chromanol, m.p. 193-196° 2,2, 3-Trimethyl-4- (4-pyridyloxy) -6-cyano-3-chromanol 2,2-Dimethyl-4-(3-pyridaziny loxy)-6-cyano-3-chromanol 2,2,3-Trimethyl-4- (3-pyridazinyloxy) -6-cyano-3-chromanol 2,2-Dimethyl-4- (4-pyrimidinyloxy) -6-cyano-3-chromanol, m.p. 93-105° 2,2, 3-Trimethyl-4- (4 -pyr imidiny loxy) -6-cyano-3-chromanol 2,2, Dimethyl-4-(2-pyrazinyloxy) -6 -cyano-3-chromanol, m.p. 103-105° 2,2,3-Trimethyl-4-(2-pyrazinyloxy)-6-cyano-3-chromanol. Example 2 A mixture of 20.1 g of Ila, 11.1 g of 2,4-di-hydroxypyridine,8 ml of pyridine and 400 mJ of ethanol is boiled for 15 hours. The mixture is evaporated, the residue is extracted with ethyl acetate, the organic phase is washed with dilute hydrochloric acid and then with water, dried and evaporated, and 2,2-dimethyl-4- (2-hydro xy-4-pyr idy loxy) -6-cyano-3-chromanol ("A") is obtained, m.p. 249-249.5° (from ethanol). -jo - 231000 The following are obtained analogously us ing 2,4-dihydroxypyridine: 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy) -6-cyano-3-chromanol, m.p. 198-200° 5 2,2-Tetramethylene-4-(2-hydroxy-4-pyridyloxy) -6-cyano-3-chromanol 2 ,2-Pentamethylene-4-( 2-hydroxy-4 -pyridyloxy) -6-cyano-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy) -6-nitro-3-10 chromanol, ( m.p. 224-226° 2,2, 3-Trimethyl-4- (2-hydroxy-4-pyr idyloxy) -6 -nitro-3-chromanol 2 , 2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-bromo-3-15 chromanol 2,2, 3-Trimethyl-4-(2-hydroxy-4-pyridyloxy) -6-bromo-3-chromanol 2,2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-methoxy-carbonyl-3-chromanol, m.p. 251-252° 20 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy) -6-methoxy-carbonyl-3-chromanol; o © ( us ing 2,3-dihydroxypyridine: 2 ,2-Dimethyl-4- (2-hydroxy-3-pyridyloxy)-6-cyano-3-chromanol, m.p. 262-265°; 25 2,2,3-Trimethyl-4-(2-hydroxy-3-pyridyloxy) -6 -cyano-3-chromanol; using 2,5-dihydroxypyridine: 2 , 2-Dimethyl-4- (2-hydroxy-5-pyridyloxy) -6-cyano-3-chromanol, m.p. 256-258°; 30 2,2,3-Triraethyl-4-(2-hydroxy-5-pyridyloxy) -6-cyano-3-chromanol; FAT LOG It Q71889 2 - 21 - 3 1000 o ( using 4,6 dihydroxypyr imidine 1 2/2-Dimethyl-4-(6-hydroxy-4-pyrimidinyloxy)-6-cyano-3- chromanol, m.p. 235-237° 2,2,3-Trimethyl-4- (6-hydroxy-4-pyrimidinyloxy) -6-cyano-5 3-chromanol; us ing 3,6-dihydroxypyridaz ine: 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol ("B"), m.p. 255-256° 2,2,3-Trimethyl-4- (6-hydroxy-3-pyridazinyloxy) - 6-cyano-10 3-chromanol, m.p. 236-239° ( 2,2-Tetramethylene-4- (6-hydroxy-3-pyridazinyloxy) -6- cyano-3-chromanol 2,2-Pentamethylene-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol, no m.p. up to 275° .15 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-nitro-3-chromanol, no m.p. up to 260° 2,2,3-Trimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-nitro-3-chromanol, m.p. 223-225° 2,2-Dimethyl-4-(6-hydroxy-3-pyridaz iny loxy)-6-bromo-3-20 chromanol, m.p. 257-259° 2,2,3-Trimethyl-4- (6-hydroxy-3-pyridazinyloxy) - 6-bromo-3-chromanol 