NZ235597A

NZ235597A - Chroman derivatives, medicaments

Info

Publication number: NZ235597A
Application number: NZ235597A
Authority: NZ
Inventors: Rolf Gericke; Manfred Baumgarth; Ingeborg Lues; Peyer Jacques De; Rolf Bergmann
Original assignee: Merck Patent Gmbh
Priority date: 1989-10-09
Filing date: 1990-10-08
Publication date: 1992-07-28
Also published as: PT95530A; DE3933663A1; KR910007907A; ZA908091B; IE903591A1; EP0422450A2; CA2027097A1; AU6391590A; HU208126B; YU188890A; IL95927A0; HU906385D0; FI904933A0; JPH03133973A; HUT58714A; NO904362L; AU633983B2; NO904362D0; EP0422450A3

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £35597 23 5 5 9 Priority Date',?-):...; '. Compete ■'cz'A'n: Fs.c-j: Class: (5)^ ....v,... Publication Data: P.O. Jourrrgt, No: v *|„n N.Z. No NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION CHROMAN DERIVATIVES We, MERCK PATENT GESELLSCHAFT MIT BESHRANKTER HAFTUNG, a German Company of Frankfurter Strasse 250, D-6100 Darmstadt. Federal Republic of Germany, 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:- ' \ c N ' X "-8 OCT 1990 - 1 - (Followed by 1A) - l A - _ , / Chroman derivatives The invention relates to novel chroman derivatives of the formula I 10 15 20 v' V ''JtSb in which X z R1 and R5 R2 or R1 and R2 R3 R* or R3 and R* R6 and R7 '/9o is O or NR11, is CHz, O, S or CHHal, are each A, is H or A, together may be alkylene having 3-6 C atoms, is OH or QAc, is H, together may be a bond, are each H, Ar HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, AC00, A-CS-O, hydroxy alk, N02, NH2/ NHA, NAj, CN, F, CI, Br, I, CFj, ASO, AS02/ AO-SO, A0-S02, AcNH, AO-CO-NH, H2NS0, HMSO, AzNSO, H2NS0 2, HANS02, AsNSOZ, H2NC0, HANCO, a2nco, h2ncs, hancs, a^ncs, asonh, aso2nh, AOSONH, A0S02NH, ACO-alk, nitroalk , cyano-alk , A-C (=N0H) or A-C (=NNH2) , Ra and R8 are each H or A or together are =0 or =S, - 2 - R10 is H, Hal, CHO or CK20H, ' ~ - / R11 is H, A, Ac or CH2OH, m is 1, 2 or 3, Hal is F, CI, Br or I, 5 A is alkyl having 1-6 C atoms, alk 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. 10 Similar compounds are known from GB-A-2,204,868. The invention was based on the object of finding novel compounds having useful • properties, in particular those which can be used for the production of medicaments -It has been found that the compounds of the 15 formula I and their physiologically acceptable salts possess, combined with good tolerability, useful pharmacological properties. Thus, they show effects on the cardiovascular system, it usually being possible to observe a preferred effect on the coronary system and on 20 the bronchial system at lower doses and an additional 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 25 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, such as are given, for example, in EP-Al-76,075, EP-A1-173,848 or AU-A-45,547/85 (Derwent 30 Fanndoc No. 86081769) and by K.S. Meesmann et al., Arzneimittelforschunq 25 (11), 1975, 1770-1776. Suitable experimental animals sore, for example, mice, rats, guinea pigs, dogs, cats, apes or pigs. The compounds can therefore be used as active 35 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— .c branched alkyl group having 1-6, preferably 1-4, inV < "**> 1 N«9 % * - 3 - 235597 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 5 isohexyl (4-methylpentyl). If R1 and R2 together are alkylene, the alkylene group is preferably unbranched, in detail preferably -(CH2)n-, where n is 3, 4, 5 or 6. The group "-alkyl" is preferably -CHZ- or 10 -CH2CH2-. Ac is preferably alkanoyl having 1-6, in particular 1, 2, 3 or 4 C atoms, in detail preferably formyl or acetyl, furthermore preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and in addition pre-15 ferably benzoyl, o-, m- or p-toluyl, 1- or 2-naphthoyl. X is preferably 0, and in addition preferably NH. Z is preferably CH2, and in addition preferably 0. R1 and R2 are preferably each alkyl, in particular each methyl or ethyl, preferably each methyl. 