CA2027097A1 - Chroman derivatives - Google Patents

Abstract

Abstract Novel chroman derivatives of the formula I
I

in which X, Z, R1 to R10 and m have the meanings given in Patent Claim 1, and their salts show effects on the cardiovascular system.

Description

2~2~7 Merck Patent Gesellschaft mit be~chr~nkter Haftung 6100 D a r m 8 t a d t Chroman derivative~

The invention relates to novel chroman deriv-atives of the formula I

~ Z
( IH2 )m~R 9 I~R3 in which X is 0 or NR11, Z is CH2, O, S or CHHal, 10 R1 and R5 are each A, R2 is H or A, Rl and R2 together are also alkylene having 3-6 C atoms, R3 is OH or OAc, R~ is H, R3 and R~ together are also a bond, R~ and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl, NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AO-SO, AO-SO2, AcNH, AO-CO-NH, H2NSO, HANSO, A2NSO, H2NSO2, HANS02, A2NSO2, H2NCO, HANCO, A2NCO, H2NCS, HANCS, A2NCS, ASONH, ASO2NH, AOSONH, AOS02NH, ACO-alkyl, nitroalkyl, cyano-alkyl, A-C~-NOH) or A-C~-NNH2), Ra and R~ are each H or A or together are =O or -S, 2~2~

Rl i8 H, Hal, CHO or CH2OH, R~ H, A, Ac or CH2OH, m i~ 1, 2 or 3, Hal is F, Cl, Br or I, A is alkyl having 1-6 C atom~, alkyl is alkylene having 1-6 C atom3 and Ac is alkanoyl having 1-8 C atem~ or aroyl having 7-11 C atoms, and their ~alt~.
SLmilar compounds are known from GB-A-2,204,868.
~he invention was ba~ed on the ob~ect of findlng novel compounds having useful propertie~, in particular those which can be used for the production ofmedicaments.
It ha~ been found that the compound~ of the formula I and their physiologically acceptable ~alts possess, comhined with good tolerability, useful pharma-cological properties. Thus, they show effects on the cardiovascular sy~tem, it usually being po~sible to observe a preferred effect on the coronary ~y3tem and on the bronchial ~ystffm at lower doses and an add~tional hypotensive effect at higher doses. In the coronary sy~tem, for example, decreases in resistance and in-creases in flow occur, the influence on the heart rate remaining low. Furthermore, the compounds show a relaxant effect on various smooth muscle organ~ (gastrointestinal tract, respiratory system and uterus). The effects of the compounds can be determined with the aid of methods whlch are known per se, such 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 ~.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 i~ a preferably un-branched alkyl group having 1-6, preferably 1-4, in 2~2'~7 particular 1, 2 or 3 C atom~, in detail preferably methyl, in addition preferably ethyl, propyl, isopropyl, butyl, i obutyl, and furthermore preferably ~ec.-butyl, tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or S isohexyl (4-methylpentyl).
If Rl and R2 together are alkylene, the alkylene group i~ preferably unbranched, in detail preferably -~CH2)n-, where n i~ 3, 4, 5 or 6.
The group "-alkyl" i~ preferably -CH2- or -CH2CH2-.
Ac i~ preferably alkanoyl having 1-6, in par-ticular 1, 2, 3 or 4 C atom~, in detail preferably formyl or acetyl, furthermore preferably propionyl, butyryl, i~obutyryl, pentanoyl or hexanoyl, and in addition pre-ferably benzoyl, o-, m- or p-toluyl, 1- or 2-naphthoyl.
X i8 preferably 0, and in addition preferably NH.
Z is preferably CH2, and in addition preferably 0.
Rl and R2 are preferably each alkyl, in particular each methyl or ethyl, preferably each methyl.
If R~ i3 H, R3 is preferably OH, and in addition O-CHO or O-COCH3.
R5 is preferably methyl, and in addition ethyl.
In R~ and R7, the following are preferably:
A: methyl, and in addition ethyl;
AO: methoxy, and in addition ethoxy;
ACOs acetyl, and in addition propionyl;
ACS: thioacetyl, and in addition thiopropionyl;
AOOC: methoxycarbonyl, and in addition ethoxy-carbonyl;
AO-CS t methoxythiocarbonyl, and in addition ethoxythiocarbonyl;
ACOOs acetoxy, and in addition propionoxy;
ACSO: thio(no)acetoxy, and in addition thio(no)-propionoxy;
35 hydroxyalkyls hydroxymethyl or 1- or 2-hydroxyethyl;
mercaptoalkyls mercaptomethyl or 1- or 2-mercaptoethyl;
NHAs methylamino, and in addition ethylamino;
NP~s dimethylamino, and in addition diethyl-amino;

