CA2022693A1 - Chroman derivatives - Google Patents

Abstract

Abstract The invention relates to novel chroman deriva-tives of the formula I

(I)

Description

2022~93 .- Merck Patent Gesellschaft : mit beschrankter Haftung ~ ` ~ 6100 D a r m s t a d t Chroman derivatives The invention relate~ to novel chroman deriv-atives of the formula I

:- R7~CH 2R2 ..,. ~
in which ~- R1 is H or A, R2 is F, C1, Br, I, OH, OA,.OAc, SA, NO2, NH2, NHA, i 10 NA2, CN or COOA, , R3 is H, OH, OA or OAc, .. . R4 is H, R3 and R4 together are also a bond, ; ~j; R5 is a pyridyl, pyridazinyl, pyrimidinyl, pyra-zinyl, oxodihydropyridyl, oxodihydropyrida-zinyl, oxodihydropyrimidinyl, oxodihydropyra-~ zinyl, 2-pyrrolidinon-1-yl or 3-oxocyclopenten-;~ ~ l-yl radical which i8 unsubstituted, monosub-stituted or disubstituted by A, P, Cl, Br, I, OH, OA, OAc, SH, NO2, NH2, NHAc, COOH and/or COOA, i, R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, : AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl, mer-captoalkyl, NO2, NH2, NHA, NA2, CN, F, Cl, Br, ~ 25 I, CF3, ASO, ASO2, AO-SO, AO-SO2, AcNH, AO-CO-: NH, H2NSO, HANSO, A2NSO, H2NSO2, HANSO2, A2NSO2, H2NCO, HANCO, A2NCO, H2NCS, HANCS, A2NCS, ASONH, ASO2NH, AOSONH, AOSO2NH, ACO-alkyl, nitroalkyl, :.

' 20226~3 cyanoalkyl, A-C(=NOH) or A-C(=NNH2), R8 is H or A, Z is O, S, NH or a bond, A is alkyl having 1-6 C atoms, ~- 5 -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 possess, combined with good tolerability, useful pharma-cological properties. Thus, they show effects on the 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-Al-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, guinea pigs, 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, preferably 1-4, in PAT LOG 16/1 02088g _ ~Q226~3 particular 1, 2 or 3 C atoms, in detail preferably methyl, in addition preferably ethyl, propyl, isopropyl, butyl, isobutyl, and furthermore preferably sec.-butyl, ; tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).
The group ''-alkylll preferably stands for -CH2- or -CH2CH2-.
Ac is preferably alkanoyl having 1-6, in par-ticular 1, 2, 3 or 4 C atoms, in detail preferably formyl 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.
is preferably A, in particular methyl or ethyl, preferably methyl.
R2 is preferably OA, in particular methoxy or ethoxy; furthermore R2 is preferably OH.
If R4 is H, R3 is preferably OH, and in addition preferably O-CHO or O-COCH3.
Z is preferably O or-a bond.
The group R5-Z is preferably 1,2-dihydro-2-oxo-1-pyridyl, furthermore 2-hydroxy-4-pyridyloxy (=1,2-di-hydro-2-oxo-4-pyridyloxy), 6-hydroxy-3-pyridazinyloxy (=1,6-dihydro-6-oxo-3-pyridazinyloxy), 2-,3- or 4-` 25 pyridyloxy, 1,6-dihydro-3-hydroxy-6-pyridazinon-1-yl,1,2-dihydro-4-hydroxy-2-oxo-1-pyridyl, 1,6-dihydro-1-methyl-- 6-oxo-3-pyridazinyloxy, 1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyloxy, 2-pyrrslidinon-1-yl or 3-oxo-1-cyclo-; pentenyloxy.
In R6 and R7, the following are preferably:
A: methyl, and Ln 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;
AO-CS: methoxythiocarbonyl, and in addition ~ ~ - 4 ~ 2 02 2~93 `;
. ethoxythiocarbonyl;
ACOO: acetoxy, and in addition propionoxy;
.. ACSO: thio(no)acetoxy, and in addition thio(no)-propionoxy;
hydroxyalkyl: hydroxymethyl or 1- or 2-hydroxyethyl;
' mercaptoalkyl: mercaptomethyl or 1- or 2-mercaptoethyl;
NHA: methylamino, and in addition ethylamino;
.~ NA2: dimethylamino, and in addition diethyl-amino;
. 10 ASO: methylsulfinyl, and in addition ethyl-sulfinyl;
ASO2: methylsulfonyl, and in addition ethyl-~ sulfonyl;
-~i AO-SO: methoxysulfinyl, and in addition ethoxy-i~ 15 sulfinyl;
-~ i AO-SO2: methoxysulfonyl, and in addition ethoxy-sulfonyl;
Ac-NH: .acetamido, and in addition formamido, propionamido or benzamido;
AO-CO-NH: methoxycarbonylamino, and in addition ethoxycarbonylamino;
~` HANSO: methylaminosulfinyl, and in addition . ~ ethylaminosulfinyl;
A2NSO: dimethylaminosulfinyl, and in addition diethylaminosulfinyl;
HANSO2: methylaminosulfonyl, and in addition ethylaminosulfonyl;
A2NSO2: dimethylaminosulfonyl, and in addition diethylaminosulfonyl;
HANCO: N-methylcarbamoyl, and in addition N-ethylcarbamoyl;
A2NOC: N,N-dimethylcarbamoyl, and in addition N,N-diethylcarbamoyl;
HANCS: . N-methylthiocarbamoyl, and in addition N-ethylthiocarbamoyl;
A2NCS: N,N-dimethylthiocarbamoyl, and in addition N,N-diethylthiocarbamoyl;

