NL8000861A - FUROCHROME DERIVATIVES AND PHARMACEUTICAL PREPARATIONS. - Google Patents

Description

Furochromone derivatives and pharmaceutical preparations.

The invention relates to "furochromone derivatives and pharmaceutical preparations prepared therefrom."

The structure of furochromone is shown in formula 1.

A derivative known under the names khelline and visamine is 7-methyl 1-4,9-dimethoxyfurochromone of the formula II, which has anti-atherogenic properties. Khelline and related furochromones are found in nature and have been used in raw form for centuries as pharmacological agents. Khelline is an extract from the 10 plant Ammi visnaga. It is found in the wild in the countries of the eastern Mediterranean. In addition to Khelline, Ammi visnaga is also a source of at least three other known and characterized fu-rochromones, in particular fishnagine (formula 3). Khellinine (formula k) and ammiol (formula 5). The systemic name of the compound with the Formula 2 is 7-methyl-1-H-methoxyfurochromone, that of the compound of the formula k 7-glucoyloxy-methyl-1-methoxyfurochromone, that of the compound of the formula k 7-hydroxy-methyl-h, 9-dimethoxyfurochromone and that of the compound of formula 5 7-hydroxymethyl-9,9-dimethoxy-20 furochromone.

In Ammi visnaga, khellinine and khelline are usually present in approximately equal amounts, while visnagine and ammiol are only present as minor or insignificant components. Khellinine is not of therapeutic significance, unlike Khellin which is more effective. See Anrep, G.V. et al., "The Coronary Vasodilator Action of Khellin" in the American Heart Journal 37: 531-5½ (19½). Anrep et al., Also report the biological activity of visnagine, which is similar to that of khelline. Khelline exhibits a broad spectrum of biological actions making it suitable for numerous pharmacological purposes (Huttrer, CP et al., Chem. Revs. * + 8-5 * 13-79 (1951) and Aubertin, E., J. Med. Bordeaux 127: 5 819-23 (1950)).

An important action of khellin is its ability to relax smooth muscle tissues. Khelline is known in particular as a powerful means of removing the coronary arteries. This potent coronary blood vessel dilating action of khellin makes the compound useful in the treatment of amgina pectoris and other diseases characterized by coronary artery insufficiency. For a description of the application of such diseases see Osher, H.L. et al., "Khelline in the Treatment of Angina Pectoris", New England Journal of Medicine 2¼: 315 (1951). Results with coated khellin for activity in the gut in cases of coronary artery insufficiency are reported by Best, M.M., et al. In J. Med. Sic. 222: 35-9 (1951).

The ability of khellin to relax the smooth muscle also extends to the smooth muscle of the gastrointestinal tract, where khellin has been shown to inhibit peristalsis, indicating anti-diarrheal activity. See Ramend-Hamet, Comp. Run. 238: 162 ^ -6 (195 * 0) Khelline may also be useful for treating gastrointestinal disorders, which exhibit a spasmotic component, as suggested by the above Anrep, CB, et al. Furthermore, the anti-spasmotic results van Khelline on the urethra described by Colombo, G., et al., Arch, Sci. Med. 97: 71095 * 0 and Manlorse, W, et al., Presse Med. 63:81 (1955)

The anti-spasmotic action of khellin also extends to the bronchial smooth muscle, making khellin useful in treating asthma and other hypoxic pulmonary lung diseases. In this regard, see Silber, E.N., et al., "The Effect of Khelline on Cardio-Pulmonary Function in Chronic Pulmonary Disease" (1951) and Anrep, C.V. et al., "Therapeutic Uses of Khelline", The Lancet, April 26, 19 * + 7 "biz · 557-8.

35 By Jordan, H., Arzneimittel-Forsch 8: 1 * + 1-3 8000861 s * bv 3 ί.

(1958) and 7: 82-5 (1957), it has been reported that Khelline has a hypotensive effect on humans. An additional report on the hypotentive activity of khellin is provided by Lian, C., et al.,

Acta. Cardiol (Brussels) 5: 373-88 (1950). Regarding the total cardol effect, however, khellin is reported to decrease this while khelline stimulates it. In this regard, see Samaan, K., et al., J.

Roy. Egept. Med. Assoc. 33,953 (1950) and J., Pharm. Pharmacol. 1: 538-UU (19 ^ 9).

In addition to the aforementioned action on the smooth muscle of the gastrointestinal tract, khellin is also known as a means of inhibiting gastric secretion and ulcer formation.

Anti-gastric secretion has been described by Hans, M.J., et al. In Compt. Run. Soc. Biol. 1501806-7 (1956) and 150: 598-9 (1956).

For a report of the antihelmintic, see Boytop, D.T., Folia, Pharm. (Turkey) 1: U8-9 (19 ^ 9)> for a report of the depressant effect of khelline to Chen, G., Proc. Expetl. Biol. Med. 78: 306-7 (1961); for a report of the cytostatic action of khellin to Apfsel, C.A., Deut. Med.

20 Wochschr. 90: ^ 1 ^ -16 (1955) »and for a report of the spermic action of Swayne, V.R., et al., Aman, J. Pharm. 125: 195-8 (1953).

Atherosclerosis in mammals is a disease that. is characterized by the deposition of atheroslerotic plaque on vessel walls. Although atherosclerosis comes in many different forms, it usually leads to angina pectoris, myocardial infarctions, seizures and transient ischemic seizures of the brain. Other forms of atheroslerotic diseases are certain peripheral vascular diseases and other ischemic diseases (for example, intestines and kidneys).

Certain forms of atheros-30 clerose have been found to be preventable or reversible. Agents capable of preventing or reversing atherosclerosis are characterized by their antiatherosclerotic action. Since serum lipids are atherogenetic, an important class of antiatherosclerotic agents is those with serum lipid modifying actions. Serum lipids that are involved in atherpgenesis include serum 8000861

V

It is cholestoerol, serum triflycerides and serum lipoproteins.

Regarding serum lipoprotein, at least three different classes of these substances have been characterized: high specific weight lipoproteins (HDGL), low specific weight (LSGL) and 5 very low specific weight lipoproteins (ZLSGL). HSG lipoproteins are often referred to as alpha lipoproteins, and those with LSG and ZLSG beta lipoproteins. It is believed that increasing to HSGL levels (hyperalfalipoprotein activity) has direct antiatheroclerotic effects. See Eaton, R.P., J. Chron. Piss. 31: 131-135 10 (19Τδ). In contrast, agents that lower serum LSGL and serum ZLSGL (hypobetaprotein agents) lead to antiatherogenic effects. See Haust, MP, "Reaction Patterns of Intimal Mesenchyme to Unjury and Repair in Antherosclerosis Adv. Exp. Med. Biol. U3: 35—57 (197 * 0, claiming that serum LSGL is a factor in the forms of antherosclerotic damages.

Numerous animal experiments have been developed to determine antiatherogenic activity. The most important of these are those for determining hypobetalipoprotex activity in the rat, anti-therosclerotic activity in the Japanese quail and lipoprotein modifying activity in the monkey. For a description of the action of the hypobetalipoprotein on rats, see Schurr, P.

E., et al., "High Volume Screening Procedure for Hypobetalipoproteinemia Activity in Rats", Adv. Exp. Med. Biol. 67: Atherosclerotic Drug Discovery, p. 215 229, Plenum Press (1975) »and for a description of the action on the Japanese quail to Day, CE, et al.," Utility of a Selected Line (SEA) of the Japanese Quail (Cotumic Cotumix Japonica) for the Discovery of New Anti-Atherosclerosis Drugs ", Laboratory Animal Science 27: 817-821 (1977).

A suitable primate for determining the anti-arherosclerotic activity of chemical compounds has been found in the cynomolgus monkey. In these animals, baseline values for ZLSGL, LSGL and HSGL can be determined by controlling the diet for several weeks and taking plasma samples daily. After establishing comparison values, the results of the treatment with the drug are determined by administering a given series of 8000 861 e *% 5 doses of test compound over a similar period (eg, 2 weeks).

U, 9-Dimethoxy furochromones are known, e.g., inter alia, 7-ethyl, 7-phenyl, 7-propyl and 7-ethoxycarbonyl-5 analogs described by Shonberg A., et al. In JACS 72: 1611-17 (1950 ); 7-Y-pyridyl analogues, described by Shonberg, A. in JACS 77 * 5 ^ -39 (1955); 7-furanyl analogs, described by Musante, C, et al. In Pharmaco (Pavie) Ed. Sci. 15: 81-9 ** (i960); 7-carboxyaldehyde analogs, described by Mustafa, A., et al. In J. Org. Chem. 26:86 (1961).

Also known are 6-substituted U, 9-dimethoxy furochromones, eg the compounds described by Hamed, Abu-Schady in UAR J.

Pharm. Sci. 11: 283 (1970). In addition, U-methoxy-7-aminomethylene furochromones have been described by Abu-damage, H. et al. In J. Pharm.

Belgian. 33: 397 (1978).