2~27~t'~J'7 ASO: methyl~ulfinyl, and in addition ethyl-sul finyl;
SO2: methylsulfonyl, and in addition ethyl-~ulfonyl;
AO-SO: methoxysulfinyl, and in addition ethoxy-~ul~inyl;
AO-SO2: methoxy~ulfonyl, and in addition ethoxy-sulfonyl;
As-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;
HANCOs N-methylcarbamoyl, and in addition N-ethylcarbamoyl;
A2NOCs N,N-dimethylcarbamoyl, and in addition N,N-diethy}carbamoyl;
HANCSs N-methylthiocarbamoyl, and in addition N-ethylthiocarb~moyl;
A2NCSs N,N-dimethylthlocarbamoyl, and in addition N,N-diethylthiocarbamoyl;
ASONH- methylsulfinylamino, and in addition ethyIsulfinylamino;
ASO2NHt methylsulfonylamino, and in addition ethylsulfonylamino;
AOSONHs methoxysulfinylamino, and in addition ;; ethoxysulfinylamino;
AOSO2NHs methoxysulfonylAm~no, and in addition ethoxysulfonylamino;
ACO-alkyls 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-: oxopentyl;
Nitroalkyls nitromethyl, 1- or 2-nitroethyl;
:`~

2 ~2~3 Cyanoalkyl: cyanomethyl, 1- or 2-cyanoethyl;
A-C(= NOH~: l-oximinoethyl, and in addition l-oxLmino-propyl;
A-C(= NNH2): l-hydrazinoethyl, and in addition 1-hydrazinopropyl.
The radical~ R6 and R7 are preferably in the 6-and 7-position of the chroman sy~tem. However, they may also be in the 5- and 6-, 5- and 7-, 5- and 8-, 6- and 8-and 7- and 8-po~ition.
One of the radicals R6 and R7 i8 preferably H, whereas the other i~ different from H. This 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 furthenmore preferably F, Cl, Br, I, CF3, H2NCO, H2NCS or NH2.
R~ and Ra together are preferably =0.
R1~ and Rl2 are preferably each H.
Rll is preferably H.
The parameter m i8 preferably 1, and in addition preferably 2.
Hal is preferably Cl or Br.
A~cordingly, the invention in particular relate~
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 ~a to Ie below, which correspond to the formula I and in which the radicals not designated in more detail have the meaning given in the formula I, in which however in Ia Rl and R2are e~ch A;
in Ib Rl and R2are each CH3;
in Ic Rl and R2together are alkylene having 3-6 C atoms;
in Id R5 is CH3;
in Ie R , R
and R5 are each CH3.
Compounds of the formulae I' and Ia' to Ie' are furthermore preferred which correspond to the formulae I

- 6 - 2~2~
and Ia to Ie, but in which in each ca~e additionally R3 is OH and R4 is H.
Compounds of the formulae I N and Ia~' to Ie~ are furthermore preferred which correspond to the formulae I
and Ia to Ie, but in which in each ca~e additionally X is O, z is CH2, m is 1, R8 and R9 together are =O and Rlc is H.
Compounds of the formulae I, I', I n ~ Ia to Ie, Ia~ to Ie' and Ia~ to Ie~ are in addition preferred, in which in each case additionally (a) RB is different from H and R7 is H;
(b) RB is different from H and is in the 6-position and R7 is H;
(c) R5 is NO2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CP3, H2NCO, H2NCS or NH2 and R7 is H;
(d) RB is N02, CN, CH0, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF3, H2NCO, H2NCS or NN2 and is in the 6-position and R7 is H;
(e) R3 is N02, CN, CHO, CH3CO, CH300C, C2H~OOC or CH3C00 and R7 is H;
(f) R is N02, CN, CH0, CH3C0, CH300C, C2H~OOC or CH3C00 and is in the 6-position ~nd R7 is H;
(g) R~ is NO2 or CN snd R7 is H;
,~ (h) R~ is NO2 or CN and is in the 6-position and R7 is H;
(i) R is CN and R7 is H;
(~) R~ is CN and is in the 6-position and R7 is N.