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-methoxy-carbonyl-3-chromanol, m.p. 242° 25 2,2,3-Trimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-methoxy-carbonyl-3-chromanol. Example 3 A mixture of 20.1 g of Ila, 11.1 g of 2-mercapto-pyridine, 6.6 ml of pyridine and 265 ml of ethanol is 30 boiled for 3 hours. The mixture is concentrated and the 2 ,2-dimethyl-4- ( 2-pyridylthio) -6-cyano-3-chromanol obtained is crystallized from diisopropyl ether, m.p. 101-103°. PUT LOO 10 071000 - 22 - 23 1 0 0 0 The following are obtained analogously: 2,2,3-Trimethyl-4-(2-pyridylthio) -6-cyano-3-chromanol 2,2-Dimethyl-4-(3-pyridylthio)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-( 3-pyridylthio) -6-cyano-3-chromanol 5 2,2-Dimethyl-4-(4-pyridyl thio) -6-cyano-3-chromanol 2,2,3-Trimethyl-4-(4-pyridylthio) -6-cyano-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3-10 chromanol 2,2-Dimethyl-4-( 6-hydroxy-3-pyridazinylthio)-6-cyano-3-chromanol 2,2, 3-Trimethyl-4 - (6 -hydroxy- 3 -pyr idaz inyl thio) -6-cyano-3-chromanol 15 2,2-Dimethyl-4-(6-mercapto-3-pyridazinylthio)-6-cyano-3-chromanol 2,2,3-Trimethyl-4 - (6-mercapto-3-pyr idaz inyl thio) -6-cyano-3-chromanol. Example 4 20 A mixture of 2 g of Ila, 1.11 g of 2-mercapto- pyridine, 60 ml of DMSO and 0.3 g of NaH (80 % strength) is stirred for 6 hours at 20° and worked up as customary. (3 2,2-Dimethyl-4- (2-pyridylthio) -6-cyano-3-chromene, m.p. 110-112° is obtained. 25 The following are obtained analogously: 2,2,3-Trimethyl-4- (3-pyridylthio) -6-cyano-3-chromene 2,2-Dimethyl-4- (3-pyridylthio) -6-cyano-3-chromene 2,2,3-Trimethyl-4- (3-pyridylthio) -6-cyano-3-chromene 2,2-Dimethyl-4-(4-pyridylthio)-6-cyano-3-chromene 30 2,2,3-Trimethyl-4-(4-pyridylthio)-6-cyano-3-chromene 2,2-Dimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3-chromene 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3- PAtt LOG 1G 071000 o - 23 - n •» _ 23 1 0 chromene 2,2-Dimethy1-4-(6-hydroxy-3-pyridazinylthio) -6-cyano-3-chromene 2,2,3-Trimethyl-4- (6-hydroxy-3-pyridazinylthio) -6-cyano-5 3-chromene 2 , 2-Dimethyl-4-(6-mercapto-3-pyridazinylthio) -6-cyano-3-chromene 2,2,3-Trimethyl-4-( 6-mercapto-3-pyridazinylthio)-6-cyano-3-chromene. 10 Example 5 2,2-Dimethyl-4- (3-hydroxy-2-pyridylamino) -6-cyano-3-chromanol, m.p. 207-208.5°, is obtained from Ila and 2-amino-3-hydroxypyridine analogously to Example 1. The following are obtained analogously: 15 2,2, 3-Trimethyl-4- {3-hydroxy-2 -pyridyl amino) -6-cyano-3-chromanol 2 , 2-Dimethyl-4-(2 -hydroxy- 4 -pyr imidinylamino) -6-cyano-3-chromanol, no m.p. up to 280° 2,2, 3 -Tr imet hy 1 - 4 - (2 -hydroxy- 4 -pyr imidinylamino) - 6-cyano-20 3-chromanol 2 ,2-Dimethyl-4-(2-hydroxy-4-pyridylamino)-6-cyano-3-chromanol 2,2, 3-Trimethyl-4-(2-hydroxy-4-pyr idylamino) -6-cyano-3-chromanol 25 2,2-Dimethyl-4-(2-hydroxy-4-pyridylamino)-6-nitro-3-chromanol 2,2, 3-Trimethyl-4- (2-hydroxy-4-pyridylamino)-6-nitro-3-chromanol 2 , 2-Dimethyl-4-(2-hydroxy-4-pyridylamino) -6-bromo-3-30 