~ 5 ~ 2022 6q3 ASONH: methylsulfinylamino, and in addition ; ethylsulfinylamino;
ASO2NH: methylsulfonylamino, and in addition ethylsulfonylamino, AOSONH: methoxysulfinylamino, and in addition ethoxysulfinylamino;
AOSO2NH: methoxysulfonylamino, and in addition ethoxysulfonylamino;
'~ ACO-alkyl: 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl;
Nitroalkyl: ni~romethyl, 1- or 2-nitroethyl;
Cyanoalkyl: cyanomethyl, 1- or 2-cyanoethyl;
A-C(= NOH): l-oximinoethyl, and in addition l-oximino-propyl;
15 A-C(= NNHz): l-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 7-, 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. Thi~ other radical ; is preferably in the 6-position, but also in the 5-, 7-or 8-position, and is preferably CN or NO2, in addition preferably CHO, ACO (in particular acetyl), AOOC (in particular methoxycarbonyl or ethoxycarbonyl), ACOO (in particular acetoxy), and furthermore preferably F, Cl, Br, I, CF3, H2NCO, H2NCS or NH2.
The radical R3 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 Ia to Ii below, which correspond to the formula I and in which the radicals not designated in more detail have the meaning "` 2022693 indicated in the formula I, in which however : in Ia R1 is A and R~ is OA;
in Ib Rl is CH3 and .; 5 R2 is OA;
in Ic R1 is CH3 and R2 is OCH3;
: in Id R5-Z is1,2-dihydro-2-oxo-1-pyridyl,2-hydroxy-. 4-pyridyloxy, 6-hydroxy-3-pyridazinyloxy, 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy, 2-pyrrolidinon-1-yl or 3-oxo-cyclo-penten-l-yl-oxy;
in Ie R5-Z is 2-pyrrolidinon-1-yl;
~ in If R5-Z is 1, 2-dihydro-2-oxo-1-pyridyl;
:; 15 in Ig Rl is CH3, . ~ R2 is OCH3, ` R5-Z is 1,2-dihydro-2-oxo-1-pyridyl,2-hydroxy-: 4-pyridyloxy, 6-hydroxy-3-pyridazinyl-oxy, 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-: 20 oxy, 2-pyrrolidinon-1-yl or 3-oxo-cyclo-penten-l-yl-oxy and Ra is H or CH3;
in Ih R1 is CH3, R2 is OCH3, R5-Z is 2-pyrrolidinon-1-yl and R3 is H or CH3;
: in Ii R1 is CH3, R2 is OCH3, R5-Z is 1, 2-dihydro-2-oxo-1-pyridyl and R3 is H or CH3 .
~ Compounds of the formulae I' and Ia' to Ii' are furthermore preferred which correspond to the formulae I
and Ia to Ii, but in which in each case additionally R3 is H, OH, OCHO or OCOCH3 and R4 is H, in particular those compounds of the formulae I' and Ia' to Ii' in which in ch case additionally R3 is OH and R4 is H.
Compounds of the formulae I" and Ia" to Ii" are ~ 7 - 20226~3 - furthermore preferred which correspond to the formulae I, and Ia to Ii, but in which in each case R3 and R4 together are additionally a bond.
Compounds of the formulae I, I', I", Ia to Ii, 5 Ia' to Ii~ and Ia~ to Ii~ are in addition preferred, in which in each case additionally (a) R8 is different from H and .: R7 is H;
~b) R6 is different from H and is in the 6-position and . R7 is H;
~ (c) R6 iR NO2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF3, H2NCO, H2NCS or NH2 and . R7 is H;
; 15 (d) R6 is NO2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF3, H2NCO, H2NCS or NH2 and is in the 6-position and R7 is H;
. (e) R6 is NO2, CN, CHO, CH3CO, CH300C, C2HsOOC or CH3COO
and R7 is H;
(f) R6 is NO2, CN, CHO, CH3CO, CH300C, C2H500C or CH3COO
and is in the 6-position and R7 is H;
i 25 (g) R is NO2 or CN and :~. R7 is H;
(h) R6 is NO2 or CN and is in the 6-position and R7 is H;
( i ) R6 is CN and R7 is H;
( ~ ) R6 is CN and is in the 6-position and : R7 is H.
: Otherwise, the radicals Rl to R~, Z, 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 ., ~ 8 - 2022~93 formula I, characterized in that a chroman of the formula i II
R ~ ~ CH2R II

in which R7 R
'' `i' 0 : 5 X-Y is -C~-CR8- or -CHE-CR3Ra- and ` i E is Cl, Br, I or a reactively esterified OH group and - R , R , , R , R7 and R3 have the meanings given in formula I, is reacted with a compound of the formula III