2~27~7 Oth~rwi~e, the radicals and parameters x, Z, R1 to Rll, m, Hal, A, -alkyl and Ac above and below have the meanings given in formula I, if not expressly stated otherwise.
- s The invention in addition relates to a process for the preparation of chroman derivatives of the formula I, characterized in that a 3,4-epoxychroman of the formula II

in which - 10 R~, R2, R~, R~ and R7 have the meanings given in formula I
is reacted with a compound of the formula III

z ~ R
~ ~ R9 III
; HX R10 $n which X, 8, Ra, R~, R10 and m have the meanings given in formula I, lS or with one of its reactive derivatives and/or in that a compound of the formula I, in whlch R3 is OH and R' i8 H, is dehydrated and/or in that one or more of the radicals X, Z, R3, R and/or R7 are converted into other radicals X, Z, R3, R~ and/or R7 in a compound of the 20 formula I and/or in that a basic compound of the formula I is converted into one of its acid addition salts by treating with an acid.
Th~ compounds of the formula I are otherwise prepared by methods which are known per se, as are described in the literature (for example in the standard works suc~ as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organ$c Reactions, John Wiley & Sons, 2 ~3 2 v ~ r~

Inc., New York; and in the abovementioned patent applica-tion~), in particular und~r reaction conditions which are known and suitable for the reactionR mentioned. In this ca~e, u~e can al80 be made of variant~ 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 ~uch a way that they are not isolated from the reaction mixture, but immediately reacted further to gi~e the compound~ of the formula I.
10Preferably, the compounds of the formula I are prepared hy reacting compounds of the formula II with compounds of the formula III, preferably in the presence of an inert solvent at temperatures between about O and 150~, preferably 15 and 30-.
15The starting materials II and III are usually known. If they are not known, they can be prepared by methods which are known per se. The starting materials of the formula II are obtainable by reacting 2-hydroxyaceto-phenones of the formula 2-Ho-R~R7C6H2-CoCH3 with ketone~ of 20 the formula Rl-CO-R2 to give corresponding 4-chromanones of the formula IVa IVa -X-Y- - -CO-CH2-IVb -X-Y- - -CO-C(=CH-Rl2)-l ll V IVc -X-Y- = -CHoH-CHR5-~ O ~ 1 . IVd -X-Y- -CH=CR5-~ R IVe -X-Y- ~ -CHBr-CR50H-condensing with aldehydes of the formula Rl2-CHO (Rl2 ~
alkyl having 1-5 C atoms) to give 3-alkylidene-4-chroman-ones of the formula IVb, raducing, for example with Na~H~, to give 3-alkyl-4-chromanols of the formula IVc, dehy-drating, 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-bromosuccinimide in aqueous solution and these can subsequently be treated with a base, for example sodium hydroxide solution.
The chromenes of the formula IVd can aleo be 2~270~7 g obtained by condensation of salicylaldehydes of the formula 2-Ho-R6R7c6H2-cHo with ketones of th~ formula Rl-Co-CH2-R5 to give hydroxyketones of the formula 2-Ho-R6R7C~H2-CHaCR5-Co-Rlr reactfon withorganolithiumcom-S pounds of the formula R2-Li and ~ubsequent hydrolysis to give diols of the formula 2-Ho-R~R7CFN2-CH-CR5-CRlR2-oH~
and cyclization with elLmination of water.
Reactive derivatives of III whlch are suitable are the corresponding ~alts, for example the Na or x salts, which can also be formed in sitù.
It i8 preferable to work in the presence of a basQ. Suitable base~ are, for example, hydroxides, hydrides and also amides of alkali metals or alk~line earth metals, such as NaOH, ROH, Ca(OH)2, N~H, RH, CaH2, NaNH2, RNH2, and in addition organic bases such as tri-ethylamine or pyridine, which can also be used in excess and then at the same time serve as solvent. In addition, it i~ often preferable to add catalytic or stoichiometric amounts of Cu2Br2, MgBr2, titanium alkoxides or Lewis acids such as BF3 etherate.
Suitable inert solvents are, in particular, alcohols ~uch as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THP) or dioxane;
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 acetonitrileS nitro compounds such a8 nitromethane or nitrobenzenes 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 asbenzene, toluene or xylene. Mixtures of these solvents with one another are furthermore suitable.
The epoxide II can also be prepared in situ, for example by the action of a base on the corresponding 2~27~