chromanol 2,2,3-Trimethyl-4- (2-hydroxy-4-pyridylamino) -6-bromo-3-chromanol 2,2-Dimethyl-4-( 6-hydroxy-3-pyridazinyleunino)-6-cyano-3- - 24 - 2310 00 chromanol 2,2/ 3-Trimethyl-4-( 6-hydroxy-3-pyridazinylami.no) -6 -cyano-3-chromanol 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinylamino) - 6-nitro-3-chromanol 2,2,3-Trimethyl-4- ( 6-hydroxy-3-pyridazinylamino) -6-nitro-3-chromanol' 2 , 2-Dimethyl-4-(6-hydroxy-3-pyridazinylamino) -6-bromo-3-chromanol 2,2,3-Trimethyl-4~( 6-hydroxy-3-pyridazinylamino)-6-bromo-3-chromanol. The following are obtained analogously from 1,6-dihydro-3-amino-1-methyl-6-pyridazinone; 2 , 2-Dime thy 1-4-(1, 6-dihydro-6-oxo-3-pyridazinylamino) -6-cyano- 3 -chromanol 2,2,3-Trimethyl-4-( 1,6-dihydro-6-oxo-3-pyridazinylami.no) -6-cyano-3-chromanol 2,2-Dimethyl-4- (1,6-dihydro-6-oxo-3-pyridazinylamino) -6-nitro-3-chromanol 2,2,3-Trimethyl-4- (1,6-dihydro-6-oxo-3-pyridazinylamino) -6-nitro-3-chromanol 2,2-Dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinylamino)-6-bromo-3-chromanol 2,2,3-Trimethyl-4 - (1,6-dihydro-6-oxo-3-pyridazinylamino) -6 -bromo- 3 -c hromano 1. Example 6 1.2 g of 80 % NaH are added to a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochroman (m.p. 89-92°; obtainable by reduction of 2,2-dimethyl-6-cyano-4-chroma-none with NaBH< in CH30H to give oily 2,2-dimethyl-6-cyano-4-chromanol and reaction with PBr3 in toluene at 20°) and 2.5 g of pyridazine-3,6-diol in 70 ml of DMS0 and the mixture is stirred at 20° for 3 days. After customary working up, 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)- - 25 - 2310 00 6-cyanochroman, m.p. 221-224°, is obtained. The following are obtained analogously: 2,2,3-Trimethyl-4-( 6-hydroxy-3-pyrida zinyloxy) -6-cyano-chroman 2 , 2-Dimethyl-4-( 6-hydroxy-3-pyridazinyloxy)-6-bromo-chroman 2,2, 3-Trimethyl-4- (6 -hydroxy- 3 -pyr idaz iny loxy) -6-bromo-chroman 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-nitro-chroman 2,2,3-Trimethyl-4- (6-hydroxy-3-pyr idaz inyloxy) -6-nitro-chroman 2 , 2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-cyanochroman 2,2,3-Trimethyl-4- (2 -hydro xy- 4 -pyridyloxy) -6-cyanochroman 2 , 2-Dime thy 1-4-(2-hydroxy-4-pyridyloxy) -6-bromochroman 2,2,3-Trimethyl-4 - (2-hydroxy-4-pyridyloxy) -6-bromochroman 2 , 2-Dimethyl-4- (2 -hydroxy- 4 -pyr idyl oxy) -6-nitrochroman 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-nitro-chroman. Example 7 A mixture of 10 g of 2,2-dimethyl-4-( 2-pyridylthio )-6-cyano-3-chromanol, 3 g of sodium hydroxide and 350 ml of dioxane is boiled for 20 minutes. The mixture is cooled and filtered, the filtrate is evaporated and 2 , 2-dimethyl-4-( 2-pyridylthio) -6-cyano-3-chromene, m.p. 110-112°, is obtained. Example 6 A mixture of 2 g of "B", 11.7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to stand at 20° for 16 hours and then wanned to 40-42° for 2 hours. After evaporating and customary working up, 2,2-dimethyl-3- - 26 - 2 3 10 0 