:. ~
~ R5-Z-H III

.~ in which R5 and Z have the meanings indicated in the formula I, or in that in order to prepare a compound of the formula I, in which R2 is OH or NH2, a compound otherwise correspond-ing to the formula I, but which carries, instead of R2, a . group -oR3 or -NHR9, in which R9 is a protecting group which can be removed by hydrogenolysis or solvolysis, is treated with a hydrogenolysing or solvolysing agent, ` 20 and/or in that a compound of the formula I, in which R3 is OH and R4 is H, is dehydrated and/or in that in a compound of the formula I, one or more of the radicals R2, R3, R5, R6 and/or R7 are converted into other radicals 1~ R2, R3, R5, R6 and/or R7 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 prepared by methods which are known per se, as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen " - 9 - 2022 693 Chemie ~Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; and in the abovementioned patent applica-tions), 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.
The starting materials may also be formed, if desired, in situ in such a way that they ar~ 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 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 =
O
~CH-CR -(3,4-epoxychromans) are preferred.
; 20 The starting materials 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 known per se. Starting materials of the formula II

X-Y- = -C~-CR8-) are obtainable by reacting 2-hydroxy-acetophenones of the formula 2-Ho-R6R7C6H2-CoCH3 with ketones of the formula R1-CO-CH2R2 to give corresponding 4-chromanones of the formula IVa R6 IVa -X-Y- = -CO-CH2-X IVB -X-Y- = -CO-C(-CH-RlO)-~ O ~ IVc -X-Y- = -CHOH-CHR8-R7 R1 IVd -X-Y- = -CH=CR -IVe -X-Y- = -C~Br-CR8OH-if desired condensing with aldehydes of the formula Rl-CHO (Rl = alkyl having 1-5 C atoms) to give 3-alkyli-dene-4-chromanones of the formula IVb, reducing, for , lO- 20226~3 example with NaBH4, to give chromanols of the formula IVc, dehydrating, for example with p-toluenesu1fonic 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-bromosuccinimide in ; aqueous solution and HBr can subsequently be eliminated from these using a base, for example sodium hydroxide solution.
In compounds of the formula II (-X-Y- =-CHE-CR3R3-), possible 'Ireactively esterified OH groups" are in particular esters with alkylsulfonic acids (in which the alkyl ~roup 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 PCl3, PBr3, SOC12 or SOBr2 or with a sulfonyl chloride such as methanesulfonyl or p-toluenesulfonyl chloride.
During the reaction of II with III it is ex-pedient to work in the presence of a base. Suitable bases ~ are preferably alkali metal alkyls, in particular methyl-- lithium or butyllithium, alkali metal dialkylamides, in particular lithium diisopropylamide, furthermore, for example, hydroxides, carbonates, alkoxides, hydrides and also amides of alkali metals or alkaline earth metals, - such as NaOH, KOH, Ca(OHJ 2, Na2CO3, R2C03, Na methoxide or K methoxide, Na 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 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 (THF) or dioxane;

:.

".

11- 2022~93 glycol 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 acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or hexa-methylphosphoramide; sulfoxides such as dimethyl sul-;~ foxide (DMSO); chlorinated hydrocarbons such as dichloro-methane, chloroform, trichloroethylene, 1,2-dichloro-ethane or carbon tetrachloride; hydrocarbons such as ~~;` benzene, toluene or xylene. Mixtures of these solvents with one another are furthermore suitable.
~,.` O
The epoxide II (X-Y - -CH-CR8- ) can also be prepared in situ, for example by the action of a base on ' the corresponding bromohydrin IVe.
A particularly preferred procedure consists in boiling equivalent amounts of the starting materials of the formulae II and III in an alcohol such as ethanol in the presence of a base such as pyridine for some time.
~, Compounds of the formula I, in which R2 is OH or :' NH2, are preferably prepared by treating a compound other-wise corresponding to the formula I, but which, instead of R2, carries a group -OR9 or -NHR9 in which R9 is a protecting group which can be removed by hydrogenolysis ; or solvolysis, with ahydrogenolysing orsolvolysing agent.
The starting materials are accessible, for example, by reaction of a compound corresponding to II, but which, instead of R2, carries a group -OR9 or -NHR9, with a compound of the formula III.
Suitable protecting groups R9 are the customary hydroxyl or amino protecting groups, such as are used, ~ for example, in preparative organic chemistry, in ;j particular in peptide chemistry. Some characteristic groups for R9 are benzyl, tetrahydropyran-2-yl, tert.-butoxycarbonyl, benzyloxycarbonyl, 2-alkoxyethoxymethyl , ~