As mentioned above, extensive pharmacological applications are known for khellin and related substances as well as for khellin analogues, in particular the halofurochromone analogues, namely 6-chloroethyl or 6-iodomethyl furochromones (Hamed, Abu-Schadz, UAE J. Pharm. Sci., 11: 283, (1970) and 6,7-dihalo-6,7-20 dihydroxy furochromones (Fabbrini, L., Ann. Chim. (Rome), U6: 130 (1956))

The invention relates to new furochromone derivatives of the formula 6, wherein A

(a) -CH = CR13-; (b) -CX = CRlir; (C) -CR1 τ-0 (£! Η3) -5 (d) -CH2-CHRlir; (e) -CHR17-; wherein R 1 is -CH 2 S R 10, -CH 2 SO R 10 or -CH 2 (SO 2) R 10, wherein R is an alkyl group of 1 to 5 carbon atoms;

R1U

(a) hydrogen; (b) an alkyl group of 1 to 8 carbon atoms; (c) alkoxymethyl group of 2 to 8 carbon atoms; (D) alkylthiomethyl group of 2 to 8 carbon atoms; 8 0 0 0 8 6 1

V

6 (e) trifluoromethyl group; (f) phenoxymethyl group; (g) phenylthiomethyl group; (h) phenoxymethyl group or phenylthiomethyl group, substituted by a chlorine or fluorine atom, a trifluoromethyl group, alkyl group with 1 to 3 carbon atoms or alkoxy group with 1 to 3 carbon atoms or (i) cycloalkyl group with 3 to 3 Is 10 carbon atoms, wherein (a) is an isopropyl group; (B) alkyl group with U through 8 carbon atoms; (c) alkoxymethyl group with 2 to 8 carbon atoms; (d) alkylthiomethyl group with 2 to 8 carbon atoms; (e) tri fluoromethyl group; (f) phenoxymethyl group; (G) phenylthiomethyl group; (h) phenoxymethyl group or phenylthiomethyl group, substituted by a chlorine or fluorine atom, a trifluoromethyl group, alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms; (I) cycloalkyl group of 3 to 10 carbon atoms; (j) -CH2-S-R10, -CH2-S0-R1q, or -CH2-S02-R10 wherein R1Q is an alkyl group of 1 to 5 carbon atoms or (k) -CHgHRgR ^ where Rg and R ^ hydrogen, an alkyl group of 1 to 12 carbon atoms or aryl group of 6 to 12 carbon atoms and which may or may not be the same in which Rg and R1 together with N form an unsaturated or unsaturated heterocyclic ring having 2 t / m 7 carbon atoms and 0,1 or 2 other hetero atoms, with the proviso that the heterocyclic ring contains U to 8 atoms in the ring and the other hetero atoms are oxygen, nitrogen or sulfur, which are heterocyclic ring is optionally substituted by an alkyl group of 1 to h carbon atoms. alkylthiomethyl group or alkoxymethyl group having 2 to 8 carbon atoms, hydroxyalkyl group having 1 to 1 * carbon atoms or phenyl group, with the proviso that R 1 represents only -CHgRRgR R 2 when R 1 represents methoxy group; R17 is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; 8000861 * * 7 one the groups R 1 or R 1 represents a methoxy group and the other represents a methoxy group or hydrogen; X is a chlorine, iodine or bromine atom;

RgQ and Rgi together form an oxo group or one of the groups and Rg1 is a hydroxy group and the other hydrogen, with the proviso that Rgg and Rg together form an oxo group only when A does not represent -CSg-CHR2 and of the groups RgQ and R ^ the one represents a hydroxy group only when A is -CHg-CHR ^ -; and its pharmacologically acceptable acid addition salts, when R 1 is -CHg-NRgRp.

According to the present process, a 7-substituted furochromone, when A is -CH 1 R 2 - in formula 6, i.e. the compound of formula 7, is a 6-halo-furochromone, when A -CX 1 CR 1 - in formula 6, i.e., the compound of formula 8, is a 6-S-substituted furochromone when A is -CR ^ ^ CiCH ^) - in formula 6, i.e., the compound of formula 9 »A 5-hydroxy-6,7-dihydrofurochromone when A is -CHg-CHR 2 in the formula 6, ie the compound of the formula 10 and a benzodifuran when A is -CHR 2 - in the formula 6, which i.e. the compound of formula 11.

The new furochromones of the formula 6 and the khellin-related products of Amni visnaga are all characterized by a pronounced anti-atherogenic action, which makes these compounds useful for treating and preventing atherosclerosis, atherogenic hyperliproteinemia (ie hypofetalipoprotein mia ) and its consequences.

People susceptible to atherosclerotic disorders and their consequences are, in particular, those physically asymptomatic patients who exhibit one or more risk factors known to have a predisposition to the development of the disorders. Such risk factors are high serum cholesterol, serum triglycerides, hypertension, fat, diabetes and a genetic predisposition. People showing two or more risk factors should be considered to be particularly susceptible to atherosclerotic diseases. The products associated with khellin 8000861 8 and furochromones of the formula 6 all exhibit pronounced oral pharmacological activity and are therefore preferred for oral administration, although other methods of administration are also contemplated, for example, rectal, vaginal, subcutaneous, intra-venous. Oral preparations include capsules and tablets.

To achieve immediate pharmacological action, the patient should be treated periodically with doses that decrease atherogenic serum lipoprotein levels (e.g., beta lipoproteins) or selectively increase antiatherogenic serum lipoprotein protein levels. Such effective doses can be readily determined on known methods. Small daily doses (50-100 mg) can be administered initially with higher subsequent doses until beneficial effects on atherogenic or antiatherogenic serum lipoprotein levels are achieved. For example, first in doses of 15 only about 50 mg per patient / day increasing doses to about 200 mg per patient / day. If the antiatherogenic response of a patient being treated with a dose of 200 mg / day is insufficient, the dose will be increased as permitted. In order to achieve more even serum levels, the preparation is administered 20 times a day (for example, k-6 times a day). With U x daily administration, the dose is usually up to 50 mg.

Doses of 1-5 mg / kg / day are usually used for animals.

The above products related to khellin are the anti-atherosclerotic active substances from Amni visnaga and in particular the compounds of formulas 2-5.

The new 7-substituted furochromones of the formula 7 are substituted in the C-7 position by R1. R ^ has preferred meanings and are the same as for the group R ^ and -CHgNRgR ^ discussed below.

The preferred 6-halofurochromones of the formula 8 are those with halogen (chlorine, bromine or iodine) instead of hydrogen at the C-6 site of the skeletal structure of khellin. These 6-halofurochromones can optionally also be substituted by 35 R 4 in the C-7 position, for example, by an alkyl, alkoxy, methyl, alkylthiomethyl, phenoxy methyl, phenylthio-methyl or hydroxymethyl group. Of the above mentioned, particular preference is given to those compounds in which there is a hydrogen atom or methyl group.

The 6-S-substituted furochromones of the formula 9 are substituted in the C-6 position by an alkylthiomethyl, alkylsulfinylmethyl or alkylsulfonylmethyl group with preference for the methylthiomethyl group.

The 5-hydroxy-6,7-dihydrofurochromones of the formula 10 are substituted in the C-7 position by R 1, the preferred meanings of which are set forth above.

Benzodifurans of the formula II preferably contain a hydrogen atom at the C-6 position.

Examples of alkyl groups having 1 to 8 carbon atoms are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, ethyl group and isomeric forms thereof.

Examples of alkoxymethyl groups having 2 to 8 carbon atoms are the methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentoxymethyl, hexoxymethyl and heptoxymethyl group and isomeric forms thereof.

Examples of alkylthiomethyl groups are the methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, pentylthiomethyl, hexythiomethyl and heptylthiomethyl group.

Examples of cycloalkyl groups with 2 to 10 carbon atoms are the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclodecyl group.

Examples of alkyl groups with 1 to 5 carbon atoms are the methyl, ethyl, propyl, butyl and pentyl group and their isomeric forms.

Examples of alkyl groups with 1-3 carbon atoms are the methyl, ethyl, propyl, n-propyl group and isomeric forms thereof.

Examples of aryl groups with 6 to 12 carbon atoms are the phenyl, o-naphthyl, fJ-naphthyl, m-methylphenyl, 8000861 p-trifluoromethylphenyl group and the like.

Examples of heterocyclic amines corresponding to the heterocyclic rings according to -NRgR ^ are: thiazolidine, 5-piperidinethanol, 2-piperidinethanol, piperadic acid, 3-piperidin-ethanol, 2-piperidine-ethanol, 10-piperazinepropanol, p- piperazinoacetoxyphenone, H-phenyl-1,2,3,6-tetrahydropyridine, U-phenylpiperidine, proline, 15 3-pyrolin dinol, tetr ahy dro fur fury lamine, pyrrolidimethanol, 3-pyrroline, thiazolidine-U-carboxylic acid, 20 thromorpholine, nipeestamide, morphholine, 2-methylpiperidine, 3-methylpiperidine, 25 U-methylpiperidine, N-methylpiperaze and -1-methylhomopiperazine.

Schemes A-F show methods by which the new furochromones of the formula VI are prepared. In these 30 schemes, X, R ^ »R ^, Rg» R ^, R10 »R. ^» R-jg »RΊ and R-, γ have the meanings indicated above.

The various 6-halofurrochromons listed herein, including their intermediates, are all prepared by methods shown in Schemes A and B. In these schemes 35, the group R12 represents the group R ^ or R ^ but no hydrogen atom. X is a chlorine, bromine or iodine atom.

3000 861 11

Referring to the reaction scheme, the compound of formula 21, khelline or U- or 9-desmethoxykhelline is converted to the methyl ketone of formula 22 at elevated temperature by hydrolysis under basic conditions, for example, aqueous potassium hydroxide. See E. Spath and W. Gruber, Chem. Ber. 106 (1938).

The benzofuranol of formula 22 is then converted to the 8-diketone of formula 23 by a Claisen condensation with a carboxylic acid ester, in which the carboxylic acid residue corresponds to the keto group, which is bound to the product of formula 23. Accordingly, the preparation of the compound of formula 23 uses a carboxylic acid ester of the formula R 1 COORg, wherein Rg is the ester moiety (e.g. preferably a simple alkyl ester such as methyl or ethyl). The reaction proceeds smoothly in an organic solvent in the presence of sodium hydride, followed by treatment with chlorine acid and alcohol. Preference is given to 3-¾ equivalents of sodium hydride and 2-3 equivalents of carboxylic acid ester per equivalent of the starting material of the formula. Furthermore, the reaction proceeds in a minimal amount of the organic solvent necessary for solubilizing the reaction components. Usually an aprotic polar solvent such as tetrahydrofuran can be used well. However, in preparing the formula 23 product, R.J2 is not a small residue with a low mole. weight; the ester itself, R ^ COORg, is used as a reaction diluent.