0 formyloxy-4- (6-hydroxy-3-pyridazinyloxy) -6-cyanochroman is obtained. The following are obtained analogously from the corresponding 3-hydroxychromans: 2,2,3-Trittethyl-3-formyloxy-4-(6-hydroxy-3-pyrid-azinyloxy) -6-cyanochroman 2 # 2-Dimethyl-3-forrayloxy-4-(2-hydroxy-4-pyridyloxy)-6-cyanochroman 2,2,3-Trimethyl-3-f ormyloxy-4- ( 2-hydroxy- 4 -pyridyloxy) -6-cyanochroman. Example 9 A mixture of 1 g of "B" and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled, worked up as customary and 2,2-dimethyl-3-acetoxy-4-(6-hydroxy-3-pyr idaz inyloxy)-6-cyanochroman is obtained,m.p.210-212° The following are obtained analogously: 2,2,3-Trixnethyl-3-acetoxy-4-(6-hydroxy-3-pyridazinyloxy) -6 -cyanochroman 2,2-Dimethyl-3-acetoxy-4-(2-hydroxy-4-pyridyloxy)-6-cyanochroman 2,2,3-Trimethyl-3-acetoxy-4- (2-hydroxy-4-pyridyloxy) -6-cyanochroman. Example 10 A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy )-6-nitro-3-chromanol in 25 ml of methanol is hydrogenated at 20° and 1 bar on 0.5 g of 5 % Pd-C to completion. The mixture is filtered, evaporated and 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-amino-3-chromanol is obtained. The following are obtained analogously: 23 1000 2,2,3-Trimethyl-4-( 2-hydroxy-4-pyridyloxy) -6-amino-3-chromanol 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-amino-3-chromanol 2,2,3-Tr imethyl-4- (6-hydroxy-3-pyridazinyloxy)-6-amino- 3-chromanol. Example 11 A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy- 4-pyridyloxy)-6-amino-3-chromanol in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. After customary working up, 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formamido-3-chromanol is obtained. Example 12 A mixture of 1 g of 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxyJ-e-amino-S-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° for 16 hours. The mixture is evaporated, purified chromatograph-ically and 2,2-dimethyl-4-( 2-hydroxy-4-pyridyloxy) -6-acetamido-3-chromanol is obtained. Example 13 HC1 is introduced with stirring for 14 hours into a boiling solution of 1 g of "B" in 50 ml of methanol and 2 ml of water. The mixture is allowed to cool and stand overnight. The 2,2-dimethyl-4 - (6-hydroxy-3-pyr idaz inyloxy) -3-chromanol-6-carboxylic acid deposited is filtered off. Example 14 A mixture of 3.13 g of "BM, 31 g of Na3P0*.12 H20, 28 ml of pyridine, 28 ml of water, 67 ml of acetic acid and 25 g of Raney Ni (water-moist) is stirred at 20° for '3 hours. After filtering, the mixture is worked up as customary and 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-formyl-3-chroiBanol, m.p. 256-257°, is obtained. - 28 - The following are obtained analogously: 23 10 00 2,2,3-Tr imethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-formyl-3-chromanol d) 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formyl-3- 5 chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formyl-3-chromanol. Q Example 15 3.13 g of "B" are dissolved in 40 ml of tert.