, ' ' . , 2022fi~

such as 2-methoxyethoxymethyl ("MEM", which can be removed, for example, with ZnBr2 or TiCl4 in dichloro-methane) or 2-trialkylsilylethoxymethyl such as 2-trimethylsilylethoxymethyl ("SEM", which can be removed, for example, with F-ions).
A compound of the formula I in which R3 = OH and R4 = H can be converted into a compound of the formula I
in which R3 and R4 together are a bond by treating with a dehydrating agent. This is carried out, for example by the action of one of the bases mentioned, for example NaOH or NaH, in one of the solvents mentioned, for example THF, dioxane or DMSO, at temperatures between O
and 150.
Furthermore, one or more of the radicals R2, R3, sl 15 R5, R6 and/or R7 can be converted into other radicals RZ, ` R3, R5, 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 ,~ 20 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 HCl in water/methanol at 20-lO0) 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 H2S in pyridine/triethylamine) into a thio-carbamoyl group and/or to dehydrate a carbamoyl group (for example with POC13) to a cyano group and/or to convert a -CO-NH- group, (for example with PzS5 or with Lawe~son reagent in toluene) into a -CS-NH- or -C(SH)=N-group.
Nitration is carried ou~ under customary condi-tions, for example using a mixture of concentrated HNO3 and concentrated H2SO4 at temperatures between O and 30.
If at least one of the substituents R6 and R7 is an electronegative group such as CN or NO2, the nitration PAT LOG 16/l 020889 ~ 13 - ~2~93 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 sol-vents 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 " 10 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, 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-~H, 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 triethyl-amine, at temperatures between about 0 and about 160,preferably between 20 and 120. Formylation is also carried out using formic acid in the presence of PAT LOG 16~1 020889 - . .

.

- 14 - 20226~
pyridine.
A base of the formula I can be conv rted 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 hetero-cyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, r 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, methanesulfonic or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unaccept-able acids, for example picrates, can be used for purify-- ing 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-cally active starting materials are used, in optically active form. If the compounds have two or more chiral centres, they may be obtained during synthesLs as mix-tures of racemates from which the individual racemates can be isolated in pure form, for example by recrystal-lizing from inert solvents. Thus, for example, compounds of the formula I in which R3 = OH and R4 = H have three chiral centres; during preparation by reaction of II with III, however, very predominantly only two racemates having the trans-position of the R5-Z group and the - 15 - 2~2269~
substituent R3 = OH are formed. Racemates obtained can, if de~ired, be separated mechanically, chemically or bio-chemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate ; 5 by reac~ion with an optically active resolving agent.
~ Suitable 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. Carbinols (I, R3 = OH) can in addition be esterified and then resolved with the aid of chiral acylating reagents, for example D- or L-~-methylbenzyl isocyanate (cf. EP-Al-120,428). The different forms of the diastereomers can be separated in a manner known per `J ~ se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated in a manner known per se from the diastereomers. Resolution of - enantiomers is in addition carried out by chromatography on optically active support materials.
The compounds of the formula I and their physio-logically acceptable salts can be used for the production 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 least one solid, liquid and/or semi-liquid excipient or auxiliary and, if desired, in combination with one or 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.
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 , " ' ' ' - ' ' ' '' ' ~

- 16 - ~022~3 compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, mag-nesium stearate, talc, lanolin or petroleum jelly.
S Tablets, coated tablets, capsules, syrups, elixirs or drops are used in particular for oral administration, - suppositories are used in particular for rectal adminis--- tration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used- in particular for parenteral administration, and ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or their mixtures with each other and/or with water) or powders are u~ed in -~ particular for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. Liposomal preparations-are in particular - 20 also suitable for topical application. The preparations mentioned can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the o~motic pressure, buffer ~ub~tances, ;,.-- 25 colourants, flavourings and/or aromatizers. They can, if desired, also contain` one or more further active com-pounds, for example one or more vitamins.
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 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 .

` "` . 2022~93 with high blood pressure, and in addition disorders which are connected with changes in the non-vascular muscula-ture, for example asthma or urinary incontinence.
In this connection, the substances according to the invention are usually administered analogously to 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 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 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 combin-ation and severity of the particular disease to which the 7' therapy applies. Oral administration is preferred.
; The compounds of the formula I and their salts are in addition 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 sul-fate, filtered and evaporated, and the residue is puri-fied by chromatography and/or crystallization.
All temperatures indicated above and below are '~