Therefore, in preparing the compound of formula 2k, the intermediate of formula 23 is normally not separated but rather directly subjected to acid-catalyzed cyclodehydration to yield the furochromone of formula 2k. This cyclohydration usually proceeds in the presence of an inorganic acid in an organic solvent, such as an alkanol (e.g. hydrochloric acid in methanol). However, when preparing the compound of formula 2U, wherein R 1 is a trifluoromethyl group, the chlorinated hydrocarbons form preferred reaction diluents.

The compound of formula 25 is then prepared from that of formula 2k by decylization with pyrrolidine.

8000861 12

The reaction proceeds in the presence of several equivalents of pyrrolidine per equivalent of compound of formula 2k at elevated temperature (e.g., reflux temperature of methanol).

Optionally, the compound of Formula 5 is directly converted to that of Formula 25 using methods and reagents used in the above-described conversion of the compound of Formula 2k to that of Formula 25. This optional method is preferred only when it represents a bulky group. Then the halogenated product of formula 26 is prepared by first halogenating the compound of formula 25 by adding molecular halogen (eg bromine in chloroform) followed by hydrolysis, whereby the 6-halo furochromone of the formula 26 is obtained. As for the halogen ring stage, other conventional halogenating agents can also be used, for example, hypochlorites. As for the latter reaction, the addition of water to the halogenated product accomplishes the desired hydrolysis and cyclodehydration.

When in scheme A is a methyl group, the compound of formula 26 is prepared directly from that of formula 21 via the pyrrolidyl intermediate of formula 25.

Scheme B shows a method by which the 6-halofurochromones described herein, wherein R 1 is a hydrogen atom (i.e. the compound of formula 33), are prepared with the benzofuranol of formula 31.

According to scheme B, the compound of formula 31 is treated with N, N-dimethylformamide demethyl acetal at an elevated temperature to obtain the enaminoketone of formula 31. Then, the compound of formula 33 from that of formula 32 is prepared by the method described in scheme A for preparing the compound of formula 26 from that of formula 25.

Scheme C gives a preferred method of preparing the compounds of Scheme A wherein the group represents R 1 -CHgNRgR 2.

8 0 0 0 8 6 1

* V

13

According to the method of scheme C, the compounds of the formula 2k from scheme A, wherein the group -®2 represents "S-CH2", are used as the starting compound of the formula H1. This compound is then converted into that of the formula 5 by treatment with methyl iodide in a chlorinated hydrocarbon, i.e. dichloromethane The compound of formula h2 thus prepared is then converted to that of formula 1 * 3 by treatment with the amine corresponding to the compound of formula 1 * 3.

Scheme D gives a method whereby the compound 10 of formula 51 »prepared according to scheme A (formula 2k) is converted into the various 6-S-substituted furochromones of formulas 53 and k.

The compound of formula 51 is first converted to that of formula 52 by treating with methyl fluorosulfonate-15 fluoride (CH2 OSOgF). The resulting sulfonium fluorosulfate (Formula 52) is then converted to the compound of Formula 53 by treatment with base (e.g. potassium hydroxide or potassium tert-butanolate. The reaction proceeds at room temperature in an organic solvent e.g. tetrahydrofuran and water.

The furochromone of the formula 53 thus prepared is then optionally oxidized in a known manner to the sulfinyl sulfonyl compounds of the formula. In the oxidation, for example, m-CBPA (metachloroperbenzoic acids) in a chlorinated hydrocarbon solvent (for example dichloromethane) is used.

Scheme E indicates a method by which the 6-bromofurochromone of the formula 61, prepared according to scheme B (the compound of the formula 33) is converted into the benzodifuran of the formula 6U.

In Scheme E, R 1 and 1 mean such that NER 1 R 1 represents a primary or secondary amine (eg, pyrrolidine).

The compound of formula 62 in scheme E is prepared from that of formula 61 by reaction with a primary or secondary amine, that is, presence of methyl 35 cyanide and potassium carbonate.

8000861

1U

The connection obtained with the. formula 62 is then treated with strong mineral acid (e.g. 6N hydrochloric acid) to yield the product of formula 63.

This product is optionally alkylated until the compound of the formula 6b is obtained by treatment with the corresponding alkyl halide in the presence of base.

Scheme F gives a method by which the compound of formula 71 prepared according to scheme A (formula 2b) is converted into the 5-hydroxy-6,7-dihydrofurochromone products of formulas 72 and 73.

The compound of formula 71 is converted to that of formula 72 by reduction preferably with a boron hydride, in particular sodium borohydride. The compound of formula 72 is then epimerized at the C-5 site to the compound of formula 73, for example, by conversion to the alkyl phosphyl sulfonate, for example, mesilate or tosylate, by reaction with the corresponding alkyl or aryl sulfonyl chloride in an amine such as solvent, for example pyridine. Thereafter, the epiomerization is completed by reaction of the sulfonate with tetra-n-butyl-ammonium acetate, followed by treatment with a deacylating agent, for example, potassium methoxide in methanol. See Baker, R., et al., JACS 1605: 1965 or Corey, E.J., et al., Chemical Communication 16: 658 (1975).

Pharmacologically acceptable acid addition salts described herein are prepared by neutralizing the free base with an inorganic or organic acid, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, lactic, benzoic, salicylic, glycolic, tartaric, tartaric, maleic, malic, tynoic, cyclohexene sulfamic, citric and methanesulfonic acids. When the acid is soluble in water, the free base can be dissolved in water containing an equivalent amount of the acid and evaporated.

In some cases, the salt precipitates from the aqueous solution, especially when cooled so that evaporation is not necessary. When the acid is soluble in a relatively non-polar solvent, for example diethyl ether or di-isopropyl ether, individual solutions of the acid and the free base in such a solvent can be mixed in equal amounts to which the acid addition salt will usually precipitate due to its relatively low solubility in the non-polar solvent. Also, the free base 5 can be mixed with an equivalent amount of the acid in the presence of a solvent of moderate polarity, for example, a lower alkanol, lower alkanone or a lower alkyl ester of a lower alkanoic acid. Examples of these solvents are ethanol, acetone or ethyl acetate. When the resulting solution of acid addition salt is mixed with a solvent of relatively low polarity, for example diethyl ether or hexane, the acid addition salt usually precipitates.

Example I

6- Hydroxy - ^, T- ^ iniethoxy-5-benzofuranylmethylketone (Formula 22 in Scheme.-A)

To a stirred solution of potassium hydroxide (193.2 g) in 1.5 l of water, heated to 75 ° C, is added 300 g of khellin (formula 21) in 50 g portions over 30 minutes. When the addition of khelline is complete, the resulting mixture is heated to reflux for 2 hours and then cooled to room temperature. Strong hydrochloric acid (300 ml) is then added to the cooled solution and the resulting precipitate is filtered off and dried in a vacuum at room temperature for 18 hours. The crude yellow solid obtained is then recrystallized from 11 methanol to give 251 g of pure title product. The melting point is 99-100 ° C. in TLC over silica gel is 0.60 in hexane and ethyl acetate (1: 1 ratio). Infrared absorption 3160, 31 ^ 0, 1700, 1695, 1680, 1620, 1590, 1550, 1300, 1265, 1150, 1075 and 1060 cm ”1.

KMR absorption: 7.52, 6.91, ^, 15, ^, 05, 2.72 and 13.06 ppm (deutero-30 chloroform). Mass spectrum maxima at: 236, 221, 206, 203, 191 »175» 163 and 119The carbon: hydrogen ratio is 60.65: 5.15

Example II

7- Methoxymethyl-U, 9-dimethoxyfurochromone (formula 2h in scheme A: R ^ and R ^ both represent a methoxy group and a methoxy-methyl group) .________ 8 0 0 0 8 6 1 16

To sodium hydride (20.1 g of a 50% dispersion in oil) and tetrahydrofuran (20 ml freshly distilled with lithium aluminum hydride) combined in a nitrogen atmosphere under a nitrogen atmosphere, a mixture consisting of the product of formula 22 is added dropwise. from Example I (20 g), methyl methyl acetate (26.1 * g) and dry tetrahydrofuran (50 ml). After completion of the addition (1.5 hours, the reaction mixture is heated on a steam bath for 15 minutes and then cooled to room temperature. Then excess sodium hydride is decomposed by carefully adding ice and water (300 ml). Washing with diethyl ether (600 ml ) yields an aqueous layer, which is diluted with methanol (100 ml) and strong hydrochloric acid (75 ml) This mixture is heated to reflux for 1 * 5 minutes and then allowed to cool to room temperature After extraction with methylene chloride (600 ml), the organic extracts are dried and concentrated under reduced pressure to give a solid (26.2 g) Recrystallization from methanol gives 18.33 g of the pure product named Melting point is 116 -117 ° C. Rf at DCL over silica gel: 0.57 (in ethyl acetate) Infrared absorption: 31 ** 0, 3120, 1665, 161 * 5, 1620, 1550, 11 * 85, 1370, 20 1360, 1125, 1105, 1075, 1060, 855 and 870 cm -1. KMR absorption: 7.66, 7.02, 6.30, 1 *, 1 * 0, 1 *, 21, l *, 0l *. and 3.51 ppm (deuterochloroform). Mass spectrum maxima at 290, 275, 261, 21 * 6, 219, 201 and 287. The carbon: hydrogen ratio is 61.96: 5.03.

The various 7-alkoxymethyl furochromones of the formula II * are obtained by the method of Example II, but replacing the methyl methoxy acetate with corresponding methyl alkoxy acetates.

Example III

7-Methyltimethylethyl-1 *, 9-dimethoxyfurochromone (formula 2k in scheme A: 30 and both represent a methoxy group and R ^ is a methylthio-methyl group).

