CS231969B2 - Manufacturing process of flavanoe derivatives - Google Patents

Description

SOCIAL BEHAVIOR CHEMICAL 1 U ϋ 1 L 1 K AND DESCRIPTION OF THE INVENTION 231969 (11) (B2) (1S) TO PATENT (51) Int. Cl.5 C 07 D 311/69 (22) Registered 14 03 79 (21) (PV 431-80) (32) (31) (33) Priority from 15 03 78 (10251-78) United Kingdom (40) Published 28 01 83 OFFICE FOR WNAlKVa osjstv (45) Published 15 12 86 (72)

The author of BATCHELOR JOHN FREDERICK, BECKENHAM, BAUER DENIS JOHN, LEATHERHEAD, HODSON HAROLD FRANCIS, BECKENHAM, SELWAY JOHN WILLIAM TALBOT, CRANBROOK, YOUNG DAVID ALBERT BLAKER, WEST WICKHAM (UK) (73)

Patent proprietor THE WELLCOME FOUNDATION LIMITED, LONDON (UK) (54) Method for producing flavan derivatives 1

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for the production of anti-viral agents useful as active ingredients of rhinovirus active pharmaceutical compositions.

Rhinoviruses cause approximately 70% of the diseases usually perceived as a common cold or upper respiratory tract inflammation, although these can also be caused by other causes, such as enteroviruses, coironaviruses and allergic reactions. Naviruses are sensitive to all humans, and thymus virus infection is the most common cause of absenteeism and is therefore of great economic importance.

The infection is transmitted by coughing or sneezing, by droplet infection so that the droplets are inhaled by another person and cause airway disease. After an incubation period of 48 hours to 2 weeks, symptoms such as sore throat, cough, sneezing, mucosal inflammation and fever due to secondary bacterial infection develop in the infected person.

There is some resistance after infection with a certain rhinovirus, but it does not relate to different serotypes. In continuous re-inactivation, serotypes that prevail in a particular society maintain the resistance to viruses of most members of this company. The next infection occurs only in the case of a new serotype, which is on average two to three times a year.

Since there is no cross-immunity and since at least 120 degrees of different immunologically detectable viruses are known, vaccination is not possible. In some cases, air disinfection has been disinfected in one of the ways of reducing the number of illnesses, but this was unsuccessful. It will be appreciated that the only useful prevention could be to discover a compound that could be administered over a longer period of time and which would be effective against all or at least almost all common rhinovirus serotypes. Despite extensive research, such a compound has not been found for the time being, so there is no chemotherapeutic agent yet to protect against the disease.

It has now been found that fiavan and various derivatives of this compound are effective against some viruses, including those that cause airway infection, such as picornaviruses, mengoviruses, arboviruses, myxoviruses, corona viruses, herpes and denovirus viruses. . These compounds are particularly effective against rnnviruses, particularly the 1B, 2 and 9 serotypes. In addition to the compounds of this class, new derivatives of these compounds have been further prepared and investigated. It has been observed that these compounds can inhibit the rhinovirusin vltro in tissue culture, and some of them have also been effective against other viruses, such as cold sore viruses, influenza viruses.

Furthermore, it has been shown that some of the compounds are effective against rhinoviruses, especially when administered in sufficient amounts to humans and other mammals. Flavan alone has good efficacy, substituted derivatives have similar or even better efficacy depending on the nature and the position of the individual substituents.