- 18 - 2022~93 3 '` in C

Example 1 A mixture of 23.1 g of 2-methoxymethyl-2-methyl-3,4-epoxy-6-cyanochroman, 9.S g of lH-2-pyridone, 12 ml of pyridine and 600 ml of ethanol is boiled for 72 hours.
About 300 ml are removed by distillation, the mixture is cooled and filtered, the solution is evaporated and the residue is worked up in the customary manner. 2-Methoxy-methyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromanol, stereoisomer mixture ("A") is obtained, which ~an be separated into isomer "A1" (CH3 and OH in ~ ~ the cis-position; m.p. 216-218) and isomer ~'A2~ (CH3 and ;~ OH in the trans-position; m.p. 210-212) by chroma-tography (silica gel; ethyl acetate/methanol).
The starting material is obtained as follows:
a) a mixture of 50 g of 3-acetyl-4-hydroxybenzo-~ nitrile, 70 ml of methoxy-2-propanone, 6 ml of sl ~ pyrrolidine and 300 ml of toluene is boiled in a water separator for 3 hours. The mixture is evaporated, the residue is worked up in the customary manner (ethyl : acetate/dil. hydrochloric acid) and 2-methoxymethyl-2-; ~ methyl-6-cyano-4-chromanone is obtained, m.p. 79-81.
b) 7 g of NaBH~ are added in portions wi~h stirring to a solution of 31.4 g of the above chromanone in 600 ml of methanol. The mixture is stirred for a further hour and evaporated, the residue is worked up in the customary manner and 2-methoxymethyl-2-methyl-6-cyano-4-chromanol is obtained, stereoisomer mixture, b.p. 160~/0.133 mbar (air bath temperature, bulb tube).
c) A solution of 13 g of the above chromanol and 0.8 g of p-toluenesulphonic acid in 100 ml of toluene is boiled in a water separator for 3 hours. The mixture is evaporated, the residue i8 dissolved in dichloromethane, the solution is chromatographed on silica gel using petroleum ether/ether and 2-methoxymethyl-2-methyl-6-cyano-3-chromene is obtained, b.p. 135/0.133 mbar (air 19- 2022~93 bath temperature, bulb tube).
d) A solu~ion of 21.1 g of m-chloroperbenzoic acid in 100 ml of dichloromethane is added dropwise with stirring and ice-cooling to a solution of 13 g of the above chromene in 50 ml of dichloromethane. The mixture is stirred at 20 for 3.5 hours, a further solution of 5 g of m-chloroperbenzoic acid in 30 ml of dichloro-methane being added dropwise after 3 hours, washed with dilute sodium hydroxide solution and worked up further in the customary manner.2-methoxymethyl-2-methyl-3,4-epoxy-' 6-cyanochroman is obtained as an isomer mixture which can be separated into two isomers (m.p. 88-90a or oil) by chromatography (silica gel; petroleum ether/ether 4:6).

The following are obtained analogously 2-methoxymethyl-2-methyl-3,4-epoxy-6-bromochroman 2-methoxymethyl-2-methyl-3,4-epoxy-6-nitrochroman 2-methoxymethyl-2-methyl-3,4-epoxy-6-methoxycarbonyl-chroman 2-methoxymethyl-2,3-dimethyl-3,4-epoxy-6-cyanochroman 2-methoxymethyl-2,3-dimethyl-3,4-epoxy-6 bromochroman 2-methoxymethyl-2,3-dimethyl-3,4-epoxy-6-nitrochroman 2-methoxymethyl-2,3-dimethyl-3,4-epoxy-6-methoxycarbonyl-chroman 2-methoxymethyl-2-methyl-3,4-epoxy-6-carbamoylchroman and, from these epoxides with lH-2-pyridone, 4-hydroxy-lH-2-pyridone, 3-hydroxy-1,6-dihydro-3-pyridazinone (=