bromohydrin Ve.
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 a~ent. This is carried out, for example by the action of one of the bases mentioned, for example NaOH, KOH or NaH, in one of the solvents mentioned, for example tetrahydrofuran, dioxane or DMSO, at temperatures between O and 150.
Furthermore, one or more of the radicals X, Z, R3, R6 and/or R7 can be converted into other radicals X, Z, R3, R6 and/or R' in a compound of tho formula I.
For example, it is poss$ble 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 HCl in waterim~thanol at 20-100) into a carboxyl group or (for example with Raney nickel in wateriacetic acid/pyridine in the presence of sodium phosphate) into a formyl group or (for example with ROH in tert.-butanol) into a carbamoyl group or (for example with H2S in pyridine/triethylamine) Lnto a thio-carbamoyl group.
Nitration i8 carried out under customary condi-tions, for example using a mlxture of concentrated HNO3 and concentr~ted H2SO~ at temperatures betweon O and 30.
Halogenation ¢an be carried out, for example, using elemental chlorine or bromine in one of the custo-mary inert solvents at temperatures botween about O 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, such as methyl chloride, bromide or iodide, dimethyl ~ulfate or methyl p-toluene~ulfonate. In addition, for 2~2 ~

example, one or two methyl group8 can be introduced with formaldehyde in the presence of formic acid. The alkyla-tion i~ preferably carried out in the presence or absence of one of the inert solvent~ mentioned, for eYample DMF, S at temperature~ between about 0 and about 120, in which case a catalyst can al~o be present, preferably a base ~uch a~ pota~sium tert.-butoxide or NaH.
Suitable acylating agent~ for the acylation of amino or hydroxyl group~ are preferably the halide~ tfor 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 i8 possible. The acylation is preferably carried out in the pre~ence or absence of an inert solvent, for example a hydrocarbon ~uch as toluene, a nitrilQ ~uch as acetonitrile, an a~ide such as DME or an excess o~ a tertiary base such a~ pyridine or triethyl-amine, at tempQratures between about 0~ and about 160,preferably between 20 and 120. Formylation 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 ~alt using an acid. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thu~, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids ~uch as orthophosphoric acid, sulfamic acid, and in addition organic acid~, in particular aliphatic, alicyclic, araliphatic, aromatic or hetero-cyclic monoba~ic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotin~c 2 ~ K~

acid, i~onicotinic acid, methanesulfonic or ethane-sulfonic acid, ethanedisulfonic acid, ~-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic and -disulfonic acid~, and S laurylsulfuric acid. Salt~ with physiologically unaccept-able acids, for example picrate~, can be us~d for purify-ing the compound~ of the formula I.
The c~mpounds of the formula I may posse~s one or more chiral centres. They can therefore be o~tained during their preparation as racemates or al80, if opti-cally active ~tartlng materialq are used, in optically active form. If the compounds have two or more chiral cQntres, they may be obtained during synthesi~ 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 R1 ~ R2, R3 3 OH and R~ - H have two chiral centres; durlng preparation by reaction of II
with III, however, very predominantly only one racemate having the trans-position of the sub3tituents R3 - OH and R5 is formed. Racemates obtained can, if desired, be ~eparated mechanically or chemically into their enantiomers by methods known per se. Thus, diastereomer~
can be formed from the racemate by reaction 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, diacetyl-tartaric 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-~-methyl-benzyl i~ocyanate (cf. EP-A1-120,428). The diffarent forms of the diastareomer~ 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 8e from the diasterQomers. Resolution of enantiomerB iB in addition carried out by chromato-graphy on optically active support materials.