Using the method of Example II, but using ethyl 2- (methylthio) acetate (56.5 g) instead of methyl methoxyacetate, the product prepared in Example I (50 g) * 17.0 g of pure is prepared title product as a tan solid. The melting point is 11 * 8-150 ° C. The Rf at TLC over silica gel is 0.63 in ethyl acetate.

Infrared absorption; 1650, 1625, 151 + 5, 11 + 80, 1380, 1125, 1070, 1θβθ, 81 + 5 and 760 cm 1. KMR absorption; 7.19, 7.05, 6.18, 1 +, 2, 1 +, 05, 3.6θ and 5 2.25 ppm (deuterochloroform solvent). Mass spectrum maxima at 306, 291, 277, 259, 2l + 1, 231, 216 and 201. The carbon; hydrogen; xwavel ratio is 58.87: 1 + .76; 10.62.

By the method of Example III but using suitable methyl or ethyl 2- (alkylthio) acetate instead of ethyl 2- (methyl acetate), the corresponding compounds of the formula II +, wherein R 1 represents an alkylthiomethyl group, are obtained.

Example IV

7-Phenylthiomethyl-1 +, 9-dimethoxyfurochromone (Formula 2 + in Scheme A: R 1 and R 2 both represent a methoxy group and is a phenylthimethyl group).

To a suspension of sodium hydride (32.1 + 1 + g) of a 50% dispersion in oil) and tetrahydrofuran (25 ml freshly distilled with lithium aluminum hydride) is added under a nitrogen atmosphere a mixture of the product prepared in Example I ( 1 + 0.0 g), methyl 2- (phenylthio) acetate (61 +, 2 g) and tetrahydrofuran (75 ml). After completion of the addition (1 hour), the resulting mixture is cooled to room temperature and gently quenched (decomposition of sodium hydride with water, 150 ml). The resulting mixture is washed with diethyl ether (800 ml) and the resulting aqueous solution is diluted with methanol (300 ml) and strong hydrochloric acid (200 ml). After heating at reflux for 3 hours, the solution is cooled to room temperature, extracted with methylene chloride, dried with sodium sulfate and concentrated under reduced pressure, 3 °, to give a brown substance. Taking this up in methanol (100 ml) and filtering gives 31.57 g of pure title product. The melting point is 132-13l + ° C. Rf at TLC over silica gel: 0.1 + 6 in hexane and ethyl acetate (1: 3 ratio). Infrared absorption: 311 + 0, 3120, 1690, 1620, 1590, 151 + 5, 11 + 85, 1385, 1365, I3I + 5, 1210, 35 10.25, 1070, 1055 and 1035 cm "1. KMR absorption: 7.18, 7.20-7.55, 7.0, 8000861 18 6.08, 1 +, 15, 1 +, 05 and 3.98 ppm (deuterochloroform solvent) Mass spectrum maxima at 368, 260 .259, 258, 231 and 216. The carbon: hydrogen: sulfur ratio is 61+, 98: U, 2U: 8.56.

By the method of Example IV but using the appropriate methyl 2-phenyl (thio) alkyl acetate of methyl

2- (phenylthiomethyl acetate, the corresponding products of the formula II + are obtained, which represents a phenylthioalkyl group. Example V

7-Isopropyl-1 +, 9-dimethoxyfurochromone (formula 2k in scheme A: R ^ and 10 R ^ both represent a methoxy group and R ^ is an isopropyl group)

To a mixture of the product prepared in Example I (50 g) and methyl isopropylcarboxylate (300 ml) is added sodium hydrate (1 + 0 g as a 50% dispersion in oil) in a nitrogen atmosphere over 25 minutes. When hydrogen gas evolution ceases, the reaction mixture is heated to reflux for 22 hours and then cooled to room temperature. Quenching (decomposition of sodium hydride) with water and diluting with diethyl ether gives a 2-phase system, from which the aqueous phase is separated 2Q and washed with diethyl ether (200 ml). The aqueous phase is then acidified with 25% hydrochloric acid and extracted with diethyl ether (1 + 00 ml). The combined ether extracts are dried over magnesium sulfate and concentrated under reduced pressure to obtain a light brown oil. This is diluted with methanol 2 ^ (300 ml). Dry salt hydrogen chloride is passed through the methanol solution. The methanol solution is then refluxed for 2 hours, cooled to room temperature, diluted with water (200 ml) and extracted with methylene chloride (1 + 00 ml). The combined organic extracts are then dried over magnesium sulfate and concentrated under reduced pressure to give a light tan oil, which is crystallized in ethyl acetate and hexane. Yield 3-3.3 g of practically pure title product. The melting point is 116-118 ° C.

Chromatography of a sample of the pure product, 16.0 g, over 1.35 kg of silica gel packed in hexane and ethyl acetate (ratio 1: 1) and elution with this solvent yields 13.98 g of pure 8000861 19 the title called product.

Rf Pij DLC over silica gel: 0.66 in hexane and ethyl acetate (ratio 1: 1). Infrared absorption 3130, 3100, 1650, 1625, 1595, 15 * 10, 1U80 and 1075 cm -1. KMR absorption: 7.6 * 1, 7.0, 6.07, * 1.15, * 1.01, 2.90 and 1.31 δ (solvent) Mass spectrum maxima 288, 273, 259, 2 * 15, 5 2, bk, 217, 2.15 and 177. The carbon : hydrogen ratio is 66.73: 5.52.

By the method of Example V, but using the appropriate methyl alkanoate instead of methyl 2-methylpropionate, the corresponding compound of the formula: 10 * 1, wherein R12 is an alkyl group, is obtained.

Example VI

7-Cyclopropyl-, 1,9-dimethoxyfurochromone (formula 2k in scheme A R ^ and R ^ both represent a methoxy group and R ^ 2 is a cyclopropyl group).

Using the method of Example V, using methyl cyelopropane carboxylate (75 g) in place of methyl isopropyl carboxylate, the product (15 g) prepared in Example I is converted into 8.60 g of pure crystalline title product. The melting point is 135-137 ° C. The Rf at TLC over silica gel: 0.55 in hexane and ethyl acetate (1: 1 ratio). Characteristic infrared absorption: at 3130, 3100, 1650, 1625, 1595, 15 * 10, and lU80 cm “1. KMR absorption: 7.62, 7.0, 6.1, U, 13, U, 13, * 1.02, 1.7-2.11 and 0.98-1.28 pnm (deuterochloroform solvent) . Mass spectrum maxina at 286, 271, 237, 2 * i3, 215, 177, 1 * Φ and 1 * i7. The carbon, hydrogen ratio is 67.00: 1.86.

By the method of Example 6, but using the appropriate methyl cycloalkanecarboxylate instead of methyl cyelopropanecarboxylate, the corresponding compounds of formula (2b) where R 1 is a cycloalkyl group are obtained.

Example VII

7-Undecyl-, 1,9-dimethoxyfurochromone (formula 2 * 1 in Scheme A: R 1 and R 1 both represent a methoxy group and R 12 is an n-un-decyl group).

To a mixture of the product prepared in Example I (60 g) and ethyl laurate (500 g) is added sodium hydride (U5 g in a 50 # oil dispersion) in a nitrogen atmosphere in 35 minutes.

8000861 20

After completion of the addition, the reaction mixture is heated at 80 ° C for 1.5 hours and then cooled to room temperature. After solidification of a light brown mass, water (dropwise) and diethyl ether (500 ml) are used to quench the reaction mixture.

Then further water (to a total of 200 ml) is carefully added and the aqueous layer is separated. The aqueous layer is washed with diethyl ether and then diluted with chloroform (300 ml) and acidified with 25% hydrochloric acid. The chloroform layer is separated and the aqueous layer is extracted with chloroform (100 ml). The combined organic phases are dried and filtered. After drying, anhydrous hydrogen chloride is passed through the chloroform solution for several minutes, after which the solution is heated at reflux for 1 hour. After cooling to room temperature, the chloroform is removed under reduced pressure to obtain a brown oil (95.32 g) which solidifies.

Chromatography of a sample of 5 g of the oil on silica gel packed in ethyl acetate and hexane (ratio 1: 1) gives 2.35 g of pure title product. The melting point is 78-T9 ° C.

Rf at TLC over silica gel: 0.73 in hexane and ethyl acetate (20: 1: 1 ratio).

Infrared absorption: 3120, 306o, 1660, 1620, 1555, 11 * 85, 1375, 1360, 1125, 1095, 81 * 5, 765 and 720 cm ”1. KMR absorption: 7.65, 7.03, 6.1, 1 *, 2, 1 *, 08, 2.65, 1.05-1, 90 and 0.87 ppm (deuterochloroform solvent) .Mass aspect took maxima at 1 * 00, 386, 385, 371, 357, 329, 25 3.15, 229, 177, 105, ** 3 and 1 * 1, The carbon to hydrogen ratio is 71.88: 8.27.

By the method of Example VII, but using the appropriate ethyl alkanoate in place of ethyl laurate, each of the corresponding products of the formula IIU wherein R130 is an alkyl group is obtained.

Example VIII

7-Trifluoromethyl-1 *, 9-dimethoxyfurochromone (Formula 2 * in Scheme A: R 1 and R 2 both represent a methoxy group and R 12 is a trifluoromethyl group).

To a sodium hydride (1 * 0.51 g of a 50% dispersion in 8000861 21 oil) is added under a nitrogen atmosphere a mixture of the product prepared in Example I (50 g) and ethyl trifluoroacetate (90 g).