3,6-pyridazindiol), l-methyl-3-hydroxy-1,6-dihydro-3-pyridazinone, 2-pyrrolidinone or 1,3-cyclopentandione:
, ~
2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-l-pyridyl~-6-bromo-3-chromanol 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-l-pyridyl)-6-nitro-3-chromanol 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-methoxycarbonyl-3-chromanol PAT LOG 16/l 020889 - 20 - 20226~3 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-cyano-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-- oxy)-6-bromo-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-nitro-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-methoxycarbonyl-3-chromanol - 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyrida-zinyloxy)-6-cyano-3-chromanol ~ 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyrida-'~ zinyloxy)-6-bromo-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyrida-: : zinyloxy)-6-nitro-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyrida-zinyloxy)-6-methoxycarbonyl-3-chromanol ;`
2-Methoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-bromo-3-chromanol 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-.. ~ 3-pyridazinyloxy)-6-nitro-3-chromanol ~3 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-methoxycarbonyl-3-chromanol 2-Methoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-cyano-3-chromanol 2-Methoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-bromo-3-chromanol 2-Methoxymethyl-2-methyl-4-~2-oxopyrrolidino)-6-nitro-3-chromanol 2-Methoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-methoxy-carbonyl-3-chromanol 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-- 21 - 2 ~2 2 ~ 9 3 cyano-3-chromanol 2-Methoxymethyl-2-methyl-4-(3-oxo-l-cyclopentenyloxy)-6-bromo-3-chromanol 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-- 5 nitro-3-chromanol 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-: ; methoxycarbonyl-3-chromanol ;
- 2-Methoxymethyl-2,3-dimethyl-4-(1, 2-dihydro-2-oxo-l-pyridyl)-6-cyano-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-/1, 2-dihydro-2-oxo-l-pyridyl) 6-bromo-3-chromanol 2-Methoxymethyl-2,3-dimethyl_4_(1, 2-dihydro-2-oxo-1-pyridyl)-6-nitro-3-chromanol 2-Methoxymeth~1-2,3-dimethyl-4-tl,2 -dihydro-2-oxo-l-pyridyl) 6-methoxycarbonyl-3-chromanol ~'.
~ 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-;~ pyridyloxy)-6-cyano-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-~ pyridyloxy)-6-bromo-3-chromanol .~ : 20 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-pyridyloxy)-6-nitro-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-pyridyloxy)-6-methoxycarbonyl-3-chromanol .
;. 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromanol : 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-bromo-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-nitro-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-methoxycarbonyl-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromanol I - 22 - 20226~3 ` 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-1-methyl-6- oxo-3-pyridazinyloxy)-6-bromo-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-nitro-3-chromanol 2-Methoxymethyl-2~3-dimethyl-4-(l~6-dihydro-l-methyl-6 oxo-3-pyridazinyloxy)-6-methoxycarbonyl-3-chromanol 2-Nethoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-cyano-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-bromo-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-nitro-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-methoxycarbonyl-3-chromanol , `-2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-oxy)-6-cyano-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-oxy)-6-bromo-3-chromanol 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-l-cyclopentenyl-oxy)-6-nitro-3-chromanol ; 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-:. ~ oxy)-6-methoxycarbonyl-1-chromanol 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-l-pyridyl)-6-carbamoyl-3-chromanol.

Example 2 1.2 g of 80~ NaH are added to a solution of 2.96 gof2-methoxymethyl-2-methyl-4-bromo-6-cyanochroman (stereoisomer mixture; obtainable from 2-methoxymethyl-2-methyl-6-cyano-4-chromanol and PBr3 in toluene at 20) and 2 g of lH-2-pyridone in 70 ml of DMSO and the mixture is stirred at 20 for 3 days. Customary working up gives 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-l-pyridyl)-6-cyano-chroman, isomer mixture.

PAT LOG 16/l 020889 :, - 23 - 2 022 ~ 9~
Example 3 A mixture of 10 g of "A", 3 ~ of NaOH and 350 ml of dioxane is boiled for 20 min. The mixture is cooled, filtered, the filtrate is evaporated and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene ("B") is obtained, m.p. 160-162.
The following are obtained analogously by dehy-dration of the corresponding 3-chromanols:

2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-bromo-3-chromene 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-nitro-3-chromene 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-methoxycarbonyl-3-chromene ~, 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-cyano-3-chrome~e 2-~ethoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-bromo-3-chromene ~ 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-!, 20 oxy)-6-nitro-3-chromene 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-methoxycarbonyl-3-chxomene , .
2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromene 25 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-bromo-3-chromene 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-nitro-3-chromene 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromene 2-Nethoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-- 24 - 20226~3 3-pyridazinyloxy)-6-bromo-3-chromene 2-Methoxymethyl-2-methyl-4-(1,5-dihydro-1-methyl-6--oxo-3-pyridazinyloxy)-6-nitro-3-chromene 2-Nethoxymethyl-2-methyl-4-(1,6-dihydro-1-methyl-6-oxo-S 3-pyridazinyloxy)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-cyano-3-chromene -` 2-Nethoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-bromo-3-chromene 2-Methoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-nitro-3-chromene - 2-Methoxymethyl-2-methyl-4-(2-oxopyrrolidino)-6-methoxy-car~onyl-3-chromene 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-,: lS cyano-3-chromene 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-.; bromo-3-chromene 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-. nitro-3-chromene ; 20 2-Methoxymethyl-2-methyl-4-(3-oxo-1-cyclopentenyloxy)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1, 2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1, 2-dihydro-2-oxo-1-pyridyl)-6-bromo-3-chromene , 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-. 6-nitro-3-chromene 2-Methoxyliethyl-2,3-dimethyl-4-(1, 2-dihydro-2-oxo-1-pyridyl)-6-methoxycarbonyl 3-chromene .~ 30 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-pyridyloxy)-6-cyano-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-pyridyloxy)-6-bromo-3-chromene - 25 - ~0~2 6g3 2-Nethoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-pyridyloxy)-6-nitro-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,2-dihydro-2-oxo-4-pyridyloxy)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-bromo-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-nitro-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-bromo-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-nitro-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy)-6-methoxycarbonyl-3-chromene .