-10 butanol and 5.6 g of powdered KOH are added with stirr-( ing. After boiling for 1 hour and customary working up, 2,2-dimethyl-4-( 6-hydroxy-3-pyridaz inyloxy) -6-carbamoyl-3-chromanol is obtained. The following are obtained analogously: 15 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-carbamoyl-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy) -6-carbamoyl-3-chromanol 2,2, 3-Trimethyl-4-( 2-hydroxy-4-pyridyloxy) -6 -carbamoyl -^ 20 3-chromanol. / Example 16 H2S is introduced at 20° for 5 hours into a solution of 3.12 g of "A" in a mixture of 20 ml of pyridine and 10 ml of triethylamine, the mixture is 25 evaporated and worked up as customary, and 2,2-dimethyl-4 - (2 -hydroxy-4-pyridyloxy) - 6 -1 hiocarbamoy 1 - 3 -c hromano 1, m.p. 242°, is obtained. The following are obtained analogously: 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-thiocarb-30 amoylchroman-3-ol. * ffftB fcOG 16 07109ft - 29 - 23 10 00 2 , 2-Dimethyl -4 - (6 -hydroxy- 3 -pyr idaz inyloxy) -6-thio-carbamoyl-3-chromanol, m.p. 142-144° 2,2,3-Trimethyl-4-( 6-hydroxy-3-pyridazinyloxy) -6-thio-carbamoyl-3-chromanol. Example 17 A mixture of 310 mg o£ "B", 808 mg of Lawesson reagent and 50 ml of toluene is boiled under N2 for 1 hour. Customary working up gives 2,2-dimethyl-4-(6-mercapto-3-pyridazinyloxy) -6-cyano-3-chromanol [2,2-dimethyl-4-(1, 6-dihydro-6-thioxo-3-pyridazinyloxy)-6-cyano-3-chromanol]. 2,2-Dimethyl-4- (2-mercapto-4-pyridyloxy) -6-cyano-3-chromanol is obtained analogously from "A". The following are obtained analogously: 2,2,3-Trimethyl-4- (6-mercapto-3-pyridazinyloxy) - 6-cyano-3-chromanol 2,2-Dimethyl-4-(6-mercapto-3-pyridazinyloxy) - 6-nitro-3-chromanol 2,2,3-Trimethyl-4- (6-mercapto-3-pyridazinyloxy) -6-nitro-3-chromanol 2,2-Dimethyl-4- (6-mercapto-3-pyridazinyloxy) - 6-bromo-3-chromanol 2,2,3-Trimethyl-4- (6-mercapto-3-pyridazinyloxy) -6-bromo-3-chromanol 2,2, 3-Tr imethyl-4- ( 2-mercapto-4-pyridyloxy)-6-cyano-3-chromanol 2,2-Dimethyl-4-( 2-mercapto-4-pyridyloxy) -6-nitro-3-chromanol 2,2,3-Tr imethyl-4- ( 2-mercapto-4-pyridyloxy) -6-nitro-3-chromanol 2 ,2-Dimethyl-4- ( 2-mercapto-4-pyridyloxy) -6-nitro-3-chromanol 2,2,3-Tr imethyl-4-(2-mercapto-4-pyridyloxy) -6-nitro-3- c (O - 30 - chromanol. 23 10 00 Example 18 A mixture of 312 mg of "A", 20 ml of acetone, 400 mg of I^COs and 0.2 ml of dimethyl sulfate is boiled 5 for 2 hours. The mixture is filtered, evaporated and chromatographed on silica gel. Using ethyl acetate/metha-nol (9 s 1), 2,2-dimethyl-4-(1,2-dihydro-l-methyl-2-oxo-4-pyridyloxy)-6-cyano-3-chromanol, m.p. 202-203°, is obtained. O 10 The following are obtained analogously: 2,2,3-Tr imethyl-4-(1,2-dihydro-l-methyl-2-oxo-4-pyridyl-oxy) - 6 - cyano -3-chromanol 2,2-Dimethyl-4-( 1, 6 -dihydro-1 -methyl - 6 -oxo- 3-pyr idaz inyl -oxy)-6-cyano-3-chromanol, m.p. 206-208° 15 2,2,3-Trimethyl-4-( l,6-dihydro-l-methyl-6-oxo-3-pyri-dazinyloxy)-6-cyano-3-chromanol, m.p. 197-199° 2,2-Dimethyl-4-( 