After the addition is complete, the resulting mixture is stirred at room temperature for an additional 30 minutes. The reaction mixture is then gently quenched with water (200 ml), followed by addition of diethyl ether (500 ml). The aqueous phase is separated, washed with diethyl ether (500 ml), diluted with chloroform and acidified with 10 # hydrochloric acid. The chloroform layer is separated and the aqueous layer is extracted with chloroform (100 ml). The combined organic phases are dried over magnesium sulfate and filtered. Dry hydrochloric acid is introduced into the chloroform solution for several minutes, followed by heating at reflux for 5 minutes. The resulting mixture is then allowed to cool to room temperature and the solvent is removed under reduced pressure to obtain a dark brown solid. After washing with diethyl ether (200 ml), 35.26 g of pure title product are obtained. Recrystallization from ethyl acetate in hexane gives a product, mp 266-268 ° C.

Rf at TLC over cilicle gel: 0.57 in 5% ethyl acetate in chloroform.

20 Infrared absorption: 3130, 1665, 1650, 1550, 1U80, 1270, 1215, 11δ5, 11 ^ 5, 1135, 1070, 950 and 870 cm ”1. KMR absorption: arrive at 7.69, 7.05, 6.60, U, 21, and U, 03 ppm (deuterochloroform solvent). Mass spectrum maxima at 31, 299, 285, 271, 270, 2U3, 215, 200, 120 and 105. The carbon: hydrogen fluorine ratio is 53.77: 2.92: 18.08.

Using the methods of Examples II-VIII, each of the various compounds of Formula 2k from Scheme A is prepared from the product prepared in Example I and the appropriate carboxylic acid ester.

Example IX

30 1— (6-Hydroxy-11,7-dimethoxybenzofuranyl) -3- (1-pyrrolidinyl) -2-buten-1-one (Formula 25 in Scheme A: and ^ both represent a methoxy group and * 12 is a methyl group).

A solution of khelline (5.2 g) in methanol and pyrrolidine (2.82 g) is heated at 80 ° C for 6 hours. After cooling, clear orange crystals precipitate from the reaction mixture. After filtration, 8000861 22, 6.3 g of a pure title product are obtained. RF "at DLC over silica gel Ο, Τ1 * in silica gel.

Infrared absorption are observed at 3180, 316o, 3120, 2300, 1630, 1600, 1530, 13 ^ 5, 1325, 1260, 1170 1155, 11U0, 1130, 5 1060, 1050 and 1030 cm \ KMR absorption are observed at 7.1 * 5, 6.8, 6.15, 0.05, 3.89, 3.22-3.70, 2.68 and 1.8-2.15 PP ». The mass spectrum shows calculation at 331, 300, 261, 220, 205, 177, 111, 110, 83 and 70. The carbon: hydrogen: nitrogen ratio is 65.09: 32: U, 18.

Using the various b, 9-dimethoxy-7-10 substituted furochromones of the formula 2b, each of the various corresponding products of the formula 25 is obtained. Example X

6-Bromo-7-methyl-1 *, 9-dimethoxyfurochromone (formula 26 in scheme R 1 and R 2 both represent a methoxy group and R 12 is a methyl group).

To a chloroform solution (20 ml) of the product prepared in Example IX (1.10 g) is added dropwise a chloroform solution (5 ml) of bromine (528 mg) at 0 ° C. After the addition is complete, the reaction mixture is diluted with water (50 ml) and stirred vigorously for 5 minutes. The chloroform layer is separated and the aqueous layer is extracted with chloroform (25 ml).

The combined organic extracts are dried over sodium sulfate and concentrated under reduced pressure to obtain 1.2 g of a dark green matter. This is chromatographed on 50 g of silica gel packed and eluted with 10% ethyl acetate and chloroform. Fractions containing the pure title product (U80 mg) are combined. The melting point is 176-177 ° C. Rf at TLC over silica gel 0.70 in ethyl acetate.

Infrared absorption: 3120, 1650, 16H0, 1625, 1610, 1590, 30 1550, 15U0, 1U80, 1250, 1330, 1265, 1070, 1050, 870, 785 and 770 cm-1.

KMR absorption at 7.65, 7.01, b, 2, k, 0b, and 2.65 ppm (deuterochloroform solvent). The mass spectrum maxima at 3 ^ 0.338, 325, 296, 295, 29b, 279, 277, 250, 177 and 175. The carbon: hydrogen: fluorine ratio is 1 + 9.7 * 1: 3.36: 23.57 .

Using the method of Example V, but replacing 8000861 23 of the product prepared in Example IX with each of the various corresponding compounds of formula 25 described under Example IX, each of the corresponding 6-bromofurochromones of formula is obtained 26.

Furthermore, the various 6-chlorofurochromones or 6-iodofurochromones of the formula 26 are obtained by replacing the bromine with the appropriate halogen by the above-mentioned methods.

Example XI

6-Bromo-H, 9-dimethoxyfurochromone (Formula 33 in Scheme B: Rg and R ^ represent a methoxy group: A. 1- (6-Hydroxy-1,1,7-dimethoxy-5-benzofuranyl) -3-dimethyl -amino-2-propen-1-one.

The (25 g) prepared in Example 1 and N, N-dimethylfor-15 mamide dimethyl acetal (13.7 g) are heated in an oil bath for 2.5 hours. The precipitated reaction product is cooled to room temperature. The excess methanol is removed under reduced pressure and the resulting solid is crystallized from methanol to obtain 23.2 g of product. The melting point is 137-139 ° C. Rf at 20 TLC over silica gel 0.12 in hexane and ethyl acetate (1: 1 ratio).

Infrared absorption: 1625, 1555, 1535, 1500, 1265, 1060, 875, 770 and 730 cm ”1. KMR absorption 8.00, 7, 7, 6.82, 6.30, U, 05, 3.90 and 2.8-3.31 ppm (deuterochloroform solvent). Mass spectrum maxima shows count at 291, 221, 220, 206, 205, 177, 163 and 98.

pC

The carbon: hydrogen: nitrogen ratio is 61.65: 6.12: 0.90.

B. 6-Bromo-9,9-dimethoxyfurochromone

To a chloroform solution (20 ml) of the reaction product from Part A (1.0 g) is added dropwise a chloroform solution (7 ml) of bromine (5 ^ 9 g). After discoloration of the bromine, the reaction mixture is diluted with water (50 ml) and stirred vigorously for 5 minutes. The chloroform layer is separated and the aqueous layer is extracted with chloroform (50 ml). The combined chloroform extracts are dried over sodium sulfate and concentrated under reduced pressure to give a light yellow oil (825 mg). Chromatography on 60 g of silica gel, packed and eluted with 8000861 2b 10% ethyl acetate in chloroform gives 6U mg of title product. Melting point is 166-167 ° C, Rf on TLC over silica gel: 0.60 in 10% ethyl acetate and chloroform.

Infrared absorption: at 3150, 3120, 2θ8θ, 166θ, 1515, 5 1590, 1550, 1U80, 1350, 1310, 1225, 11 ^ 5, 1070, 10l + 0 and 770 cm ”1.

KMR absorption: 8.22, 7.71, 7.06, U, 28 and 1 *, 11 ppm. The mass spectrum maxima at 326, 32¾, 311, 309, 297, 295, 28¾. 282, 281, 280 and 53.

The carbon: hydrogen: bromine ratio is 1 * 3.22: 2.70: 21 *, 57.

By the method of Example XI but using a chlorine or iodine, the various compounds of the formula 33 are obtained, wherein X represents a chlorine or iodine atom. Example XII

6-chloro-9,9-dimethoxyfurochromone (formula 33 in scheme B: and R ^ represent a methoxy group).

The reaction product of Example XI, part A (5.0 g) in chloroform (100 ml) is cooled to 0 ° C and treated dropwise with vigorous stirring for 3 minutes with a chloroform solution of t-butyl hypochlorite (1.85 g in 10 ml chloroform ). Dry hydrogen chloride is then bubbled through the solution to give the reaction mixture a dark brown color. After stirring for an additional 2.5 hours, water (58 ml) is added and stirring is continued for 1 * 5 minutes. The organic layer is then separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3.83 g of a dark brown solid. Successive crystallizations from methanol give 1.75 g of pure title product. The melting point is 178-179 ° C · Rf at TLC on silica gel: 0.57 in ethyl acetate and chloroform (ratio 1: 9) ·

Infrared absorption: 3150, 3120, 1660, 1615, 1590, 1550, 11 * 80, 1350, 1310, 111 * 5, 1070, 10l * 0 and 770 cm "1. KMR absorption: 8.1,

Or) T, 65, 7.02, l +, 20 and b, 02 δ (deuterochloroform solvent). The mass spectrum paints Ml, 280, 267, 265, 251, 2l * 7, 2l * 6, 222, 209, 181,

177. The carbon: hydrogen: chlorine ratio is 55.61 *: 3.1 * 1: 12.52. Example XIII

1 *, 9-Dimethoxy-7-methyl-6-methylthiomethylfurochromone 35 (formula 53 in scheme D: R 1 and R 1 represent a methoxy group and 8000 861 R 10 is a methyl group).

A. (h, 9-Dimethoxy-5-oxy-5H-furo [3,2-ξ} -benzopyran-7-yl) -methyl-dimethylsulfonium fluorosulfate (formula 52).

To a solution of the product prepared in Example III (3.06 g, 10 mmol) in methylene chloride (50 ml) is added dropwise methyl fluorosulfonate (1.1 * +, 10 mmol) in methylene chloride (15 ml) at room temperature added about 30 minutes. The solution is stirred for an additional 30 minutes during which a precipitate forms.

The reaction mixture is filtered to give 2.78 g (66%) of a tan solid with a melting point of 193-195 ° C. The carbon: hydrogen: sulfur analysis is * + 6.01: * +, 37: 15.28.

KMR absorption 7.82, 7.10, 6, k0, * +, 20, * +, 00 and 3.15 ppm. Infrared absorption: 3120, 2080, 1665, 1635, 1605, 1555, 1 * + 8o, 1350, 1295, 1205, 112U, 1085 and 1070 cm ”1.