These substances have very low toxicity, the LD 50 is higher than 500 mg / kg. The efficacy can be determined by conventional agar plate tests using discs, which measure the reduction in plaque count after administration of the active ingredient. The procedure is to form a monolayer cell culture in a Petri dish, which is infected with a virus suspension and is coated with nutrient agar in gel form. This gel ensures that the virus does not spread further and localized damage to the cells or plaques is formed. In the plaque inhibition, a disc of filter paper is deposited on the surface and retains 0.01 ml of the solution used when impregnated with the active compound solution. The active ingredient can then diffuse through the gel such that the highest concentration of the substance will be applied to the disk at the lowest concentration in the periphery. The potency of the compound used can be measured by the radius of inhibition of plaque formation of the disc. In the plaque reduction test, the potency is detectable. Various concentrations of the active ingredients are incorporated into the gel which is overlaid, usually in fractional molar concentrations. Plaque suppression is usually directly dependent on the concentration of the compound used. Typically, the plaque count is% in comparison to the control assays, so that an inhibition curve can be generated for the drug concentration. The ED 50 can be determined from this curve at which 50% plaque is suppressed. The full range of flavans is known in the chemical literature, but none have been reported to be useful for therapeutic purposes except for the 3,3 ', 4,4', 5,7-hexahydro- in addition, 3-hydroxyflavan has been successfully used against viral inflammation [Lancet, 2, 1153 (1977)], furthermore 3,6-dialkyl- or 3,6-dialkoxylflavans (USpatent No. 3,553,047] used after lowering blood cholesterol levels, 1-epi-3 ', 4', 5 ', 5,7-pentahydroxyflavan-3-ol (JM Gazave, Fruits, 32, 275-284) , (1977)), was used as a scurvy preventing agent and 3,3 ', - 4', 5,7-pentahydroxyflavan (French Patent Publication Nos. 988 332 and 988 333) has similarity to effect on blood capillaries.

The present invention provides a process for the production of flavan derivatives of formula (II)

as well as pharmaceutically acceptable salts thereof, wherein R 1A to R 1D and R 2A to R 2E are hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, 1 to 4 alkoxy carbon atoms, amine groups, mono- and dialkylamino groups having from 1 to 4 carbon atoms in the alkyl or hydroxy group, provided that at least one of the groups, but not more than four of the groups R 1A to R 10 and R 2A to R 2E are different from the hydrogen atom , with the exception of the following derivatives: 6-aminoflavan, 4'-hydroxyflavan, 5-hydroxyflavan, 6-hydroxyflavan, 7-hydroxyflavan, 4'-methoxyfluan, 5-methoxyflavan, 6-methoxyflavan, 7-methoxyflavan, 8-methoxyf lavan, 6-methylflavan, 8-methylflavan, 3 ', 4'-dihydroxyfluan, 4', 7-dihydroxyfluan, 5,7-dihydroxyflavan, 3 ', 4'-dimethoxyfluan, 4', 6-dimethoxyfluan, 4 ' , 7-dimethoxyphalan, 4 ', 8-dimethoxyphalan, 5,7-dimethoxyflavan, 7,8-Dimethoxyflavan, 5,7-dimethylflavan, 6-dimethylflavan, 4'-hydroxy-6-methoxyfluan, 4'-hydroxy-7-methylfluan, 5-hydroxy-7-methoxyfluan, 4 '- methoxy-6-hydroxyflavan 4'-isopropoxy-6-hydroxyphalan, 4'-n-butoxy-6-hydroxyphalan, 4'-sec-butoxy-6-hydroxyphalan, 6-hydroxy-7-methoxyphalan, 4'-methoxy-7 -hydroxyphalan, 5-methoxy-7-hydroxyphalan, 231969 3 5-methyl-7-hydroxyphalan, 6-methyl-7-hydroxyflavan, 7-hydroxy-8-methylflavan, 6-ethyl-7-hydroxyphalan, 6 -n-butyl-7-hydroxyphalan, 4'-methoxy-6-methylphalan, 4'-methoxy-6-tert-butylflavan, 4'-methoxy-7-methylphalan, 5-methyl-8-isopropylf lavan, 6-tert-butyl-8-methylphalan, 3 ', 4', 6-trihydroxyflavan, 3 ', 4', 7-trihydroxyflavan, 4 ', 5,7-trihydroxyflavan, 3', 4 ', 7- trimethoxyphalan, 4 ', 5,7-trimethoxyflavan, 4', 6,7-trimethoxyflavan, 3 ', 6-diimethoxy-4'-hydroxyphalan, 4', 5-dihydroxy-7-methoxyphalan, 5-, 7 -dihydroxy-4'-methoxyflavan, 5-hydroxy-7-methoxy-8-methylfuran, 5.8- di methyl 7-hydroxyflavan, 3 ', 6-dimethoxy-4'-ethoxyflavan, 6.8-dimethyl-4'-methoxyflavan, 4', 6-dimethoxy-8-methylfluan, 3 ', 4', 5,7-tetrahydroxyflavan , 3 ', 4'-dihydroxy-5,7-dimethoxyphalan, 3.5.7-trihydroxy-4'-methoxyflavan, 4', 6-dihydroxy-5,7-dimethoxyphenol, 3 ', 4', 5,7 tetramethoxyphalan, 3 ', 4', 5 ', 7-tetramethoxyflavan, 4.6.7.8-tetrachloroflavan, 4'-hydroxy-7-methoxyphalan, 6-tert-butoxy-4'-methoxyphalan, 6,4'- dihydroxyflavan, 5-ethyl-7-hydroxyflavan, 7-hydroxy-4'-methylphalan, 4'-isobuthoxy-6-methoxyphalan, 4'-isopropoxy-6-methoxyphalan, 7-hydroxy-5-methoxy- 8-methylflavan, 7,4'-dimethoxy-5-hydroxyflavan, 3 ', 4'-dimethoxy-6-methylfluan, 5,7-dimethyl-6-hydroxyflavan, 7-hydroxy-5-methoxy-6-methylfluan , 4'-hydroxy-7-methoxy-8-methylphalan, 7,8,4'-trihydroxyflavan, 7,8,3'-trimethoxyflavan, 5,7-dihydroxy-3 ', 4'-dimethoxyflavan, 6,4 7'-dihydroxy-5,7-dimethoxyflavan, 7,8,3 ', 4'-tetramethoxyflavan, 7,3', 4 ', 5'-tetrametho xyflavan,