2~7~

The compounds of the formula I and their physio-logically acceptable salt~ can be used for the production of pharmaceutical preparations, ln particular in non-chemical ways. In this connection, they can be brought into a ~uitable 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 administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, poly~thylene glycols, glyceroI triacetate, gelatin, carbohydrates such a~ lactose or starch, mag-nesium stearate, talc or petroleum ~elly. In particular, tablets, coated tablets, capsules, syrups, elixirs or drops are used for oral admini~tration, suppositories are used for ractal administration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implantJ are u~ed for parenteral adminlstra-tion, and ointments, creams or powders are used for topical appllcation. The novel compounds can al80 be lyophilized and the lyophilizates obtained used, for example, for the production of in~ection preparations.
The preparations mentioned can be sterilized and/or can contain auxlliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and flavourings and/or aromatizers. They can, if desired, also contain one or more further active compounds, for example one or more vitamins.
The compounds of the formula I and their physio-logically acceptable salts can be administered to humans 2027~7, or anLmal~, in particular mammal~ such as apes, dogs, cats, rat~ or mic~ and can b~ used in the therapeutic treatment of the human or anLmal body and al~o in the control of diseases, ln particular in the thHrapy and/or prophylaxis of disturbances of the cardiovascular sy~tem, in particular d~compen~ated cardiac insufficiency, angina pectoris, peripheral or cerebral vascular di~orders, and di~ease conditions which are connected 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 known antianqinals or hypotensives, for example nicoran-dil or cromakalim, preferably in doses between about 0.01and 5 mg, in particular between 0.02 and 0.5 mg per dose unit. The daily dose i8 preferably between about 0.0001 and 0.1, in particular betweQn 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 thetherapy applies. Oral administration ia preferred.
In the following example~ ~customary working up"
meanss water is added, if necessary, the mixture is extracted using an organic solvent such as ethyl acetate, the org~nic 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.
Example 1 2.1 g of 1,3-cyclopentanedione are dissolved in 200 ml of THF under N2, 650 mg of NaH (80% in mineral oil) are added, the mixture is stirred for 1 hour, a solution 2 ~ 3 ~

of 4.6 g of 2,2,3-trLmethyl-3,4-epoxy-6-cyanochroman (~IIa~) in 20 ml of THF, then 2.4 ml of BF3 etherste are added succeRsively and the mixture i8 stirred overnight at 20. The mixture i8 evaporated and the 2,2,3-tri-S methyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-eyano-3-chrom-anol ("A~) obtained is purified by chromatography on silica gel (ethyl acetate~methanol 100:1); m.p. 204 -206 (from isopropanol).
2,2,3-trimethyl-4-(3-oxo-1-cyelohexen-1-yloxy)-6-eyano-3-ehromanol is obtained analogously using 1,3-cyelohexanedione.
2,2,3-trLmothyl-4-(3-oxo-1-cyelopenten-1-yloxy)-3-ehromanol 2,2,3-trimethyl-4-(3-oxo-1-eyclopenten-1-yloxy)-6-ehloro-3-ehromanol 2,2,3-trimethyl-4-(3-oxo-1-eyelopenten-1-yloxy)-6-bromo-3-chromanol 2,2,3-trimethyl-4-(3-oxo-1-eyelopenten-1-yloxy)-6-acetyl-3-chromanol 2,2,3-trimethyl-4-~3-oxo-1-cyelopenten-1-yloxy)-6-methoxyearbonyl-3-ehromanol 2,2,3-trimethyl-4-~3-oxo-1-eyelopenten-1-yloxy)-6-ethoxy-earbonyl-3-ehromanol 2,2,3-trimethyl-4-(3-oxo-1-eyelopenten-1-yloxy)-6-nitro-3-ehromanol 2,2,3-trimethyl-4-(3-oxo-1-eyelopenten-1-yloxy)-6-aeet-amLdo-3-ehromanol 2,2,3-trimethyl-4-(3-oxo-1-eyclopenten-1-yloxy)-7-aeet-amido-3-ehromanol 2,2,3-trimethyl-4-(3-oxo-1-eyclopenten-1-yloxy)-6-aeet-amido-7-nitro-3-chromanol 2,2-diethyl-3-methyl-(3-oxo-1-eyelopenten-1-yloxy)-6-cyano-3-ehromanol 2~2-tetr~methylene-3-methyl-(3-oxo-l-cyclopenten yloxy)-6-eyano-3-ehromanol 2,2-pentamethylene-3-methyl-(3-oxo-1-eyelopenten-1-yloxy)-6-eyano-3-ehromanol are obtained analogously froms 2,2,3-trimethyl-3,4-epoxy-ehroman 202~