20 If R* is H, R3 is preferably OH, and in addition O-CHO or O-COCHg. R5 is preferably methyl, and in addition ethyl. In R6 and R7, the following are preferably: A: methyl, and in addition ethyl; 25 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; 30 AO-CS: methoxythiocarbonyl, and in addition ethoxythiocarbonyl; ACOO: acetoxy, and in addition propionoxy; ACSO: thio(no)acetoxy, and in addition thio(no)- propionoxy; 35 hydroxyalkyl: hydroxymethyl or 1- or 2-hydroxyethyl; mercaptoalkyl: mercaptomethyl or 1- or 2-mercaptoethyl; NHA: methylamino, and in addition ethylamino; NA^ dimethyl amino, and in addition diethyl- amino; 235597 - 4 10 15 20 25 30 35 ASO: ASOz: AO-SO: A0-S02: Ac-NH: AO-CO-NH: HANSO: AjNSO: HANS02: A2NS02: hanco: AjNOC: hancs: AjNCS: ASONH: AS02NH: AOSONH: A0S02NH: ACO-alkyl: Nitroalkyl: methylsulfinyl, and in addition ethyl-sulfinyl; methylsulfonyl, and in addition ethyl-sulfonyl; methoxysulfinyl, and in addition ethoxy-sulfinyl; methoxysulfonyl, and in addition ethoxy-sulfonyl; acetamido, and in addition formamido, propionamido or benzamido; methoxycarbonyl amino, and in addition ethoxycarbonylamino; methylaminosulfinyl, and in addition ethylaminosulfinyl; dimethylaminosulfinyl, and in addition diethylaminosulfinyl; methylaminosulfonyl, and in addition ethylaminosulfonyl; dimethylaminosulf onyl, and in addition diethylaminosulfonyl; N-methylcarbamoyl, and in addition N-ethylcarbamoyl; N,N-dimethylcarbamoyl, and in addition N,N-diethylcarbamoyl; N-methylthiocarbamoyl, and in addition N-ethylthiocarbamoyl; N,N-dimethylthiocarbamoyl, and in addition N,N-diethylthiocarbamoyl; methylsulfinylamino, and in addition ethylsulfinylamino; methylsulfonylamino, and in addition ethylsulfonylamino; methoxysulf inylamino, and in addition ethoxysulf inylamino; methoxysulfonylamino, and in addition ethoxysulfonylami no; 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl; nitromethyl, 1- or 2-nitroethyl; 235597 - 5 - Cyanoalkyl: cyanomethyl, 1- or 2-cyanoethyl; A-C(= NOH): 1-oximinoethyl, and in addition 1-oximino- propyl; A-C(= NNH2): 1-hydrazinoethyl, and in addition 1-5 hydrazinopropyl. The radicals R5 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. 10 One of the radicals R5 and R7 is preferably H, whereas the other is 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 N02, in addition preferably CHO, ACO (in particular acetyl), AOOC (in 15 particular methoxycarbonyl or ethoxycarbonyl), ACOO (in particular acetoxy), and furthermore preferably F, CI, Br, I, CF3, H2NCO, H2NCS or NH2. Rs and R9 together are preferably =0. R10 and R12 are preferably each H. 20 R11 is preferably H. The parameter m is preferably 1, and in addition preferably 2. Hal is preferably CI or Br. Accordingly, the invention in particular relates 25 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 Ie below, which correspond to the formula I and in which the 30 radicals not designated in more detail have ths meaning given 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; 35 in Id R5 is CH3; in Ie R1, R2 and R5 are each CH3. Compounds of the formulae I' and la' to Ie' are furthermore preferred which correspond to the formulae I - 6 - 23559/ and la to Ie, but in which in each case additionally R3 is OH and R4 is K. Compounds of the formulae I" and la" to Ie" are furthermore preferred which correspond to the formulae I 5 and la to Ie, but in which in each case additionally X is 0, Z is CH2, m is 1, R8 and R9 together are =0 and 10 R10 is H. Compounds of the formulae I, I', I", la to Ie, la' to Ie' and la" to IeM are in addition preferred, in which in each case additionally (a) R6 is different from H and 15 R7 is H; (b) R6 is different from H and is in the 6-position and R7 is H; (c) R6 is N02, CN, CHO, ACO, H00C, AOOC, AC00, F, CI, 20 Br, I, CF3, H2NC0, H2NCS or NH2 and R7 is H; (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 25 R7 is H; (e) Rs is N02, CN, CHO, CH3C0, CH300C, C2H5OOC or CH3COO and R7 is H; (f) R6 is N02, CN, CHO, CH3CO, ch3ooc, C2H5OOC or CH3COO 30 and is in the 6-position and R7 is H; (g) Rs is N02 or CN and R7 is H; (h) R6 is N02 or CN and is in the 6-position and 35 R7 is H; (i) R6 is CN and R7 is H; (j) R6 is CN and is in the 6-position and R7 is H. 235597 - 7 - Otherwise, the radicals and parameters X, Z, R1 to R11, m, Hal, 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 I, characterized in that a 3,4-epoxychroman of the formula 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 R8 JfVm r9 hi H X V<> in which X, Z, R8, R9, R10 and m have the meanings 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 R* is H, is dehydrated and/or in that one or more of the radicals Xf 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. 