characterized in that a compound of formula V is condensed at 150-250 ° C

wherein X represents a hydroxyl group or a halo gene and

R1A to R1D are as defined above with a compound of formula VI

wherein R 2A to R 2E are as defined above, and optionally converting a compound of formula II to another compound of formula II and converting a salt thereof acceptable from the pharmaceutical aspect of the reaction with a compound of formula II containing an amino or hydroxy group; with the appropriate inorganic or organic acid or base in the aqueous reaction medium.

Effectiveness has also been found to depend on the size of the substituent. For example, when the substituents are located at positions 4 6 and 6, higher potency is associated with a substituent having a [R] D of less than 15, preferably less than 10.

The value of [R] D is corrected by molecular volume as described by S. Glasstons, Textbook of Physical Chemistry, 2. issue 1948, MacMillan, London, p. 528. It can be calculated from the molar mass M, the density p and the refractive index n of the sublericum:

Values for a variety of substituents were determined by Vogel and reported in C-hem. Soc. during 1948.

The choice of the number of substituents, their position, and their type is made to increase the likelihood of greater efficacy. However, it should be appreciated that the resulting properties of the compound also depend on other physical and biological conditions.

Salts of the compounds of formula (II) may be formed when the compound bears a hydroxyl or amino group. In particular, the pharmaceutically acceptable salts are those of the invention. salts with inorganic acids such as hydrochloric or sulfuric acid and organic acids such as lactic acid, maleic acid and acetic acid. They may also be salts with bases such as sodium or potassium.

The compounds of the invention may be non-diverse substituents, taking into account the preferred substituents of the above mentioned conditions. The most preferred novel compounds in terms of activity in the above tests are 4-fluorophilane, 3 ', 4'-dichloro-6-methylflavan, 4'-methyl-7-methylflavan, 6-chloro-4'-methoxyflavan , 6-methoxyflavan, 4'-methylflavan, 6-chloro-4'-methylflavan and 4 ', 6-dichloroflavan. The starting materials are commercially available or can be prepared by known methods.

The compounds of the present invention can be formulated into pharmaceutical formulations which contain, as an active ingredient, the compound of general formula (II), the tautomer of the compound, or a pharmaceutically acceptable salt of the compound. The pharmaceutical composition comprises an effective dose of a compound of formula (II) and a conventional pharmaceutical carrier. With regard to the term effective dose, this term refers to a predetermined amount of the anti-viral compound so that the composition is effective in vivo. Pharmaceutically acceptable carriers are known to be commonly used in the manufacture of pharmaceutical formulations and may be solid, liquid, or gaseous. Otherwise, these carriers are inert to the active agent and harmless to the human body.