2,2,3-trimethyl-3,4-epoxy-6-chloro-chroman 2,2,3-trimethyl-3,4-epoxy-6-bromo-chroman 2,2,3-trimethyl-3,4-epoxy-6-acetyl-chroman 2,2,3-trimethyl-3,4-epoxy-6-methoxycarbonyl-chroman 2,2,3-trimethyl-3,4-epoxy-6-ethoxycarbonyl-chroman 2,2,3-trimethyl-3,4-epoxy-6-nitro-chroman 2,2,3-trimethyl-3,4-epoxy-6-acetamido-chroman 2,2,3-trimethyl-3,4-epoxy-7-acetamido-chroman 2,2,3-trimethyl-3,4-epoxy-6-acetamido-7-nitro-chroman 2,2-diethyl-3-methyl-3,4-epoxy-6-cyano-chroman 2,2-tetrAmethylene-3-methyl-3,4-epoxy-6-cyano-chroman 2,2-pentamethylene-3-methyl-3,4-epoxy-6-cyano-chroman using 1,3-cyclopentanedione Example 2 lS (3S,4R)-2,2,3-Trimethyl-4-(3-oxo-1-cyclopenten-l-yloxy)-6-cyano-3-chromanol is obtained analogously to ~xample 1 from (-)-(3S,4S)-2,2,3-trimethyl-3,4-epoxy-6-cyano-chroman t"(-)-IIan] and 1,3-cyclopentanedione.
(3R,4S)-2,2,3-Trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-cyano-3-chromanol is obtained analogously from (+)-(3R,4R)-2,2,3-trimethyl-3,4-epoxy-6-cyano-chroman.
Example 3 2.15 g of IIa are dissolved in 30 ml of DMS0 under N2, 0.2 g of NaH is first added with stirring, then l.S g of 3-amino-2-cyclopenten-1-one are added in portions and the mixture is stirred for 24 hours at 20-.
Customary working up gives 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-l-ylamino)-6-cyano-3-chromanol (~
2,2,3-Trimethyl-4-[2-oxofuran-4(5H)-ylamino]-6-cyano-3-chromanol is obtained an~logously from IIa and 4-amino-2(SH)-furanone.
2,2,3-Trimethyl-4-lN-methyl-N-(3-oxo-1-cyclopen-ten-l-yl)-amino]-6-cyano-3-chromanol is obtained analog-ously from IIa and 3-methylamino-2-cyclopenten-1-one.
2,2,3-trimethyl-4-lN-methyl-N-(2-oxofuran-4(SH)-yl)-aminol-6-cyano-3-chromanol is obtained analogously from IIa and 4-methylamino-2(SH)-furanone.
2,2,3-Trimethyl-4-tN-methyl-N-(l-methyl-2-oxo-pyrrol-4(SN)-yl)-amino]-6-cyano-3-chromanol i8 obtained 2~7~7 analogou~ly from IIa and l-methyl-4-methylamino-2(5H)-pyrrolone.
The following are obta$ned analoqously from the corresponding 3,4-epoxychromones:
2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yl-amLno)-3-chromanol 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yl-amino)-6-chloro-3-chromanol 2,2,3-trim~thyl-4-(3-oxo-1-cyclopenten-1-yl-amino)-6-bromo-3-chromanol 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yl-amino)-6-methoxycarbonyl-3-chromanol 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yl-amino)-6-ethoxycarbonyl-3-chromanol 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yl-amino)-6-~- nitro-3-chromanol Ex~mple 4 2,2,3-Trimethyl-4-t2-oxofuran-4(5H)-yloxyl-6-cyano-3-chromanol is obtained analogously to Example 1 from IIa and tetronic acid.
2,2,3-Trimethyl-4-~2-oxothiophen-4~SH)-yloxy]-6-cyano-3-chromanol i~ obtained analoqously from IIa and thiotetronic acid.
Example S
A mixture of 3.12 g of ~B~, 20 g of formic-acetic anhydride and S0 ml of THP is stlrred under N2 for 7 hours. The mlxture is evaporated, worked up ln the customary manner and 2,2,3-trimethyl-4-tN-formyl-N-(3-oxo-l-cyclopenten-l-yl)-amino]-6-cyano-3-chromanol is obtained.
Example 6 A solution of 3.12 g of nB~ in lS0 ml of acetone i8 mixed three times every hour with 2.5 ml of 37 aqueous form4ldehyde ~olution and ~tirred at pH 8-9 (addition of sodium hydroxide solutionl) for a total of 5 hours. Customary working up gives 2,2,3-trimethyl-4-(2-hydroxymethyl-3-oxo-l-cyclopenten-l-yl~mino)-6-cyano-3-chromanol.