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 Chemie (Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, 23 5 5 - 8 - 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 5 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 are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I. 10 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°, preferably 15 and 30°. 15 The 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-R6R7C6H2-COCH3 with ketones of 20 the formula R1-CO-R2 to give corresponding 4-chromanones of the formula IVa IVa -X-Y- = -CO-CH2-IVb -X-Y- = -CO-C (=CH-R12) -IVc -X-Y- = -CHOH-CHR5-25 1 Ivd -X-Y- = -CH=CR5- r7 R IVe -X-Y- = -CHBr-CR50H— condensing with aldehydes of the formula Ru-CHO (R12 = alkyl having 1-5 C atoms) to give 3-alkylidene-4-chroman-ones of the formula IVb, reducing, for example with NaBH4, 30 to give 3-alkyl-4-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. 35 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 also be 4* 235 5 - 9 - obtained by condensation of salicylaldehydes of the formula 2-HO-R6R7C6H2-CHO with ketones of the formula R1-CO-CH2-R5 to give hydroxyketones of the formula 2-HO-R6R7C6H2-CH=CR5-CO-R1, reaction with organolithium com-5 pounds of the formula R2-Li and subsequent hydrolysis to give diols of the formula 2-HO-R6R7C6H2-CH=CR5-CR1R2-OH, and cyclization with elimination of water. Reactive derivatives of III which are suitable are the corresponding salts, for example the Na or K 10 salts, which can also be formed in situ. It is preferable to work in the presence of a base. Suitable bases are, for example, hydroxides, hydrides and also amides of alkali metals or alkaline earth metals, such as NaOH, KOH, Ca(0H)2, NaH, KH, CaH2, 15 NaNH2, KNH2, 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 is often preferable to add catalytic or stoichiometric amounts of Cu2Br2/ MgBr2, titanium alkoxides or Lewis 20 acids such as BF3 etherate. 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; 25 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 30 nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or hexa-methylphosphoramide; sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloro-methane, chloroform, trichloroethylene, 1,2-dichloro-35 ethane or carbon tetrachloride; hydrocarbons such as benzene, 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 235597 - 10 - bromohydrin Ve. 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 5 dehydrating agent. 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 0 and 150°. 10 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 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 15 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 20 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. 25 Nitration is carried out under customary condi tions, for example using a mixture of concentrated HN03 and concentrated H2S04 at temperatures between 0 and 30°. Halogenation can be carried out, for example, using elemental chlorine or bromine in one of the custo-30 mary 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 35 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 235597 ~N - 11 - 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, 5 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 10 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 15 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-20 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 pyridine. A base of the formula I can be converted into the 25 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, 30 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, 35 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 - 12 - 235597 acid, isonicotinic acid, methanesulfonic or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic and -disulfonic acids, and 5 laurylsulfuric acid. Salts with physiologically unaccept 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 10 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 synthesis as mixtures of racemates from which the individual racemates 15 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 = OH and R* = H have two chiral centres; during preparation by reaction of II with III, however, very predominantly only one racemate 20 having the trans-position of the substituents R3 = OH and R5 is formed. Racemates obtained can, if desired, be separated mechanically or chemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction with an 25 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, 30 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-a-methyl-benzyl isocyanate (cf. EP-A1-120,428). The different forms of the diastereomers can be separated in a manner 35 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 the diastereomers. Resolution of enantiomers is in addition carried out by chromatography on optically active support materials. 