2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-cyano-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-bromo-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-nitro-3-chromene : 2-Methoxymethyl-2,3-dimethyl-4-(2-oxopyrrolidino)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-oxy)-6-cyano-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-oxy)-6-bromo-3-chromene 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-, - 26 -oxy)-6-nitro-3-chromene 2 0 2 2 6 9 3 2-Methoxymethyl-2,3-dimethyl-4-(3-oxo-1-cyclopentenyl-oxy)-6-methoxycarbonyl-3-chromene 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoyl-3-chromene.

Example 4 , A mixture of 1 g of 2-methyl-2-(2-tetrahydro-pyranyloxymethyl)-4-(1,2-dihydro-2~oxo-1-pyridyl)-6-cyano-3-chroman [obtainable from 1-(2-tetrahydropyranyl)-2-propanone via 2-methyl-2-(2-tetrahydropyranyloxy-methyl)-6-cyano-4-chromanone, 2-methyl-2-(2-tetrahydro-pyranyloxymethyl)-6-cyano-4-chromanol, 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-3-chromene and the corresponding 3,4-epoxide] and 15 ml of 10% methanolic i I5 HCl solution is boiled for lS min. Cooling and customary workingup gives 2-hydroxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene.

; Example 5 A solution of 1 g of 2-benzyloxycarbonylamino-methyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene tobtainable from 1-benzyloxycarbonylamino-2-propanone ("l-CBZ-2-propanone") via 2-CBZ-aminomethyl-2-methyl-6-cyano-4-chromanone, the corresponding 4-chromanol, the corresponding 3-chromene and the cor-responding 3,4-epoxide] in 20 ml of dioxane is hydro-genated on 0.5 g of 5% Pd-carbon at 20 and 1 bar until the calculated amount of H2 has been absorbed. The mixture is filtered, the solution is evaporated and 2-amino-methyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene is obtained.

Example 6 A mixture of 2 g of "A", 11. 7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to ~tand at 20 for 16 hours and subsequently warmed to 40 for 1 hour.

:. :

_ 27 - 202~6~3 Evaporation and customary working up gives 2-methoxy-methyl-2-methyl-3-formyloxy-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyanochroman, an isomer mixture which can be separated by chromatography.

Example 7 A mixture of 1 g of ~A~ and 5 ml of acetic anhydride is boiled for 1 hour. The mixture i8 cooled, worked up in the customary manner and 2-methoxymethyl-2-methyl-3-acetoxy-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyanochroman, an isomer mixture which can be separatedby chromatography, is obtained.
Example 8 A solution of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-nitro-3-chromanol in 25 ml of methanol is hydrogenated at 20 and 1 bar on 0.5 g of 5% Pd-C until hydrogenation stops. The mixture is filtered, the filtrate is evaporated and 2-methoxy-methyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol, an isomer mixture which can be separated by chromatography, is obtained.
Example 9 A solution of 4 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carb~moyl~3-chromene is hydrogenated on 4 g of 20% Pd-C at 20 and 1 bar in 200 ml of methanol, the mixture is filtered, the filtrate is evaporated and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoylchroman is obtained, m.p. 177-179.
Example 10 A solution of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol in 15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. Customary working up gives 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-formamido-3-chromanol.

- 28 - 2 022 6 ~ 3 Example 11 A mixture of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20 for 24 hours. The mixture is evaporated, worked up in the customary manner and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-acetamido-3-chromanol is obtained.
Example 12 HCl is passed into a boiling solution of 1 g of "B~ in 50 ml of methanol and 2 ml of water with stirring for 12 hours. The mixture is allowed to cool and to stand overnight. The precipitated 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-3-chromene-6-carboxylic acid is filtered off.
Example 13 A mixture of 2.98 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoylchroman, 2 ml of POCl3 and 200 ml of 1,2-dichloroethane is boiled for 45 min. Cooling and customary working up gives 2-methoxy-methyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-chroman.
Example 14 A mixture of 1 g of "B", 10 g of trisodium phosphate dodecahydrate, 9 ml of pyridine, 9 ml of water, 22 ml of acetic acid and 8 g of Raney nickel (water-moist) is stirred at 20 for 3 hours. The mixture is filtered, the filtrate is worked up in the customary mannerand2-methoxym0thyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-formyl-3-chromene i8 obtained.
Example 15 H2S is passed into a solution of 1 g of "B" in a mixture of 7 ml of pyridine and 7 ml of triethylamine at 20 for 3 hours, the mixture is evaporated, the residue is worked up in the customary manner and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-thiocarbamoyl-3-chromene is obtained.