~7~n Example 7 1.4 g of the product obtained according to Example 6 are oxidized u~ing 2.2 g of Collin~s reagent in 250 ml of dichloromethane for 10 minutes, worked up a~
customary (chromatography on silica gel; dichloromethane/
methanol 97:3) and 2,2,3-trimethyl-4-(2-formyl-3-oxo-1-cyclopenten-l-ylamino)-6-cyano-3-chromanol i~ obtained.
Example B
A ~olution of 1.1 g of ~B~ in a mixture of 35 ml of dichloromethane and 35 ml of dioxane i8 mixed with 700 mg of xenon difluoride, stirred at 20- for 5 hours and poured into water~ Cu3tomary working up gives 2,2,3-trimethyl-4-(2-fluoro-3-oxo-1-cyclopenten-1-ylamino)-6-cyano-3-chromanol.
- 15 Example 9 A solution of 156 mg of ~B" in a mixture of S ml of dichloromethane and S ml of dioxane i8 stirred at 20-for 1 hour wlth 77 mg of N-chlorosuccinimide and worked up in the customary manner. 2,2,3-Trimethyl-4-(2-chloro-3-oxo-1-cyclopenten-1-ylamino)-6-cyano-3-chromanol i~
obtained.
2,2,3-Trimethyl-4-~2-bromo-3-oxo-1-cyclopenten-l-ylamino)-6-cyano-3-chromanol is obtained analogously using N-bromosuccinimide.
Example 10 A mixture of 2 g of "A~, 11.7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to stand at 20-for 16 hours and is flubsequently warmed to 40-45- for 2 hours. Evaporation and customary working up gives 2,2,3-trimethyl-3-formyloxy-4-(3-oxo-1-cyclopenten-1-yloxy)-6-cyano-chroman.
~xample 11 A mixture of 1 g of ~A~ and 5 ml of acetic anhydride is boiled for 1 hour. The mixture i~ cooled, worked up in a customary manner and gives 2,2,3-trimeth-yl-3-acetoxy-4-(3-oxo-1-cyclopenten-1-yloxy)-6-cyano-chroman.
~xample 12 solution of 3.46 g of 2,2,3-trimethyl-4-(3-oxo-1 9 2 ~ ~ ~ v 1 l-cyclopenten-l-yloxy)-6-methoxycarbonyl-3 chroma~ol in 100 ml of 33~ ethanolic dimethylamine solution i~ h~ated to 100 in an autoclave for 10 days. The mixture is cooled, worked up in a customary manner and give8 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-dimethyl-aminocarbonyl-3-chromanol.
Example 13 HCl is passed into a boilin~ solution of 1 g of nA" in 50 ml of metharol and 2 ml of water with ~tirring for 14 hours. The mlxtura i~ allowed to cool, worked up in a cu~tomary manner and give~ 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy)-6-carboxy-3-chromanol.
Example 14 A mixture of 3.13 g of "A", 31 g of Na3PO4 12H20, 28 ml of pyridine, 28 ml of water, 67 ml of acetic acid and 25 g of Raney Ni ~water-mo~st) is stirred at 20 for 3 hour~. After filtration, the mixture is worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-l-yloxy)-6-formyl-3-chromanol.
Example 15 3.13 g of "A" are dissolved in 45 ml of tert.-butanol and 5 g of powdered ROH are added with stirring.
Boiling for 1 hour and customary working up gives 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-carbamoyl-3-chromanol.
Example 16 H2S is passed into a solution of 3.13 g of "A~ in a mixture of 20 ml of pyridine and 10 ml of triethylamine at 20- for 5 hours, and the mixture i8 evaporated, worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy)-6-thiocarbamoyl-3-chromanol.
The examples below relate to pharmaceutical preparations which contain compounds of the formula I or their phy~iologically acceptable salts 5 Example A Tablets A mixture of 0.2 kg of "A~, 136.3 kg of calcium hydrogenphosphate, 15 kg of cornflour, 10 kg of micro-crystalline cellulose, 5.5 kg of insolublè polyvinylpyr-rolidone (PVP), l.S kg of highly disperse SiO2 and 1.5 kg - 20 - 2 ~ 2 r~ ~3 ~ r~