235597 - 13 - The compounds of the formula I and their physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular in non-chemical ways. In this connection, they can be brought 5 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 10 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 15 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, polyethylene glycols, glycerol triacetate, 20 gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, elixirs or drops are used for oral administration, suppositories are used for rectal administration, solutions, preferably 25 oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for 30 example, for the production of injection preparations. 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 osmotic pressure, buffer substances, 35 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 physiologically acceptable salts can be administered to humans - 14 - 235597 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 5 prophylaxis of disturbances of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, peripheral or cerebral vascular disorders, and disease conditions which are connected with high blood pressure, and in addition disorders which are connected 10 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 antianginals or hypotensives, for example nicoran-15 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 20 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-25 ation and severity of the particular disease to which the therapy applies. Oral administration is preferred. In the following examples "customary working up" means: water is added, if necessary, the mixture is 30 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 35 °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 - 15 - 23 5 "" of 4.6 g of 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman ( "Ila") in 20 ml of THF, then 2.4 ml of BF3 etherate are added successively and the mixture is stirred overnight at 20°. The mixture is evaporated and the 2,2,3-tri-5 methyl-4-( 3-oxo-l-cyclopenten-l-yloxy)-6-cyano-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-l-cyclohexen-l-yloxy) -10 6-cyano-3-chromanol is obtained analogously using 1,3-cyclohexanedione. 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy)-3-chromanol 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy) - 6-chloro-15 3-chromanol 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy)-6-bromo-3-chromanol 2,2,3-trimethyl-4- (3-oxo-l-cyclopenten-l-yloxy) -6-acetyl-3-chromanol 20 2,2, 3-trimethyl-4- ( 3-oxo-l-cyclopenten-l-yloxy)-6-methoxycarbonyl-3-chromanol 2,2,3-trimethyl-4- (3-oxo-l-cyclopenten-l-yloxy) -6-ethoxy-carbonyl-3-chromanol 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy)-6-nitro-25 3-chromanol 2,2,3-trimethyl-4- (3-oxo-l-cyclopenten-l-yloxy) -6-acet-amido-3-chromano1 2,2,3-trimethyl-4- (3-oxo-l-cyclopenten-l-yloxy) -7-acet-amido-3-c hromano 1 30 2,2,3-trimethyl-4- (3-oxo-l-cyclopenten-l-yloxy) -6-acet- amido-7-nitro-3-chromanol 2,2-diethyl-3-methyl-( 3-oxo-l-cyclopenten-l-yloxy) -6-cyano-3-chromano1 2,2-tetramethylene-3-methyl-(3-oxo-l-cyclopenten-l-35 yloxy)-6-cyano-3-chromanol 2,2-pentamethylene-3-methyl-(3-oxo-l-cyclopenten-l-yloxy) -6-cyano-3-chromanol are obtained analogously from: 2,2,3-trimethyl-3,4-epoxy-c hroman 235597 - 16 - 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 us ing 1,3-cyclopentanedione Example 2 (3S, 4R) -2,2,3-Trimethyl-4-( 3-oxo-l-cyclopenten-l-yloxy) -6-cyano-3-chromanol is obtained analogously to Example 1 from (-)-{3S,4S)-2,2,3-trimethyl-3,4-epoxy-6-cyano-chroman ["(-)-IIa"] and 1,3-cyclopentanedione. (3R, 4S) -2,2,3 -Trimethyl-4-(3-oxo-l-cyclopenten-l-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 Ila are dissolved in 30 ml of DMSO under N2, 0.2 g of NaH is first added with stirring, then 1.5 g of 3-amino-2-cyclopenten-l-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-l-cyclopenten-l-ylamino)-6-cyano-3-chromanol ("B"). 