B. + +, 9-Dimethoxy-6-methylthiomethyl-7-methyl furochromone.

The reaction product from part A (5.1 * 1 g, 12.12 mmole) is added to a tetrahydrofuran solution (150 ml) of potassium tert-butoxide (1.26 g, 12.2 mmol). Then 10 ml of water is added to this heterogeneous solution. The solution first turns pink, then red, and, after stirring overnight, yellow. The reaction mixture is poured into methylene chloride (250 ml) and the resulting solution is washed with 5% hydrochloric acid (3 x 100 ml). The methylene chloride solution is dried over magnesium sulfate and the solid is removed in vacuo to give 3.59 g of a light-colored solid. This is chromatographed on 200 g of silica gel packed in 10 # EtOAc on a column of CHCl 2. Two 100 ml fractions are collected. Fractions 2 and 3 are combined to give 3.39 g (87%) of the desired product, melting point 1.5 SISO 1.52 ° C. The carbon: hydrogen: sulfur analysis is 60.00: ^, 92: 9.89.

The mass spectrum maxima at 320, 305, 290, 275, 273, $ 59, 205 and 177. KMR absorption: 7.65, 7.03, U, 18, 1 +, 02, 3.68, 2.5 and 2, 15 δ. Infrared absorption 3120, 3100, 1630, 1615, 1600, 15 * + 5, 1 * + 85, 1270, 1135, 1265 and 780 cnfl.

Using the method of Example XIII, each of the various compounds of formula 53 is prepared from the corresponding 8000861 26 thioether of formula 51.

Example XIV

9,9-Dimethyl-7-methyl-6-methylsulfinylmethyl-furochromone (formula 5¾ in scheme D: R 1 and R 1 represent a methoxy group 5 and R 1 is -CH 2 -SO-CH 3).

The reaction product from Example XIII (32.0 g, 0.1 mol) is added with stirring to 1 L of CHgClg. To this solution is added dropwise m-CPBA (20.23 g in 200 ml CH 2 Clg) over 10 minutes. The reaction is stirred at room temperature for 2 hours, then diluted 10 with a saturated NaHCO 2 solution (300 ml) and stirred vigorously for 15 min. The CH 2 Cl 2 solution is separated and the aqueous layer is extracted with CH 2 Cl 2 (200 ml). The CH 2 Cl 2 solution is dried over magnesium sulfate and the solvent is removed in vacuo to give 31.53 product. Chromatography of 20 g of this over 2.1 kg of silica gel gives 9.73 g of pure title product with a melting point of 190-191 ° C. The carbon: hydrogen: sulfur analysis is 57.35:,, 98: 9.36.

Mass spectrum maxima at: 336, 305, 27 ^, 273, 258, 2U3, 230, 220, 205, 191, 177 and 53. KME absorption 7.65, 7.02, U, 19, M ^, 20 3.98 and 2.62 ppm. Infrared absorption at 3130, 3100, 3070, 1630, 1620, 1595, 1550, 1U85. 1365, 1270, 1120, 1065 and 1050 cm "1.

By the method of Example XIV, but using the various 6-alkylthiomethyl furochromones of the formula 53, each of the various corresponding sulfinyl-25 products of the formula III is obtained.

Example XV

U, 9-Dimethoxy-7-methyl 1-6-methyl Isulfonylmethyl furochromon (formula 5 ^ in scheme D: R ^ and R ^ represent a methoxy group and R ^ is -CH ^ -SO8-CH ^).

The reaction product from Example XIII (10 g, 31.2 mmol) is added to CH2 Cl2 (500 ml). A CH 2 Clg (200 ml) solution of m-CPBA (13.15 g) is added to this solution at room temperature over 15 minutes. The reaction is stirred for a total of 30 minutes. Saturated NaHCO 2 solution (100 ml) is added to the reaction and stirring is continued for about 15 minutes. Then 8000861 27 the material is poured into a separatory funnel and the organic layer is separated. The aqueous layer is extracted with CH 2 Cl 2 (50 ml), the combined CH 2 Cl 2 solution is dried over magnesium sulfate and the solvent is removed in vacuo to give a light yellow solid. It becomes completely homogeneous by TLC and after several washings with ether gives 10, Uhg (95%) of the title product with a melting point of 237-239 ° C. The carbon: hydrogen: sulfur analysis is 51 +, 31 +: 1 +, 69: 9.36.

The mass spectrum shows counts at 352, 27b, 273, 272, 230, 220, 205, 177 and 53. KMR absorption is observed at 7.80, 7.0, 1 +, 32, 1 +, 02, 3, 85, 2.85 and 2.1 + 7 ppm. Infrared absorption are observed at 3150, 3120, 1635, 1625, 1595, 1550, 1U85, 1365, 1300, 1190, 111 + 0, 1115 and 1065 cm -1.

By the method of Example XV, but using each of the different 6-alkylthiomethyl furochromones of the formula 53, each of the different products of the formula 5I + is obtained.

Example XVI

1+, 9-Dimethoxy-7- (1 + morpholinomethyl) furochromone (Formula 2 + in Scheme A: R 1 and R 1 represent a methoxy group and R 12 is the 1 + morph olinomethyl group).

NaH (1 + 1 g, 50 # in oil, 0.85 mol) and 1 + 00 ml hexane are placed in a 5 L flask equipped with a mechanical stirrer, condenser and nitrogen introduction tube. This mixture is stirred for 5 minutes and then allowed to settle. The solvent is removed using a gas dispersion tube. The gray solid residue is then suspended in dry THF (25 ml) in a solution of khellinone (formula 22), the reaction product of pre-prepared XIII, 30 part A, (50 g, 0.211 mol) and ethyl morpholinoacetate (76 g, 0.1 +39 mol) after which 200 ml of dry THF is added dropwise. Gas development is initially slow. Heat is used to initiate the reaction. The reaction then proceeds moderately exothermically.

After 1 hour, the addition is complete and dry dimethylacetamide 35 (5 ml) is added. The resulting mixture is heated to the reflux condenser for 2 hours and then allowed to cool to room temperature. The cool reaction mixture is gently quenched with ice water (200 ml) and concentrated in vacuo to a black syrup, which is diluted with water to about 1 L to a homogeneous solution. The solution is extracted with ether (2 x 150 ml) and the ether extracts are removed. The aqueous phase is successively treated with methanol (250 ml) and yielding. HCL (125ml) to pH 1. After several hours, the pasty mixture is filtered and the solid is washed with water (50ml) and acetone (200ml). After air drying, the solid is taken up in CHCl 2 (800 mL), saturated with dilute hydrochloric acid and heated to reflux for 1 hour.

The 2-phase mixture is allowed to cool to room temperature, after which it is washed with 2 N NaOH (3 x 100 ml). The combined basic washings are extracted once with CHCl 2 and the solution is dried in CHCl 2 (NagSO 2) and concentrated in vacuo to a solid residue (29 g). The residue is recrystallized from EtOAc / hexane to obtain 26 g of pure product, mp 117-118 ° C, in a yield of 35%. The carbon: hydrogen: nitrogen analysis is 62.62: 5.59: ¼.05.

20 Mass spectrum maxima at 3 ^ 6, 3 ^ 5 »330, 316, 272, 259, 231, 216, 201 and 100. KMR absorption: 7.69, 7.07, 6.37, 1 +, 22, 1+ .01, 3.78, 3.55 and 2.65 ppm. Infrared absorption: 3120, 3100, 3060, 1650, 1630, 1615, 1550, 1U80, 1365, 131 * 5, 1.115 and 1075 cm-1.

Example XVII

25 U, 9-Dimethoxy-7 - (1 * -morph olinomethyl) fur ochromon- (Z) -2-butenedionate.

The product from Example XVI (3.23g, 9.36mmol) is suspended in dry methanol (30ml) and a solution of maleic acid (1.09g, 9.36mmol) in methanol (20ml) is added suddenly added. A clear solution is obtained and after 2 minutes a precipitate appears. After a total of 5 minutes, the mixture is diluted with 25 ml of water and the precipitate is filtered off. The crystalline solid is then recrystallized from a mixture of methanol and ether to obtain 3.55 g (7.7 mmol) of pure maleate salt. The melting point is 162-166k ° C (82 $ yield). The carbon: hydrogen: 8 0 0 0 8 6 1

Yr 29 nitrogen analysis is 57.20: ^, 9¼: 3.0¼.

KMR absorption: 7.85, 7.11, 6.28, 6.2¼. 5.67, U, 19, 3.75 and 2.70 ppm. Infratfood absorption 3150, 3120, 1260, 1990, 1930, 1705, 1665, 161 * 5, 1620, 1565, 15I + 5, 11 * 80, 1385, 1360, 1125, 1075, 1060 and 870 r -1 5 cm.

Using the method of Example CVII, various salt tradition salts are prepared from the corresponding acids.

Example XVTII

¼,9-Dimethoxy-7- (piperidinylmethyl) furochromone (formule 2¼ in Scheme R 1 and R 2 represent a methoxy group and R 1 is the piperidinylmethyl group.

NaH (39.1 g 50% in oil, 0.81 mol) is placed in a 3 L flask equipped with a mechanical stirrer, condenser and nitrogen inlet tube. Iexane (250 ml) is added and the NaH is suspended for 5 minutes and allowed to settle. The supernatant is removed using a gas dispersion tube and the remaining dry NaH is suspended with stirring in dry THF (25 ml). To this suspension is added a warm solution of khellinone (formula 22), the reaction product of Example XIII, part A, 20 (1 * 5.8 g, 0.19¼ mol) and ethyl piperidinoacetate (69.7 g, 0.1 * 0 mol ) in THF (150 ml) added dropwise. After the first 10 ml of the solution have been added to the NaH, the reaction is started with heat. The addition rate is such that gentle heating of the reflux condenser is maintained. After completion of the addition, the resulting mixture is heated to reflux for 2.5 hours, then cooled in ice water and quenched with water (200 ml). This aqueous solution is concentrated in vacuo to about 2/3 of the volume, then diluted with 1 L of water and extracted with ether (2 x 200 ml). The aqueous layer is c.