The pharmaceutical compositions of the compounds of the present invention may be administered parenterally, orally, nasally or in the form of suppositories, by inhalation, such as by ointment, cream, powder, aero-sol, vapor or nasal drops, and the like. In general infection or protection for this infection, freehoflavan in pharmaceutical formulations ranges from 0.125 micrograms to 1.25 mg per kilogram, preferably 0.25 micrograms to 0.125 mg per kg, especially from 8 to 30 micrograms per kg. kg weight, the product is used in several daily doses in a total amount of 10 micrograms to 100 mg, usually 0.1 to 10 mg per single dose. In the case of oral administration, the powders or granules may contain a carrier, a dispersing and / or a surfactant and may be administered in water or in a syrup, and the capsule or suspension of non-aqueous nature may be filled with the material. wherein a suspending agent can be used. Tablets can be made with filler and glidant, preservative, flavoring, thickening or emulsifying agent in all cases. A preferred type of preparation is a tablet, capsule, or granule, all of which can be coated. Active substance solutions in oil can also be used. The formulations may also be administered by inhalation, aerosol or spray or inhalation vapor containing compounds of Formula II. For parenteral administration or in the case of aerosol or drops, an aqueous solution having a concentration of 0.1 to 10%, preferably 0.1 to 1%, in particular 0.2% (w / v), may be formed. . The solution may contain antioxidants, buffers and the like.

The invention will be illustrated by the following examples. Example 1

Process for preparing 6,8-dichloroflavan

A mixture of 15.3 g of 2,4-dichlorophenol, 100 ml of 10% aqueous sodium hydroxide solution and 37.5 ml of a 40% aqueous formaldehyde solution is heated at 95-100 ° C for 4 hours, then the mixture is cooled. and acidifying by the addition of 70 ml of 2 N sulfuric acid. The oily liquid precipitates, which is extracted with toluene, the extract washed with sodium bicarbonate solution, then dried and evaporated. The residue is recrystallized from boiling water to give 3.5 g of dichloro-2-hydroxybenzyl alcohol (4.0 g), m.p. 81-82 ° C, after drying at 56 ° C and 2660 Pa. 4.0 g of 3,5-dichloro-2-hydroxybenzyl alcohol and 2.19 g of styrene are heated for 3 hours at ISO degrees Celsius. The desired 6,8-dichloroflavane is obtained by chromatography of the crude reaction mixture on alumina, which is eluted with toluene and petroleum ether, b.p. 60 DEG-80 DEG C. in a 1: 1 ratio, to give 2.6 g of product, m.p. C. Example 2

Process for the preparation of 8-chloroflavan 3-chloro-2-hydroxybenzyl alcohol was prepared as described in Zinatea et al., J. Prakt. Chem. 126.3.96 g of alcohol is heated with 2.6 g of styrene at 180 ° C for 2 hours, the reaction mixture is chromatographed on alumina, the eluent is toluene, the oil obtained by evaporating the eluate was distilled in vacuo to give 0.12 g of 8-chloroflavan, b.p. 155-160 ° C at 10.7 Pa.

By the method of Examples 1 and 2 the following compounds can be obtained: 231969 9 10 Example