2,2,3-Trimethyl-4- [ 2-oxof uran-4 (5H) -ylamino]-6-cyano-3-chromanol is obtained analogously from Ila and 4-amino-2(5H)-furanone. 2,2,3-Trimethyl-4-[N-methyl-N-( 3-oxo-l-cyclopen-ten-l-yl)-amino]-6-cyano-3-chromanol is obtained analogously from Ila and 3-methylamino-2-cyclopenten-l-one. 2,2,3-trimethyl-4- [N-methyl-N- (2-oxofuran-4 (5H) -yl)-amino]-6-cyano-3-chromanol is obtained analogously from Ila and 4-methylamino-2(5H)-furanone. 2,2,3-Trimethyl-4-[N-methyl-N-(1-methyl-2-oxo-pyrrol-4(5H)-yl)-amino]-6-cyano-3-chromanol is obtained 235597 - 17 - analogously from Ila and l-methyl-4-methylamino-2(5H)-pyrrolone. The following are obtained analogously from the corresponding 3,4-epoxychromones: 5 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yl-amino)-3-chromano1 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yl-amino)-6-chloro-3-chromanol 2,2, 3-trimethyl-4-( 3-oxo-l-cyclopenten-l-yl-amino) -6-10 bromo-3-chromanol 2,2, 3-trimethyl-4-( 3-oxo-l-cyclopenten-l-yl-amino) -6-methoxycarbonyl- 3 -chromanol 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yl-amino)-6-e tho xyc arbony 1 - 3- chromanol 15 2,2, 3-trimethyl-4-(3-oxo-l-cyclopenten-l-yl-amino) -6-ni tro- 3 -c hromano 1 Example 4 2,2,3-Trimethyl-4-[2-oxofuran-4(5H)-yloxy]-6-cyano-3-chromanol is obtained analogously to Example 1 20 from Ila and tetronic acid. 2,2,3-Trimethyl-4-[2-oxothiophen-4(5H)-yloxy]-6-cyano-3-chromanol is obtained analogously from Ila and thiotetronic acid. Example 5 25 A mixture of 3.12 g of "B", 20 g of formic-acetic anhydride and 50 ml of THF is stirred under Nz for 7 hours. The mixture is evaporated, worked up in the customary manner and 2,2,3-trimethyl-4-[N-formyl-N-( 3-oxo-1-cyclopenten.-l-yl)-amino ]-6-cyano-3-chromanol is 30 obtained. Example 6 A solution of 3.12 g of "B" in 150 ml of acetone is mixed three times every hour with 2.5 ml of 37% aqueous formaldehyde solution and stirred at pH 8-9 35 (addition of sodium hydroxide solutionI) for a total of 5 hours. Customary working up gives 2,2,3-trimethyl-4-(2-hydroxymethyl-3-oxo-l-cyclopenten-l-ylamino)-6-cyano-3-chromano1. ^5 5 9 » - 18 - Example 7 1.4 g of the product obtained according to Example 6 are oxidized using 2.2 g of Collin's reagent in 250 ml of dichloromethane for 10 minutes, worked up as 5 customary (chromatography on silica gel; dichloromethane/ methanol 97:3) and 2,2,3-trimethyl-4-(2-formyl-3-oxo-l-cyclopenten-l-ylamino)-6-cyano-3-chromanol is obtained. Example 8 A solution of 1.1 g of "B" in a mixture of 35 ml 10 of dichloromethane and 35 ml of dioxane is mixed with 700 mg of xenon difluoride, stirred at 20° for 5 hours and poured into water. Customary working up gives 2,2,3-t rime thy 1-4- (2-f luoro-3-oxo-l-cyclopenten-l-ylamino) -6-cyano-3-chromanol. 15 Example 9 A solution of 156 mg of "B" in a mixture of 5 ml of dichloromethane and 5 ml of dioxane is stirred at 20° for 1 hour with 77 mg of N-chlorosuccinimide and worked up in the customary manner. 2,2,3-Trimethyl-4-(2-chloro-20 3-oxo-l-cyclopenten-l-ylamino)-6-cyano-3-chromanol is obtained. 2,2, 3-Trimethyl-4-(2-bromo-3-oxo-l-cyclopenten-1-ylamino)-6-cyano-3-chromanol is obtained analogously using N-bromosuccinimide. 25 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 subsequently warmed to 40-45° for 2 hours. Evaporation and customary working up gives 2,2,3-3 0 trimethyl-3-formyloxy-4- (3 -oxo- 1-cyc lopenten-1 -yloxy) - 6 -cyano-chroman. Example 11 A mixture of 1 g of "A" and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled, 35 worked up in a customary manner and gives 2,2,3-trimeth-yl-3-acetoxy-4-(3-oxo-l-cyclopenten-l-yloxy) -6-cyano-chroman. Example 12 A solution of 3.46 g of 2,2,3-trimethyl-4-(3-oxo- 235597 - 19 - 1-cyclopenten-l-yloxy)-6-methoxycarbonyl-3-chromanol in 100 ml of 33% ethanolic dimethylamine solution is heated to 100° in an autoclave for 10 days. The mixture is cooled, worked up in a customary manner and gives 2,2,3-trimethyl-4-( 3-oxo-l-cyclopenten-l-yloxy) -6-dimethyl-aminocarbonyl-3-chromanol. Example 13 HC1 is passed into a boiling solution of 1 g of "A" in 50 ml of methanol and 2 ml of water with stirring for 14 hours. The mixture is allowed to cool, worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-1-cyc lopent en-1 -yloxy) - 6 -carboxy- 3 -c hromano 1. Example 14 A mixture of 3.13 g of "A", 31 g of Na3P0* - 12H20, 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 filtration, the mixture is worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-yloxy ) -6-f ornry 1-3-chromanol. Example 15 3.13 g of "A" are dissolved in 45 ml of tert.