NO773968L - LITHIUM SALTS OF 1,4-BENZDIAZEPINES AND PROCEDURES FOR PRODUCING THE SAME - Google Patents

Description

Process for the preparation of O-substituted

derivatives of (+)-cyanidan-3-ol.

The present invention relates to new O-substituted derivatives of (+)-cyanidan-3-ol3, especially 3-0-substituted derivatives of (+)-cyanidan-3-ol which correspond to formula I

where R represents

an optionally substituted hydrocarbon radical; an alkyl radical of an organic carboxylic acid with at least 2 carbon atoms} of a carboxylic acid or an organic sulfonic acid; or a

'radical of an inorganic acid containing at least one oxygen atom with the exception of a glucosidic radical;

as well as salts of said compounds, a method for their preparation as well as their use in therapeutics and medicines containing these new products.

By the term "lower" radicals are meant radicals, with up to 7 carbon atoms, more particularly up to ^ carbon atoms.

An optionally substituted hydrocarbon radical represented by the group R can e.g. be an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic hydrocarbon radical. These radicals can be substituted and can contain from 1

to 24 carbon atoms.

An alkyl radical of a carboxylic acid can more particularly be an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic acid radical with from 2 to 24 carbon atoms and which may optionally be substituted.

A carboxylic acid radical represented by the group R can e.g. be a radical of an esterified or amidated carboxylic acid.

An organic sulphonic acid radical can e.g. be an optionally substituted aliphatic, aromatic or aromatic-aliphatic sulfonic acid radical containing from 1 to 12 carbon atoms.

An inorganic acid radical can e.g. be a radical from an acid whose main atom has an atom from one of groups III, IV, V or VI in the periodic table, especially from periods 1 and 2. Examples of such main atoms are sulphur, phosphorus, boron and nitrogen.

An aliphatic hydrocarbon radical may in particular be a saturated hydrocarbon radical, such as an alkyl radical or an unsaturated hydrocarbon radical such as an alkenyl or alkynyl radical. These can be linear or branched. Such radicals may, if desired, be monosubstituted, disubstituted or polysubstituted by means of functional groups, in

An optionally substituted cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical can e.g. be a monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl radical, or a cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl, cycloalkyl-lower alkenyl or cycloalkenyl-lower alkenyl radical, where a cycloalkyl radical can e.g. contain up to 12 carbon atoms, e.g. from 3 to 8, preferably from 3 to 6 ring carbon atoms, while a cycloalkenyl radical can e.g. contain .up to 12, e.g. from 3 to 8, preferably from 5 or 6 ring carbon atoms as well as one or two double bonds, while the aliphatic group of a cyclo-aliphatic-aliphatic radical can e.g. contain up to 7, preferably up to 4 carbon atoms. The above-mentioned cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, be monosubstituted, disubstituted or polysubstituted.

An optionally substituted aromatic hydrocarbon radical can e.g. be a monocyclic, bicyclic or polycyclic aromatic hydrocarbon radical, more particularly a phenyl radical, but may also be a naphthyl radical which, if desired, may be monosubstituted, disubstituted or polysubstituted.

An optionally substituted aromatic-aliphatic hydrocarbon radical can e.g. be an optionally substituted aliphatic hydrocarbon radical with up to 3 optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon radicals, and can be represented by a phenyl-lower alkyl radical, but can also be a phenyl-lower alkenyl radical or a phenyl-lower alkynyl radical and such radicals can e.g. contain from 1 to 3 phenyl groups, and can, if desired, be monosubstituted, disubstituted or polysubstituted in the aromatic and/or aliphatic part.

A heterocyclic radical can e.g. be a monocyclic radical, but may be a bicyclic or polycyclic, preferably a saturated or unsaturated aza-, thia-, oxa-, thiaza-, oxaza- or diaza-cyclic radical, e.g. of an aromatic nature, and which preferably has from 2 to 7 carbon atoms, and which may, if desired, be monosubstituted, disubstituted or polysubstituted. The aliphatic group in a heterocyclic-aliphatic radical can e.g. have the meaning given above for the aliphatic group in the corresponding cycloaliphatic-aliphatic or aromatic-aliphatic radicals.