- 29 - 2022 ~g3 Example 16 A solution of 280 mg of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-bromo-3-chromanol is hydrogenated on 140 mg of 20% Pd-C in 80 ml of methanol at 20 and 1 bar, the mixture is filtered, the filtrate is evaporated and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-3-chromar~l, m.p. 244-246, is obtained after chromatographic p~rification on silica gel.
The examples below relate to pharmaceutical preparations which contain compounds of the formula I
and/or their physiologically acceptable salts.
Example 1: Tablets A mixture of 0.2 kg of "B", 136.3 kg of calcium hydrogenphosphate, 15 kg of cornflour, 10 kg of microcrystalline cellulose, 5.5 kg of insoluble poly-vinylpyrrolidone (PVP), 1.5 kg of highly disperse silica and l.S kg of magnesium stearate is compressed to give tablets in a customary manner. Each 170 mg tablet con-tains 0.2 mg of active compound.
Example 2: Coated tablets Tablets are pressed analogously to Example 1, but without the addition of PVP, and are subsequently coated in a customary manner with a coating of sucrose, corn-flour, talc, tragacanth and colourant.
Example 3: Lacquered tablets Tablet cores (170 mg), which are subsequently lacquered in a customary manner so that each lacquered tablet is coated with 3.922 mg of a lacquer which com-prises 2.2 mg of hydroxypropylmethylcellulose, 0.53 mg of polyethylene glycol 400, 0.85 mg of titanium dioxide, 0.12 mg of iron(III) oxide (yellow), 0.002 mg of iron(III) oxide (red) and 0.22 mg of silicone oil, are pressed from 0.2 kg of "B", 151.3 kg of lactose, 10 kg of microcrystalline cellulose, 5.5 kg of insoluble PVP, 1.5 kg of highly disperse silica and 1.5 kg of calcium stearate.

, . . . - ;
.

Example 4: Capsules Granules are prepared from 10 g of "Al", 27.5 kg of lactose, 0.35 kg of hydroxypropylmethylcellulose and 0O7 kg of cornflour, these are mixed with 0.15 kg of highly disperse silica and 0.3 kg of magnesium stearate and the mixture is poured into hard gelatin capsules in a customary manner so that each capsule contains 0.1 mg of active compound.
Example 5: Ampoules A solution of 10 g of "A2" in 70 l of 1,2-pro-panediol is made up to 100 l with double-distilled water, sterile filtered, and the solution i9 filled into 1 ml ampoules which are then sealed in a sterile manner. Each ~mpoulo contalns 0.1 ~g of act1ve co~pound.

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Claims (7)

1. Chroman derivatives of the formula I

I

in which R1 is H or A, R2 is F, Cl, Br, I, OH, OA, OAc, SA, NO2, NH2, NHA, NA2, CN or COOA, R3 is H, OH, OA or OAc, R4 is H, R3 and R4 together are also a bond, R5 is a pyridyl, pyridazinyl, pyrimidinyl, pyra-zinyl, oxodihydropyridyl, oxodihydro-pyridazinyl,oxodihydropyrimidinyl,oxodihydro-pyrazinyl, 2-pyrrolidinon-1-yl or 3-oxocyclo-penten 1-yl radical which is unsubstituted, monosubstituted or disubstituted by A, F, Cl, Br, I, OH, OA, OAc, SH, NO2, NH2, NHAc, COOH
and/or COOA, R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl, mercaptoalkyl, NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AO-SO, AO-SO2, AcNH, AO-CO-NH, H2NSO, HANSO, A2NSO, H2NSO2, HANSO2, A2NSO2, H2NCO, HANCO, A2NCO, H2NCS, HANCS, A2NCS, ASONH, ASO2NH, AOSONH, AOSO2NH, ACO-alkyl, nitroalkyl, cyanoalkyl, A-C(=NOH) or A-C(=NNH2), R8 is H or A, Z is O, S, NH or a bond, 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-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromanol;
b) 2-Methoxymethyl-2-methyl-4-(1-benzyl-1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene.

3. Process for the preparation of chroman deriva-tives of the formula I according to Claim 1, character-ized in that a chroman of the formula II
II
in which X-Y is or -CHE-CR3R8- and E is Cl, 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

in which R5 and Z have the meanings indicated in the formula I, or in that in order to prepare a compound of the formula I, in which R2 is OH or NH2, a compound otherwise cor-responding to the formula I, but which carries, instead of R2, a group -OR9 or -NHR9 in which R9 is a protecting group which can be removed by hydrogenolysis or sol-volysis, is treated with a hydrogenolysing or solvolysing agent, and/or in that a compound of the formula I, in which R3 is OH and R4 is H, is dehydrated and/or in that in a compound of the formula I, one or more of the radicals R2, R3, R5, R6 and/or R7 are converted into other radicals R2, R3, R5, R6 and/or R7 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.

4. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I and/or one of its physiologically acceptable salts is brought into a suitable form for administration together with at least one solid, liquid or semi-liquid excipient or auxiliary.

5. Pharmaceutical preparation which contains at least one compound of the formula I and/or one of its physiologically acceptable salts.

6. Use of compounds of the formula I for the produc-tion of a medicament.

7. Use of compounds of the formula I in the control of diseases.