-butanol and 5 g of powdered KOH are added with stirring. Boiling for 1 hour and customary working up gives 2,2,3-trimethyl-4-(3-oxo-l-cyclopenten-l-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 is evaporated, worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-l-yloxy)-6-thiocarbamoyl-3-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 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 insoluble polyvinylpyrrolidone (PVP), 1.5 kg of highly disperse Si02 and 1.5 kg </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 20 - 235597 of magnesium stearate is compressed in a customary manner to give tablets. Each 17 0 mg tablet contains 0.2 mg of active compound. Example B Coated tablets 5 Tablets are pressed analogously to Example A, but without adding PVP, and are subsequently coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant. Example C Capsules 10 Granules 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 disperse Si02 and 0.3 kg of magnesium stearate and the mixture is poured into hard gelatine capsules in a 15 customary manner so that each capsule contains 0.1 mg of active compound. Example D Lacquered tablets Tablet cores (170 mg) are pressed from 0.2 kg of "A", 151.3 kg of lactose, 10 kg of microcrystalline 20 cellulose, 5.5 kg of PVP, 1.5 kg of highly disperse Si02 and 1.5 kg of magnesium stearate, and are then lacquered in a customary manner so that each lacquered tablet is coated with 3.922 mg of a lacquer which consists of 2.2 mg of hydroxypropylmethylcellulose, 0.53 mg of 25 polyethylene glycol 400, 0.85 mg of Ti02 , 0.122 mg of Fe203 and 0.22 mg of silicone oil. Example E Ampoules A solution of 10 g of "A" in 70 1 of 1,2-propane-diol is made up to 100 1 with double-distilled water, 30 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 35 other active compounds of the formula I and/or their physiologically acceptable salts, are obtainable analogously. - 21 - WHAT WE CLAIM IS:

1. Chroman derivatives of the formula I in which X Z R1 and R5 R2 or r1 and R2 or r3 and R* R8 and R7 is O or NR11, is CH2/ 0, S or CHHal, are each A, is H or A, together may be alJcylene having 3-6 C atoms, is OH or QAc, is H, together may be a bond, are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-0, hydroxyalk, N02, NH. 2 / NHA, NAj, CN, F, Cl, Br, I, CF3, ASO, AS02, AO-SO, A0-S02, AcNH, AO-CO-NH, H2NS0, HANSO, HANCO, AS02NH, cyano- AjNSO, H2NS02, HANS02, A^SO;,, HjNCO A;NC0, H2NCS, HANCS, AjNCS, ASONH, AOSONH, A0S02NH, ACO-alk, nitroalk, alk, A-C (=N0H) or A-C(=NNH2), Ra and R8 are each H or A or together are =0 or =S, is H, Hal, CHO or CH20H, is H, A, Ac or CHjOH, ,10 V c .• » - 22 - m Hal A alk is 1, 2 or 3, is F, Cl, Br or I, is alkyl having 1-6 C atoms, is alJcylene 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-l-cyclopenten-l-yloxy) -6-cyano-3-chromanol.

3. Process for the preparation of. chroman derivatives of the formula I according to claim 1, 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 a ,8 III HX JO in which X, 2, R3, Ra, Ri0 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 R* is H, is dehydrated and/or in that one or more of the radicals X, Z, R3, R8 and/or R7 are converted into other radicals X, Z, R3, Re and/or R7 in a compound of the,--'"' ' -■* formula I and/or in that a basic compound of the formulas? 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 according to claim 1 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 according to claim 1 and/or one of its physiologically acceptable salts.

6. Compounds of the formula I according to claim 1 for the 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 the 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..

11. A process according to claim A substantially as herein described or exemplified.

12. A pharmaceutical preparation according to claim 5 substantially as herein described or exemplified. merck Latent gesellechaft mit MIT BESCH^RMIKTER HAFTUNG By Their/At/t( :orneys HENRY Hukihs LIMITED Per: I \ 'I9s </div>