Hydrochloric acid acidified to pH 1, diluted with methanol (125 ml) and heated to reflux for 1.5 hours. After cooling, the mixture is brought to PH 8 with sodium hydroxide and extracted with CHgClg (3 x 300 ml). Evaporation of the extract in vacuo gives 27 g of a bright yellow solid. This is bubbled through the suspension. The resulting red-orange mixture is heated to reflux for 1.5 hours, 8000861, then allowed to cool at room temperature and extracted with 2N sodium hydroxide. The CHCl 2 layer is dried over magnesium sulfate and evaporated, yielding 27 g of crude oil. After two crystallizations from EtOAc / hexane (ratio 1: 1.5), pure pro-5 duet (10 g) is obtained with a melting point of 8U-85 ° C in a yield of 15%. The carbon: hydrogen: nitrogen ratio is 66.6.02: H, 15.

Mass spectrum maxima at 3 ^, 3 ^ 3, 328, 260, 231 and 98. KMR absorption 7.65, 7, 6.30, k, 16, 4.0U, 3, ^ 8, 2.50 and 1.52 ppm.

10 Infrared absorption: at 3120, 3100, 3060, 27 ^ 0, 1650, 1635, 1620, 1595, 1550, 1U80, 1385, 1365, 13fc0, 1130, 1075 and 1065 cm-1.

Example XIX

b, 9-Dimethoxy-7- (N, N-dimethylaminomethyl) furochromone (formula 2b from scheme A: R 1 and R 1 represent a methoxy group and R 12 is the N, N-dimethylaminomethyl green).

NaH (61 g, 50% in oil, 1.27 mol) in hexane (600 ml) is placed in a 5 L flask equipped with a mechanical stirrer, reflux condenser and nitrogen tube. After stirring for 5 minutes, the suspended NaH is allowed to settle and the supernatant is removed using a gas dispersion tube. The residual solid is suspended in dry THF (30 ml) and a warm solution of khellinone (formula 22), reaction product from example XIII. part A (7 ¾ g, 0.315 mol) in THF (200 ml) is added dropwise over 30 minutes. Dimethylaminogly-25-cine ethyl ester (82.2 g, 0.627 mol) is then carefully added. The reaction is initiated by heat, with vigorous foaming and reflux heating. After about 10 minutes, the reaction becomes less violent and the mixture is heated to reflux for 5 hours. After cooling to room temperature, ice is added carefully and then water (approx. 500 ml). This solution is extracted with ether (2 x 300 ml) and the ether extracts are removed. The aqueous mixture is treated with pH hydrochloric acid to pH 1 and left overnight. The resulting yellow precipitate is collected, the filtrate is concentrated in vacuo to about 200 ml and then filtered again. The collected solids are combined and washed with ether (200 ml) to give 11.5 g of yellow solid.

A portion (120 g) of this is taken up in CHCl 2 (1.2 L) and treated with hydrogen chloride for H minutes. The resulting ro-5 solution is heated to reflux for 1 hour and then stirred at room temperature overnight. The CHCl 2 mixture is shaken with 2N sodium hydroxide (2 x 300 ml) and brine (1 x 100 ml) and dried over sodium sulfate.

The solvent is removed under reduced pressure to give 11 * g of a crude product which is chromatographed on 1 kg of silica gel packed on a 10 # column.

MeOH: CHCl 3. 500 ml fractions are collected. Fractions 5.6 and T are combined. The residue from these fractions is recrystallized from EtOAc / hexane to obtain 2.25 g of yellow prisms, mp 108-109.5 ° C. Yield 2.3 #. The carbon: hydrogen: nitrogen analysis is 63.63: 5.66: 1 *, 66.

Mass spectrum maxima at 30U, 303, 288, 2jk, 2l * 3, 231, 81 *, 71 and 58. KMR absorption absorption: 7.65, 7.03, 6.28, 1 *, 19, **, 05, 3.1 * 5 and 2.38 ppm. Infrared absorption: 3120, 3080, 3060, 2790, 1650, 20 1630, 1620, 1595, 15 ^ 5, 11 * 85, 1385, 1075 and 1055 cm -1.

Example XX

5B-Hydroxy-6,7-dihydro-1 *, 9-dimethoxy-7-methylfurochromon (Formula 72 in Scheme F: and R1 * represent a methoxy group and is a methyl group).

25 NaBH2 (51.0 g, 1.36 mol) and 100 ml EtOH are placed in a 5 L flask equipped with an addition funnel, mechanical stirrer, and condenser. A solution of khelline (51.7 g, 1.98 mol in 1.5 hours and 1 * 1 warm EtOH) is carefully added to this suspension, after which the resulting mixture is heated for 1 * to the reflux condenser. cool the solution and concentrate in vacuo to a thick paste, which is treated with 2 L of aqueous NaHCOg with vigorous stirring for 2 hours The mixture is diluted 1 L of water and 1 1 CHgClg and stirred overnight, then the layers are separated and the aqueous phase is extracted with 32000861 32 CHgClg (¾ x 750ml). The organic extracts are combined, shaken with brine (500ml), filtered over Na 2 SO 4 and filtered in vacuo to a solid. taken up in 200 ml EtOAc, filtered quickly and taken up in hexane (350 ml). On cooling 5 white crystals (20.7 g) with a melting point of 88-90 ° C precipitate. with a melting point of 88.91 g and a yield of 55% Analytically pure material Rial is obtained by recrystallization from a mixture of ethanol and ether. Melting point: 91-92 ° C. The carbon: hydrogen ratio 10 is 63.63: 6.06.

KMR absorption taken at 7.1 * 6, 6.82, 5.22, 1 *, 20, 1 *, 10, 1 *, 00, 3.80, 2.33, 1.92 and 1.50 ppm. Infrared absorption: 351 * 6, 3133, 1626, 1598, 1555, IW7, 1257, 1lfcl, 1060 and 10l + 5 cm "1.

Example XXI

15H, 8-Dimethoxybenzo, 2-b; 5, ^ - b ^ \ difuran-3- (2H) -one (formula 63 from scheme E: R ^ and ^ represent a methoxy group).

A. (Z) -2- \ 1-pyrrolidinyl} methylate ^ -1 *, 8-dimethoxybenzo ^ 1,2-b; 5, ^ - b) difuran-3- (2H) -one (formula 62) (6.5 g, 20 mmol) and potassium carbonate are added to CH 2 CN (200 ml). This solution is stirred at room temperature. The CH 2 CN is removed in vacuo to leave a yellow solid, which is washed with water, filtered and dried to give 3.19 g (5% yield) of the above product, mp 216-217 ° C. The carbon: hydrogen: nitrogen analysis is 6H, 8H: 5.55: 1 *, 1 * 2.

The mass spectrum proceeds at 315, 301, 300, 286, 285, 231, 230 and 217. KMR absorption is observed at 7.5, 7 * 19, 6.91, 1 *, 29, 1 *, 12, 3 , 72, 1.99. Infrared absorption are observed at 311 * 0, 3100, 1675, 1625, 1600, 1585, 151 * 5, 11 * 95, 131 * 0, 1270, 1235, 1125 and 1065 cm -1.

B. The reaction product from part A (12.55 g, 39.8 mmol) is added to 500 ml of a mixture of tetrahydrofuran and 2N HCl, ratio 1: 1. This mixture is heated to reflux for 16 hours with the reaction mixture turning dark red. After cooling to room temperature, the solid is filtered off to obtain 2.91 g of material (insoluble in both HgO and CHClg).

ï D 0 0 8 6 1 * 33

The filtrate is evaporated in vacuo to give a heterogeneous solution, which is filtered to give 5.20 g of crude product. The filtrate is extracted with CHgClg (1+ x 75ml) to give 710mg of product. 5.91 g of the crude reaction product is chromatographed (high pressure liquid chromatography) on 5 250 g of silica gel, packed on a column of 20% EtOAc / CHCl 2 to give 1 +, 25 g (1 + 1 + $ yield) of the title product with a melting point of 11 + 6-11 + 8 ° C. The carbon to hydrogen ratio is 61.32: 1 + 50.

The mass spectrum maxima at 23l +, 220, 219, 205, 191, 10 176, 163, 153 and 77. KMR absorption: 7.1 + 7, 6-, 88, i +, 67, 1 +, 22 and 1 +, 10 ppm. Infrared absorption: 3000, 2950, 2850, 1710, 1600, 1550, 1500, 11 + 1 + 0, 1380, I3I + 0, 1260, 1120 and 106o cm ”1.

Using the methods of the above examples, but using the appropriate desmethoxy starting materials (e.g.

1 + -desmethoxykhelline of the (formula 21 wherein R ^ is a hydrogen atom and R ^ is a methoxy green or 9-desmethoxykhelline of the formula wherein R ^ is a hydrogen atom and R ^ is a methoxy group), the corresponding desmethoxy products from Schemes AF are obtained . Such desmethoxy starting materials are known. 1+ -Desmethoxykhelline 20 is described, for example, in U.S. Pat. No. 3,099,660 and 9-desmethoxykhelline is the naturally occurring fishnagine of the formula III.