The acyl radicals R of an aliphatic carboxylic acid can e.g. be•radicals of alkanecarboxylic acids, especially of lower alkanecarboxylic acids, but can also be radicals of alkenecarboxylic acids, then especially of loweralkenecarboxylic acids, and also of loweralkanedicarboxylic acids or of'lower-alkenedicarboxylic acids.

The acyl radicals-R of a cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid have, in the ring and/or the aliphatic radical, the same meaning as stated above for the cycloaliphatic, aromatic or heterocyclic radicals or the corresponding aliphatic radicals. They may have substituents.

The acyl radicals R of an esterified or amidated carboxylic acid can be aliphatic, aromatic or araliphatic esters of carboxylic acid, such as a lower alkoxycarbonyl, aryloxycarbonyl or aryl-loweralk.oxycarbonyl group or of a carbamic acid, preferably mono- or di-substituted with aliphatic, aromatic or araliphatic radicals.

The functional groups that can act as complementary substituents in one or more of the radicals

which is mentioned above can e.g. be free, esterified or etherified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkyl mercapto groups, optionally substituted ■phenyl mercapto groups or phenyl-lower alkyl mercapto groups, lower alkoxycarbonyloxy groups or lower alkanoyloxy groups as well as halogen atoms and also nitro groups, optionally substituted amino groups, alkyl groups, such as lower alkanoyl groups or optionally functional modified carboxy groups, such as lower alkoxycarbonyl groups, optionally N-substituted carbamoyl groups or cyano groups. The aromatic or heterocyclic radicals can also carry

as substituents alkyl radicals, preferably lower alkyl radicals.

By ethereal hydroxy groups is meant in particular lower alkoxy groups as well as substituted lower alkoxy groups such as halogen-lower alkoxy groups in addition to lower alkenyloxy groups, lower alkenedioxy groups, cycloalkoxy groups, phenyloxy groups, phenyl-lower alkoxy groups or lower alkoxy groups substituted with monocyclic mono-aza-, mono-oxa- or mono-thia- cyclic groups of an aromatic nature, such as pyridyl-lower alkyl groups, furyl-1'averyl oxy groups or thienyl lower alkyl groups.

Preferred mercapto groups can be mentioned lower alkyl mercapto groups, phenyl mercapto groups or phenyl-lower alkyl mercapto groups.

The esterified hydroxy groups can in particular be halogen atoms as well as lower alkanoyloxy groups.

The substituted amino groups are monosubstituted or disubstituted amino groups where the substituents optionally represent substituted monovalent or bivalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals as well as alkyl groups. Such amino groups can e.g. be lower alkylamino groups

or di-lower alkylamino groups or lower alkyleneamino groups optionally interrupted by heteroatoms such as oxygen atoms, sulfur atoms or, if desired, optionally substituted nitrogen atoms, e.g. with lower alkyl groups in addition to alkyl amino groups, then especially lower alkanoyl amino groups.

In the above and in the following, the general terms can have the following meaning: An alkyl radical is preferably a lower alkyl radical, e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl radical, but also a pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tricosyl or tetracosyl radical and isomers thereof, while an alkenyl radical is preferably a lower alkenyl radical, and can e.g. be a vinyl, allyl, n-propenyl, isopropenyl, 2- or 3-methallyl or 3-butenyl group, and an alkynyl radical can e.g. be propar-gyl or 2-butyryl radical..

The substituted aliphatic hydrocarbon radicals preferably include hydroxy groups, lower methoxy groups and halogen atoms and can be hydroxy-lower oxy or lower alkoxy-lower oxy radicals, where the hydroxy groups or the lower alkoxy groups are separated, preferably by at least two carbon atoms from the oxygen atom carrying a lower aliphatic radical substituted in this way, such as 2-hydroxyTetyl, 2-hydroxypropyl; 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 3-methoxypropyl or 3-ethoxypropyl radicals as well as hydroxymethyl radicals.