1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl-oxy) - 6 -nitro- 3 -c hromano 1 2,2,3-Tr imethyl-4-(l,6-dihydro-l-methyl-6-oxo-3-pyri-20 dazinyloxy)-6-nitro-3-chromanol 2,2-Dimethyl-4- (1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl-oxy) - 6 -bromo - 3 -chr omano 1 2,2,3-Triethyl-4-( l,6-dihydro-l-methyl-6-oxo-3-pyri-daz inyloxy) -6 -bromo-3-chromanol 25 2,2-Dimethyl-4-( 1,2-dihydro-l-ethyl-2-oxo-4-pyridyloxy) -6-cyano-3-chromanol 2,2, 3-Tr imethyl-4 - (1,2-dihydro-l-ethyl-2-oxo-4-pyridyl-oxy) -6-cyano-3-chromanol 2,2 -Dimethyl - 4 - (1,2 -dihydro- l-ethyl-6-oxo-3 -pyrida z iny 1 -30 oxy)-6-cyano-3-chromanol, m.p. 164-167° 2,2,3-Trimethyl-4-( 1,2-dihydro-l-ethyl-6-oxo-3-pyri-dazinyloxy)-6-cyano-3-chromanol,m.p. 166-168°. ■PAT LOG 1G 071000 - 31 - 23 10 00 Example 19 A mixture of 313 mg of "B", 1 g of KzC03, 0.65 ml of dimethyl sulfate and 16 ml of DMF is boiled for 3 hours and worked up as customary. 2,2-Dimethyl-4-(6-methoxy-3-pyridazinyloxy)-6-cyano-3-chromanol, m.p. 224-227°, is obtained. The following are obtained analogously: 2 , 2 , 3-Tr imethyl-4- (6 -methoxy- 3 -pyridaz inyloxy) - 6-cyano-3-chromanol 2 , 2-Dimethyl-4 - (2 -methoxy-4-pyridyloxy) -6-cyano-3-chromanol 2,2, 3-Tr imethyl-4- (2-methoxy-4-pyridyloxy) -6-cyano-3-chromanol. Example 20 In analogy to Example 18, 2,2-dimethyl-4-(l,6-dihydro-l-isopropyl-6-oxo-3-pyridazinyloxy)-6-cyan-3-chromanol is obtained from "B" and 2-bromopropane/ m.p. 201-203°. Example 21 a) A mixture of 5 g of "B", 5 g of (+)-campher-10-sulfonic acid chloride and 50 ml of pyridine is warmed to 70° for 5 hours. After working up with dilute hydrochloric acid and ethyl acetate as usual and chromatographic separation on silica gel with mixtures of dichloromethane and ethyl acetate, there are obtained two epimers of "B"-(+)-campher-10-sulfonic acid ester, m.p. 223-224° and m.p. 127-150°, respectively. 32 n b) A mixture of 2 g of the "unpolar" epimer (m.p. 223-224°), 16 g of "sodium hydroxide on carrier" ("Natriumhydroxid auf Trager", E. Merck, catalogue O "Reagenzien, Diagnostica, Chemikalien", 1987/88, 5 page 587, No. 1567) and 80 ml of methanol is stirred for 20 hours at 20°. The mixture is concentrated to dryness and dissolved in water. HC1 is added until pH 8 and the 2,2-dimethyl-4-(l, 6-di-d) hydro-6-oxo-3-pyridazinyloxy)-6-cyan-3-chromene 10 thus obtained (m.p. 226-228°) is filtered off. Working up of the filtrate with hydrochloric acid/ ethyl acetate at pH 4 and chromatography on silica gel with dichloromethane/ethyl acetate/methanol yields (-)-2,2-dimethyl-4-(1,6-dihydro-6-oxo-15 pyridazinyl-oxy)-6-cyan-3-chromanol, m.p. 229°; [a] -168.5°. c) Analogously, (+)-2,2-dimethyl-4-(l,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyain-3-chromanol (m.p. 232-233° [a] +170.0°) is obtained from the "polar" epimer 20 (m.p. 127-150°). Analogously, 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyan-3-chromene (m.p. 263-264°) as well as (-)- and ( + )-2,2-dimethyl-4- (2-hydroxy-4-pyridyl-oxy )-6-cyan-3-chromanol are obtained from "A" via the corresponding 25 (+)-campher-sulfonic acid esters. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 23 10 0 0 - 32a - Analogously* 2,2-dimethyl-4-(i,6-dihydro-1~methy1-6-oxo~3-pyr1daz1ny1-oxy )-6-cyano~3-chromene (m.p.144-146°) as well as (-)-2,2-dimethy1-4R-(1,6-d1hydro-1-methyl~6-oxo-3-pyr1daz1ny1~oxy)-6-cyano-3S-chromanol (m.p.164° ;(aj -165.'°) and (+)-2,2-dlmethyl-4S-(l,6-dihydro-1-methyl-6-oxo"*3~pyr1dazlnyl-oxy)-6-^ cyano-3R-chromanol (m.p. 161-162°; [a] +171.8®) are attained from 2,2- dlmethyl-4-( 1,6-d 1 hydro-1 -methy 1-6-oxo-3-pyr i daz i ny 1 -oxy )-6-cyano-3-chromano 1 via the corresponding (+)~camphersulfonic acid esters. Ana1ogous1y> 2,2,3-trimethyl-4-(1,6-d1hydro-6-oxo-3-pyr1dazinyl-oxy)-6-cyano-^ 3-chromene as well as (-)-2,2,3-trimethy1-4-(1,6-d1hydro-6-oxo-3-pyrldazinyl~ oxy)-6-cyan»-3~chromanol (m.p. 131-134°; [a] -222.2°) and <+)-2,2,3-trin«thyl-4-(1,$-dihydro-6~oxo-3-pyr1d«zinyl-oxy)-6-cyano-3-chronianol (m.p.131-134°; r- ta] +222.2°) are obtained from the racemic chromanol. The examples below relate to pharmaceutical preparations which contain compounds of the formula I or their physiologically acceptable salts: Example a Tablets A mixture of 1 g of 2,2-dimethy1~4-(1,6-dihydro-l-methyl-$-oxo-3-pyr1daz1nyl-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 is pressed to give tablets In a customary manner, in such a way that each tablet contains 0.1 mg of active compound. /--N Example B Coated tablets Tablets are pressed analogously to Example A, and are subsequently coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colourant. Hard gelatin capsules are filled in a customary manner using 1 kg of 2,2,3~tr1m«thyl-4-(6-hydroxy-3-pyrldaz1nyl-oxy)-6~cyano-3-chromano1 so that each capsule contains 0.5 mg of active compound. Example 0 Ampoules A solution of 10 g of 2,2-dimethyl-4-(6-hydroxy-3~pyridazlnyl-oxy)-6-cya«o-3-chromano1 1n 70 1 of 1,2-propanediol 1s filled up to 100 1 with twice-distilled water, filtered under sterile conditions and filled into ampoules which are closed under sterile conditions. Each ampoule contains 0,1 mg of iictlve agent. - 33 - what //WE clatm is- 1. Chroman derivatives of the formula 1 in which Rl R2 and Ra is A, are each H or A, or r1 and rz together are an alkylene having 3-6 C atoms. or r3 and r4 R6 and R7 is H, OH, OA or QAc, is H, together are a bond, is a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl or oxodihydropyra zinyl radical which is unsubstituted, monosubstituted or disubstituted by A, F, CI, Br, I, OH, OA, OAc, SH, N02, NH2, AcNH, HOOC and/or AOOC, are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, N02, NH2, NHA, NAj, CN, F, CI, Br, I, CF3, ASO, AS02, AO-SO, A0-S02/ AcNH, AO-CO-NH, H2NSO, HANSO, AjNSO, H2NS02, HANS02, A^NSOz, H2NCO, HANCO, AaNCO, H2NCS, HANCS, AgNCS, ASONH, AS02NH, AOSONH, A0S02NH, ACO-allcyl, ni t r <^lkyl7~e vano-alkyl, A-C( =NOH) or A-C (=NNH2), Z is O, S, or NH, f tmp lqq is ofiaee ' - 34 - 23 1000 A is alkyl having 1-6 C atoms, alkyl is alkylene having 1-6 C atoms and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms and their salts. 