, 000861

Claims (30)

3¾ Furochromone derivative characterized by the formula 6, wherein A; * (a) -C-CR ^ -; (b) -CX = CR14-; 5 (c) -CRn «C (CH 3) -; (d) -CH2-CHR1J + -; (e) -CHR 2 - - R 1 is -CHgSR 1 2, -CH 2 SO 4 R1 or -CH 2 (SO 5) R 1 (), wherein R 10 is an alkyl group of 1 to 5 carbon atoms; 10 R1l. (a) hydrogen; (b) an alkyl group of 1 to 8 carbon atoms; (c) alkoxymethyl group of 2 to 8 carbon atoms; (d) alkylthiomethyl group of 2 to 8 carbon atoms; (E) trifluoromethyl group; (f) phenoxymethyl group; (g) phenylthiomethyl group; (h) phenoxymethyl group or phenylthiomethyl group substituted by a chlorine or fluorine atom, a trifluoromethyl group, alkyl group having 1 to 3 carbon atoms or alkoxy group having 1 to 3 carbon atoms or (i) cycloalkyl group having 3 to 10 carbon atoms, wherein R. ^ (a) an isopropyl group; (b) alkyl group with H to 8 carbon atoms; (C) alkoxymethyl group of 2 to 8 carbon atoms; (d) alkylthiomethyl group of 2 to 8 carbon atoms; (e) trifluoromethyl group; (f) phenoxymethyl group; (g) phenylthiomethyl group; (H) phenoxymethyl group or phenylthiomethyl group, substituted by a chlorine or fluorine atom, a trifluoromethyl group, alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms; (i) cycloalkyl group with 3 to 10 carbon atoms; (j) -CH2-S-R1q, -CHg-SO-R ^ Q or -CHg-SOg-R ^ Q, where R10 is an alkyl-8000861 3 ^ a group of 1 to 5 carbon atoms or (k) -CHgHBgRg, wherein Rg and R ^ are hydrogen, an alkyl group having 1 1 to 12 carbon atoms or aryl group having 6 to 12 carbon atoms and which may or may not be the same or wherein Rg and R 2 are together with 8 0 0 0 8 6 1 35 N form an unsaturated or unsaturated heterocycle, with 2 to 7 carbon atoms and 0,1 or 2 other hetero atoms, provided that the heterocyclic ring has U to 8 atoms in the ring and the other hetero- atoms are oxygen, nitrogen or zv atoms, which heterocycle is optionally substituted by an alkyl group with 1 to 1 carbon atoms, alkylthiomethyl group or alkoxymethyl group with 2 to 8 carbon atoms, hydroxyalkyl group with 1 to 1 carbon atoms or phenyl group, with the proviso , which represents -CHgNRgR ^ only when R ^ represents a methoxy group: R 10 is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; // r represents the groups Rg or Rg a methoxy group and the other a methoxy group or hydrogen; X is a chlorine, iodine or bromine atom; R20 and R21 together form an oxo group or one of the groups R2Q and R21 is a hydroxy group and the other hydrogen, with the proviso that Ron and n21 together form an oxo group only when A does not represent dü K -CHg-CHR2 and of the groups R 2q and R 21, the one represents only a hydroxy group, when A is -CHg-CHR 2 -; and its pharmacologically acceptable acid addition salts, when R ^ - 20 is CHg-NRgRp. Furochromone derivative according to claim 1, characterized in that A is -CX = CR ^ -. Furochromone derivative according to claim 2, characterized in that R 1 is a hydrogen atom or alkyl group with 1 to 8 carbon atoms. b. Furochromone derivative according to claim 3, characterized in that R 1 is hydrogen or an alkyl group having 1 to 2 carbon atoms. 5. 6-Bromo-1,9-dimethoxyfurochromone according to claim U, characterized in that R1 is a hydrogen atom. 6. 6-Bromo-7-methyl-9,9-dimethoxyfurochromone according to claim b, characterized in that R 1 is a methyl group. 7. 6-Chloro-7-methyl-9,9-dimethoxyfurochromone e.g. U, characterized in that R 1 is a methyl group. Furochromone derivative according to claim 2, characterized in that R 1 and heather represent a methoxy group. Furochromone derivative according to claim 2, characterized in that R 1 is a hydrogen atom and R 1 is a methoxy group. 10. Furochromone derivative according to claim 2, characterized in that R 1 is a hydrogen atom and R 1 is a methoxy group. Furochromone derivative according to claim 1, characterized in that A-CR is ^ = C (CH ^) -. Furochromone derivative according to claim 11, characterized in that R 1 is a methoxy group and R 1 is a hydrogen atom. Furochromone derivative according to claim 11, characterized in that R 1 is a hydrogen atom and R 1 is a methoxy group. 1U, Furochromone derivative according to claim 11, characterized in that R 1 and R 2 both represent a methoxy group. 15, 9-Dimethoxy-7-methyl-6-methylthiomethyl furochromone according to claim 1U, characterized in that R 1 is a methylthiomethyl group. U, 9-Dimethoxy-7-methyl-6-methylsulfinylmethyl-furochromone according to claim 1, characterized in that R 1 represents a methylsulfinyl-methyl group. 17. H, 9-Rimethoxy-7-methyl-6-methylsulfonylmethyl furochromone according to claim 11, characterized in that R 1 is a methylsulfonylmethyl green. 18. Furochromone derivative according to claim 1, characterized in that A is -CH "CR-1. Furochromone derivative according to claim 18, characterized in that R 1 is a methoxy group and R 1 is a hydrogen atom. Furochromone derivative according to claim 18, characterized in that R 1 is a hydrogen atom and R 1 is a methoxy group. 21. Furochromone derivative according to claim 18, characterized in that R 1 and R 2 both represent a methoxy group, 22 b, 9-Dimethoxy-7- (U-morpholinylmethyl) furochromone according to claim 21, characterized in that that R 1 is a morpholinylmethyl group. 23. 9-Dimethoxy-7- (morpholinylmethyl) furochromone (z) -2-butenedioate according to claim 21, characterized in that R 1 is the morpholinylmethyl group. 3 0 0 0 8 6 1 37 2k. 9,9-Dimethoxy-7-piperidinylmethyl furochromone according to claim 21, characterized in that the piperidinylmethyl group is. K, 9-Dimethoxy-7- (N, N-dimethylaminomethyl) furochro-mon according to claim 21, characterized in that R 1 is the N, N-dimethylamino methyl group. 26. 9,9-Dimethoxy-7-methylsulfonylmethylfurochromone according to claim 21, characterized in that the methylsulfonylmethyl group is. 27. 9-Dimethoxy-7-methylsulfinylmethylfurochromone according to claim 21, characterized in that R 1 is the methylsulfinyethyl group. 28. 9,9-Dimethoxy-6-methylthiomethylfurochromone according to claim 21, characterized in that R 1 is the methylthiomethyl group 15. 29. Furochromone derivative according to claim 1, characterized in that A is -CHgCHR 2 -. 30. Furochromone derivative according to claim 29, characterized in that R 1 is a methoxy group and R 1 is a hydrogen atom. 31. Furochromone derivative according to claim 29, characterized in that R 1 is a hydrogen atom and R 1 is a methoxy group. 32. Furochromone derivative according to claim 29, characterized in that R 1 and R 2 heather represent a methoxy green. 33. 6,7-Dihydro-9-dimethoxy-5-hydroxy-7-methyl furochromone according to claim 32, characterized in that R 1 is a methyl group. 3 ^. Furochromone derivative according to claim 1, characterized in that A is -CHR 2 -. Furochromone derivative according to claim 3, characterized in that Rg is a methoxy group and Rg is a hydrogen atom. 36. Furochromone derivative according to claim 3, characterized in that R 1 is a hydrogen atom and R 1 is a methoxy group. 37. Furochromone derivative according to claim 3, characterized in that R 1 and R 2 both represent a methoxy group. 38. 8-Dimethoxybenzo 1,2-b, 5, U-b difuran-3 (2H) -one according to claim 37, characterized in that R 1 is a hydrogen atom. 8000861 38 39 * Pharmaceutical preparation, characterized in that the preparation as active ingredient contains a furochromone derivative as defined in claims 1-38. ^ 0. Compounds, methods and compounds available therewith as described in the description and examples. 3300861 ï S HjC O O HjCO O -cCO rïVi γίϊ \ S> Af'SACH5 V ^ oYh * 1 oh, 2 3 H, c? 2 T ° H H> co o. gC (X Κγ „„ ςδώ, 0. CH ^ -O ^ 0H 4 0CHs 5 JHo R2, Rj 0 Rj o ζψ3 q% 6 Rji 7 R * 15 8 f5 u r Ri 0H Ri 0 w; ζγχ, g ^ r ”7 '4, ^“ ς & ~ - Ύ "·; Ξ- g>' V r <32 R4 33 -C- Rj o Rj o Ri o ^ ltCjC ^ X - * ^ - *" C ^ yCa 0 T ° CH4I 0 T 0 CHeNRsR, Rj, Rj> R 4 4! ^ 0 0 0 8 6 1 U i3 The Upjohn Company, Kalamazoo, Michigan, USA America yA— Rj OR, O Rj4 R4 οο 21 22 '' Rj Ο R * 0 Ο - oOCX "· —γίγΊΓ '^' '' r * I 1 23 R4 24 / R * Ri 0 NN ^ r * 0 P ^ J ^ R, -. róÖC "Sd'Y'oh ° T ° \. , r R ^ 25 R4 26 -D- R3 OR * O, ΛΑ CH * 0S02 F 1 Jl ζ ^ νζΧ - 'CQU ® T 10 CH2-S-R1o ^^ Y ^ O ^ CHi-S ^ HiSR ^ SOjF R4 R ^ 51 52 '1 Rj O r3 O ^ LiL-Rfl 1 Jl CHjS— R, o wX, ^ ou I LH * υ J ^ XCH | R4 R /, ^ 0 0 086 1 54 53 The Upjohn Company, in Kalamazoo, Michiaasti, Ver, St.v. America ^ r3 o r3 o 1 I .Br I j CH-NR, ^ [^ xy __ cyy R4 61 Rj62 f5 II R} 0 - υφύ: '"R ^ 63 i, 64 - F- R $ 0 R3 0H wi., - R if RJf 71 72 R »OH v & x, R4 Rrt 73 The Upjohn Company, Kalamazoo, Michigan, USA America —T? M 8 0 0 0 8 6 1