A cycloalkyl radical can e.g. be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals as well as an adamantyl group, and a cycloalkenyl group can e.g. be a 2- or 3-cyclopentenyl group, or a 1-, 2- or 3-cyclohexenyl group,■ or a 3-cycloheptenyl group as well as a 2-cyclopropenyl group. A cycloalkyl-lower alkyl radical or cycloalkyl-lower alkenyl radical can e.g. be a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or

-1,3-propyl, -vinyl or -allyl radical, while a cycloalkeny1-lower alkyl or cycloalkenyl-lower alkenyl radical represents e.g. a 1-, 2- or 3-cyclopentenyl-, 1-, 2-'or

3-cyclohexenyl- or 1-, 2- or 3-cycloheptenyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, - vinyl or -allyl radical.

A naphthyl radical is a 1- or 2-naphthyl radical

while a diphenyl radical can e.g. be a 4-diphenyl radical.

A phenyl-lower alkyl or phenyl-lower alkenyl radical can e.g. be a benzyl radical as well as 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.

A substituted phenyl lower alkyl radical can be a benzyl radical which can be mono-, di- or polysubstituted in the phenyl ring, and the substituents can be the same or different. As substituents, e.g. halogen atoms or lower alkyl groups as well as lower alkoxy groups or trifluoromethyl groups are mentioned, while the benzyl radicals in the substituted nucleus can carry a substituent, preferably in the para position.

As heterocyclic radicals, one can e.g. mention monocyclic mono-aza-, mono-thia- or mono-oxa-cyclic ■ radicals of an aromatic nature, such as pyridyl radicals, e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl radicals, thienyl radicals, e.g. 2-thienyl radicals or furyl radicals, e.g. 2-furyl radicals or bicyclic mono-aza-cyclic radicals of an aromatic nature, such as quinolinyl radicals or 2-quinolinyl radicals or 4-quinolinyl radicals or isoquinolinyl radicals, e.g. 1-isoquinolinyl radicals or monocyclic thiaza- or oxaza-cyclic radicals of an aromatic nature as well as diaza-cyclic radicals of the same type, such as oxazolyl, isoxazolyl, thiazolyl or isothiazolyl radicals,

besides pyrimidinyl radicals. Aliphatic heterocyclic radicals are lower alkyl or lower alkenyl radicals containing heterocyclic radicals, especially those indicated above.

The acyl radicals of alkane carboxylic acids can e.g.

be propionic acid, butyric acid, isobutyric acid or valerian acid and higher homologues up to stearic acid, while those of alkanedicarboxylic acids can e.g. contain from 2 to 10, preferably from 3 to 6, carbon atoms, or of alkenedicarboxylic acids can e.g. contain from 4 to 7 carbon atoms, e.g. of 2-methylsuccinic acid, glutaric acid, 3-methylglutaric acid, 3-ethylglutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid or sebacic acid, preferably maleic acid and succinic acid: mention may also be made of alkyl radicals of unsaturated aliphatic acids such as acrylic acid, propiolic acid, methacrylic acid, crotonic acid or oleic acid, then especially maleic acid or fumaric acid.

The acyl radicals of carboxylic acids can e.g. be cyclohexanecarboxylic acid and benzoic acid which may be substituted, e.g. with a lower alkyl group such as methyl, with an alkoxy group such as methoxy or ethoxy or a carboxy group,

and of these one can mention phthalic acid, isophthalic acid, terephthalic acid, cinnamic acid or toluic acid, as well as 1- or 2-naphthoic acid or 1,2-cyclohexanedicarboxylic acid.

The acyl radicals of heterocyclic acids can e.g. be those of furoic acid, tenoic acid, nicotinic acid, isonicotinic acid and picolinic acid.

A lower alkoxycarbonyl group can e.g. be

a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, tert-butoxycarbonyl or tert-pentyloxycarbonyl group.