Compound

M.p. ° C 3 4'-ethylflavan 94 4 7-chloroflavan 37-40 5 6-chloro-4'-methylflavan 132-134 6 4'-6-dofluorine 97-99 7 6-chloro-4'-methoxyfluan 83 to 84 8 4 ', 6-dimethylflavan 90-91 9 4'-methoxy-6-methylflavan 57 10 4', 7-dichloroflavan 62-65 11 7-chloro-4'-methylphenola 77-78 12 4'- chloro-6-methylphalan 89 13 3 ', 4'-dichloroflavan 76 14 7-chloro-4'-methoxyflavan 84 15 2', 4'-dichloroflavan boiling point 138 to 142 pressure 6,7 Pa ie 2 ', 6' -dichloroflavan 87-89 17 4'-bromoflavin 78-79 18 2'-methylflavan 73-75 19 3 ', 4'-dichloro-6-methylfuran boiling point 170 to 180 g 20 Pa 20 4'- chlorflavan 76 to 77 21 4 ', - methoxyflavan 80 to 81 22 2'-chloroflavan boiling point 130 to 135 pressure 13,3 Pa 23 3'-chloroflavan boiling point 120 to 125 pressure 9,3 Pa 24 3'-methoxyflavan 53 to 55 25 4'-fluorophlavan 66-67 26 4'-bromo-6-chlorophen 10 5-107 27 6-fluorophlavan 66-68 28 6-bromoflavan 5 8 to 59 29, 6-bromo-4'-methylflavan 129-130 30 6-bromo-4'-chlorophane 78-81 31 2'-methoxyflavan 80-8132 3'-trifluoromethylflavan 64-6533 6-methoxyflavan 85 to 86 34 4 ', 8-dichloroflavan boiling point 137 to 142 pressure 8 Pa 35 4'-hydroxyphenane 97 to 98 36 2'-hydroxyflavan boiling point 130 to 135 pressure 60 Pa 37 6-chloroflavan 71-72 38 6-methylflavan boiling point 138 to 148 pressure 67 Pa 39 3'-methylflavan boiling point 114 to 120 pressure 13 Pa 40 4'- [Ν, Ν-dimethylaminate 77 to 78 41 4'-aminoflavan 85 to 87 42 4'- isopropylflavan. 46 to 47 43 6-chloro-4'-isopropylfluorine 117 to 119 44 6-ethylflavan boiling point 130 to 140 pressure 20 Pa 45 4 ', 5,7-trihydroxyflavan 212 to 215 46 4'-chloro-6-ethylfluorine 61 to 63 47 6-bromo-4'-methoxyphalan 121 to 123 48 2 ', 4'-dimethylfabane boiling point 135 to 145 pressure 107 Pa Example 49

In vivo experiments 4, 6-dichloroflavan was dissolved in olive oil at a concentration of 3 mg / ml and 1 mg / ml. Always 0.1 ml of these solutions were administered by the mouse-oral route. 1/2 hour after this dose, 1 hour and then every hour until 7 am, the mice were removed from the retro-orbital venous braid of blood. Blood plasma was investigated for the antiviral activity as described above. Faeces of 231969 11 12 mice were also collected over 24 hours, this faeces was smeared with as low an absolute alcohol as possible and the resulting liquid was examined for antiviral activity in the same manner. The gallbladders were then removed in all mice and each was extracted with 10 ml of absolute alcohol. The extract obtained was also investigated for antiviral activity as described above.

Two hours after dosing, an anti-viral effect in blood plasma, gallbladder content, and faeces could be observed. After calibration with the standard curve, the plasma concentration of the drug 1 hour after administration was shown to be 2 to 4 micromoles to be given a lower dose and 10 micromromoles to the higher dose mice (doses are approximately 30 mg / kg and 100 mg / kg of mouse body weight). Annexes 50 and 50

Intranasal administration - stimulation in vitro

Petri dishes were prepared in the same manner as in the inhibition assay and a single cell layer was prepared on the gel surface. 4, 6-D, chloroflavan was dissolved in ethanol and loaded onto a 1 liter petri dish. After removal of the ethanol by evaporation, a sufficient amount of the active ingredient permeates into the gel layer so that complete inhibition of the formation of the pressures can be demonstrated. EXAMPLES 51-52 Various pharmaceutical formulations were prepared in the following manner in the following examples and were intended to be administered to mammals. Example 51

The composition for use in the inhalation device was prepared from the following components:

Compound amount of 4, 6-dichloirflavan 0.6 g isopropyl myristate 10 g

Polyoxyethylene (20) sorbitan monooil 0.5 g

Sorbitan monooleate 0.5 g methyl p-hydroxybenzoic acid 0.1 g water to 100 ml Example 52

The suspension for use as nasal drops was prepared from the following components:

Compound amount 4 6, 6-dichloroflavan 0.6 g Xanthan gum 0.1 g sodium chloride 0.5 g sodium lauryl sulfate 0.1 g methyl p-hydroxybenzoic acid 0.1 g water to 100 ml

Xanthan gum is a polysaccharide rubber whose main hexose units are D-glucose, D-mannose and D-glucuronic acid, the rubber also contains pyruvate and is partially acetylated.