2. a) 2 , 2-Dimethyl-4-( 2-hydroxy-4-pyridyloxy) - 6-cyano-3-chromanol; b) 2,2, 3-Trimethyl-4- (2-hydroxy-4-pyridyl -oxy)-6-cyano-3-chromanol; c) 2 , 2-Dimethyl-4 - (6 -hydroxy-3-pyr idaz inyloxy) -6-cyano-3-chromano1; d) 2,2,3-Trimethyl-4-(6-hydroxy-3-pyri-dazinyloxy)-6-cyano-3-chromanol; e) 2,2-Dimethyl-4-( 1,6-dihydro-l-methyl-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromanol; f) 2,2, 3-Tr imethyl-4 - (1,6-dihydro-l-methyl-6 -oxo- 3 -pyridaz inyloxy) -6 -cyano-3-chroman-ol. 3. Process for the preparation of chroman derivatives of the formula I according to Claim 1, characterized in that a chroman of the formula II II in which O X-Y is -CH-CR3- or -CHE- CR3Ra - and E is CI, Br, I or a reactively esterified OH group and R1, R2, R3, R6, R7 and R8 have the meanings given in formula I is reacted with a compound of the formula III R5—ZH III in which R5 and Z have the meanings indicated in formula - 35 - 231000 i, or with one of its reactive derivatives and/or in that a compound of the formula I in which R3 is OH and R* is H, is dehydrated and/or in that one or more of the radicals R3, Rs, R6 and/or R7 are converted into other radicals R3, R3, R8 and/or R7 in a compound of the formula I and/or in that a basic compound of the formula I is converted into one of its acid addition salts by treating with an acid. preparations, characterized in that a compound of the formula I according to claim 1 and/or one of its physiologically acceptable salts is brought into a suitable form for admin istration together with at least one solid, liquid or semi-liquid excipient or auxiliary and, if desired, in combination with one or more further active compound(s). 5. Pharmaceutical preparation which contains at least one compound of the formula I according to claim 1 and/or one of its physiologically acceptable salts. 6. Compounds of die formula I according to claim 1 for die control of diseases. 7. use of compounds of the formula I according to claim 1 for the production of a medicament. 8. Use of compounds of th$ formula I according to claim 1 in the control of diseases in non-human animals. 9. A compound according to claim 1 substantially as herein described or exemplified. 10. A process according to claim 3 substantially as herein described or exemplified. described or exemplified. 12. A pharmaceutical preparation according to claim 5 substantially as herein described or exemplified. 13. (-)-2,2-Dimethy l-4R-( 1,6-dihydro-l -methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3S-chromanol. 4. Process for the production of pharmaceutical 11. A process according to claim '4 substantially as herein Reference has been directed, in pursuance of section 14 of the Patents Act 1953, to specification No.228991. K B POPPLEWELL ' Assistant Commissioner of Patents </div>