of magne~ium steara~e is compre~sed in a customary manner to give tablet~. Each 170 mg ~ablet contain~ 0.2 mg of active compound.
Example B Coated tablets Tablets are pressed analogoùsly to Example A, but without adding PVP, and are subcequently coated in a cuætomary manner with a coating of ~ucrose, potato ~tarch, talc, tragacanth and colorant.
Example C Capsules Granule~ are prepared from 10 g of "A", 27.5 kg of lactose, 0.35 kg of hydroxypropylmethylcellulose and 0.7 kg of cornflour, these are mixed with 0.15 kg of highly di~perse Si~2 and 0.3 kg of magnesium ~tearata and the mixture is poured into hard gelatine cap~ules in a customary manner so that each capsule contain~ 0.1 mg of active compound.
Example D Lacquered tablets Tablet cores l170 mg) are pres~ed from 0.2 kg of "A~, 151.3 kg of lacto~e, 10 kg of microcrystalline cellulose, S.S kg of PVP, 1.5 kg of highly di3perse SiO2 and 1.5 kg of magnesium stearate, and are then lacquered in a customary manner 80 that each lacquered tablet is coated with 3.922 mg of a lacquer which consists of 2.~ mg of hydroxypropylmethylcellulo~e, 0.53 mg of polyethylene glycol 400, 0.85 mg of TiO2, 0.122 mg of Fe203 and 0.22 mg of silicone oil.
Example E Ampoules A solut$on of 10 g of ~A~ in 70 1 of 1,2-propane-diol is made up to 100 1 with double-distilled water, sterile-filtered and poured into 1 ml ampoules which are then closed under sterile conditions. Each ampoule contains 0.1 mg of active compound.
Tablets, coated tablets, capsules, lacquered tablets or ampoules, which contain one or more of the other active compounds of the formula I andJor their physiologically acceptable salt~, are obtainable analogously.

Claims (8)

1. Chroman derivatives of the formula I
in which X is O or NR11, Z is CH2, O, S or CHHal, R1 and R5 are each A, R2 is H or A, R1 and R2 together are also alkylene having 3-6 C atoms, R3 is OH or OAc, R4 is H, R3 and R4 together are also a bond, R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl, 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, cyano-alkyl, A-C(=NOH) or A-C(=NNH2), R8 and R9 are each H or A or together ate =O or =S, R10 is H, Hal, CHO or CH2OH, R11 is H, A, Ac or CH2OH, m is 1, 2 or 3, Hal is F, Cl, Br or I, 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. 2,2,3-Trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-cyano-3-chromanol.

3. Process for the preparation of chroman derivatives of the formula I, characterized in that a 3,4-epoxychroman of the formula II
II

in which R1, R2, R5, R6 and R7 have the meanings given in formula I
is reacted with a compound of the formula III
III

in which X, Z, R8, R9, R10 and m have the meaning given in formula I, or with one of its reactive derivatives 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 one or more of the radicals X, Z, R3, R6 and/or R7 are converted into other radicals X, Z, R3, R5 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.

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. Compounds of the formula I for the control of diseases.

7. Use of compounds of the formula I for the production of a medicament.

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