Capsules 1

Compound amount 4 ‘6-dichloroflavan 6 g spray dried lactose 300 g

500 mg of the mixture is filled into size 0 gelatin capsules, the capsule containing 10 mg of the active ingredient. Example 54

Capsules 2

Compound Amount 4 6 6-dichloroflavan 6 g spray dried lactose 208 g corn starch 20.8 g polyvinylpyrrolidone 5.2 g Size 1 gelatin capsules are filled with 400 milligrams of the above mixture. The capsule contains 10 mg of active ingredient. Example 55

Tablets containing 4, 6-dichloroflavan

A mixture for the production of tablets containing 10 mg4 6 6-dichloroflavan, 90 mg lactose, 10 mg maize starch and 1 mg magnesium stearate is prepared by wet granulation.

A tablet formulation, each containing one of the flavan derivatives of Examples 1 to 50, is prepared by the method of Example 55.

Claims (1)

EXAMPLE 106 Flavan Derivative ED 50 (μový) An oily solution of 4 ', 6-dichloroflavan is 3', 4'-dichloro-6-methyl-0.017 but can be prepared from the following components: 4'-fluoro-0.0175 4 -bromo-8-chloro-0.021 Compound of Quantity 4'-Bromo-0,036 4'-Chloro-0,04 4 ', 6'-Dichloroflavan 1g 3', 4'-Dichloro-0,04 Olive Oil BP 1g 4 ', 6-dimethyl-0.042 flavain 0.046 Dissolve the active substance in olive oil 2', 6'-dichloro-0.048 µl for oral administration. 4 ', 7-dichloro-0.048 4'-amino- 0.05 Example 107 6-chloro-0.05 4'-hydroxy- 0.06 Various flavano derivatives were examined by 2', 4'-dichloro-0.064 test for inhibition plaques as described above with 4'-acetoxy-0.067. The ED 50 for these compounds against 4-methoxy-0,07 novir serotype 1B is shown in the following 7-chloro-0.077 table: 4-methyl-7-chloro-0.083. 4‘-methoxy-6-methyl-0,1 Flavan derivative ED 50 (μΜ) 2‘-chloro-0,112 3‘-methoxy- 0,125 4 ‘6-dichloro-0.0014 6-methyl-0,15. 4'-methyl-6-chloro-0.0023 4'-N, N-dimethylamino-0,265 4'-methyl-0.0125 3'-chloro-0,27 6-methoxy-0,0125 3'-methyl- 0.29 4'-methoxy-6-chloro-0.013 2'-methoxy-0.37 2'-methyl-0.015 2'-hydroxy-0,78 4'-chloro-7-methyl-0,0155 3 ' -Fluoromethyl-1,4, SUBJECT OF THE INVENTION Process for the production of flavan derivatives of o-6-aminoflavan, formula II 4'-hydroxyflavan, as well as their pharmaceutically acceptable salts, wherein R 1A to R 1D and R 2A to R 2E are hydrogen, halogen, nitro-sapines, cyano, trifluoromethyl, C 1 -C 4 -alkyl, 1 to 4 alkoxy residues carbon atoms, amino groups, mono- and dialkylamino groups having from 1 to 4 carbon atoms in the alkyl or hydroxy group, provided that at least one of the groups of at most 4 of the groups R 1A to R 1D and R 2A to R 2E is different from the hydrogen atom , with the exception of the following derivatives: 5-hydroxyflavan, 6-hydroxyflavan, 7-hydroxyflavan, 4'-methoxyfluan, 5-methoxyflavan, 6-methoxyfluan, 7-methoxyfluan, 8-methoxyfluan, 6-methoxyflavan, 8 -methylfluorine, 3 ', 4'-dihydroxyfluan, 4', 7-dihydroxyfluan, 5,7-dihydroxyfilane, 4'-dimethoxyflavan, 4 ', 6-dimethoxyfluan, 4', 7-dimethoxyfluan, 4 ', 8 -dimethoxyflavan, 5,7-dimethoxyflavan, 7,8-dimethoxyflavan, 6,7-dimethylflavan, 6,8-dimeth ylflavan, 4'-hydroxy-6-methoxyflavan, 4'-hydroxy-7-methoxyphalan, 5-hydroxy-7-methoxyphalan, 4'-methoxy-6-hydroxyflavan, 4'-isopropoxy-6-hydroxyflavan, 4 ' n-butoxy-6-hydroxyphalan, 4'-sec-butoxy-6-hydroxyphalan, 6-hydroxy-7-methoxyphalan, 4'-methoxy-7-hydroxyflavan, 23196913 5-methoxy-7-hydroxyflavan, 5-methyl-7-hydroxyflavan, 6-methyl-7-hydroxyphalan, 7-hydroxy-8-methylflavan, 6-ethyl-7-hydroxyphalan, 6-n-butyl-7-hydroxyphalan, 4'-imethoxy-6- methylallavan, 4'-imethoxy-8-tert-butylflavan, 4'-methoxy-7-methylflavan, 5'-methyl-8-isopropylfluan, 6-tert-butyl-8-methylfluan, 3 ', 4', 6 trihydroxyphalan, 3 ', 4', 7-trihydroxyflavan, 4 ', 5,7-trihydroxyphalan, 3', 4 ', 7-trimethoxyflavan, 4', 5,7-trimethoxyflavan, 4 ', 6,7- trimethoxyflavan, 3 ', 6-dimethoxy-4'-hydroxyflavan, 4', 5-dihydroxy-7-methoxyphalan, 5,7-diihydroxy-4'-methoxyflavan, 5-hydroxy-7-methoxy-8-methylflavan, 5.8- dl methyl 7-hydroxyflavan, 3 ', 6-dimethoxy-4'-ethoxyflavan, 6.8-dimethyl-4 4'-methoxyflavan, 4 ', 6-dimethoxy-8-methylflavan, 3', 4 ', 5,7-tetrahydroxyflavan, 3', 4'-dihydroxy-5,7-dimethoxyflavan, 3,5,7-trihydroxy-4'- methoxyflavan, 4 ', 6-dihydroxy-5,7-dimethoxyflavan, 3', 4 ', 5,7-tetramethoxyflavan, 3', 4 ', 5', 7-tetramethoxyflavan, 4.6.7.8- tetrachloroflavan, 4'-hydroxy -7-: methoxyflavan, 6- tert -butoxy-4'-methoxyphalan, 6,4'-dihydroxyflavan, 5-ethyl-7-hydroxyphalan, 7-hydroxy-4'-methylflavan, 4'-isobutoxy-6- methoxyflavan, 4'-isopropoxy-6-methoxyflavan, 7-hydroxy-5-methoxy-8-methylflavan, 7,4'-dimethoxy-5-hydroxyflavan, 3 ', 4'-dimethoxy-6-methylflavan, 5.7-dimethyl 6-hydroxyflavan, 7-hydroxy-5-methoxy-6-methylflavan, 4'-hydroxy-7-methoxy-8-methylflava, 7,8, 4'-trihydroxyflavan, 7,8,3'-trimethoxyflavan, 5.7 - dihydroxy-3 ', 4'-diimethoxyflavan, 6,4'-dihydroxy-5,7-dimethoxyflavan, 16,7,8,3', 4'-tetramethoxyflavan, 7,3 ', 4', 5'-tetramethoxyflavan, characterized in that it is condensed at a temperature of 150-250 ° C general formula V wherein X is a hydroxyl group or halogen and R 1A to R 1D are as defined above, with a compound of formula VI wherein R 2A to R 2E are as defined above and optionally converting the compound of formula (II) to another compound of formula (II) and optionally converting the compound of formula (II) containing an amino or hydroxyl group into a salt acceptable in the pharmaceutical arts by reaction with the appropriate inorganic or organic acid or base in the aqueous reaction medium. Severografia, n. P., Race 7, Most Price 3.40 KCs