The optionally N-substituted carbamoyl group

can e.g. be N-lower alkyl or N,N-di-lower alkyl carbamoyl groups, such as N-methyl, N-ethyl,' N,N-dimethyl or N,N-diethyl carbamoyl groups, N-aryl, N, N-diaryl or N-aryl-N-alkylcarbamoyl groups, such as N-phenyl-, N,N-diphenyl- or N-phenyl-N-methyl- or -ethylcarbamoyl groups, optionally substituted or unsubstituted in the phenyl nucleus.

A lower alkoxy group can e.g. be a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy or tert-pentyloxy group.

A lower alkenyloxy group can e.g. be vinyloxy or allyloxy group.

A lower alkylenedioxy group can e.g. be methylenedioxy or ethylenedioxy group as well as an isopropyl

lidene dioxy group.

A cycloalkoxy group. can e.g. be cyclopentyloxy, cyclohexyloxy or adamantyloxy group.

A phenyl-lower oxy group can e.g. be a benzyloxy or 1- or 2-phenylethoxy group.

A pyridyl-lower oxy group can e.g. be 2-, 3- or 4-pyridylmethoxy group.

A fury1 lower-area oxy group can e.g. be the furfuryloxy group. .A tieny1-lower oxy group can e.g. be the 2-thienyloxy group.

A lower alkyl mercapto group can e.g. be the methyl mercapto or the ethyl mercapto group.

A phenyl lower alkyl mercapto group can e.g. be benzyl mercapto or 1- or 2-phenylethyl mercapto group.

A halogen atom can e.g. be a bromine or iodine and more particularly a chlorine or fluorine atom.

A mono- or di-lower alkylamino group can e.g. be methylamino, dimethylamino, ethylamino or diethylamino group.

A lower alkylene amino group optionally interrupted

of a heteroatom, can e.g. be a pyrrolidino, piperidino, morpholino, thiamorfoliho or 4-methyl-piperazino group.

A lower alkanoylamino group can e.g. be the acetylamino or propionylamino group.

The acyl radicals of mineral acid can e.g. be

those of sulfonic, sulfinic, sulfenic, phosphoric, boric or nitric acid.

Compounds according to the present invention which include a radical containing a salt-forming group can also be in the form of salts.

Salts of compounds containing a free carboxy group can e.g. be metal salts, especially alkali metal salts. e.g. sodium or potassium salts, as well as alkaline earth metal salts, e.g. magnesium or calcium salts, as well as salts of transition metals such as zinc, copper, iron, silver or mercury salts or ammonium salts, e.g. those of ammonia and organic bases such as tri-lower alkylamines, e.g. trimethylamine or triethylamine, then especially . pharmaceutically acceptable non-toxic salts of the above type.

Compounds according to the present invention which include basic groups can also be in the form of addition salts with acids, as especially in the form of pharmaceutically acceptable non-toxic salts, e.g. with mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic sulphonic or carboxylic acids such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic acids, e.g. acetic acid, propionic acid, succinic acid, glycolic acid,, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, phenylacetic acid, benzoic acid, 4-amino-benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, aminosalicylic acid, embonic acid or nicotinic acid, as well as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, phenylsulfonic, 4-methylphenylsulfonic, naphthalenesulfonic, sulfaniline or cyclohexylsulfamic acids.

Compounds containing basic groups may also be in the form of their quaternary ammonium compounds.

The new compounds have valuable pharmacological properties. More particularly, they have valuable activity in that they prevent hepatic necrosis and inhibit lipoperoxidation. The present compounds are also capable of inhibiting both the breakdown of collagen and the activity of lysosomal enzymes by increasing the stability of the membrane in the lysosomes. The • present derivatives are also capable of influencing vascular permeability and tone.

The value of the new compounds is evident in the treatment of various liver disorders such as acute hepatitis (of the viral type, alcoholic or toxic) steatosis and chronic hepatitis, especially of alcoholic origin. The value of the present compounds is also evident in the treatment of disorders involving a breakdown or weakening of the connective tissue, especially genetic disorders a<y>collagen such as Ehlers-Danlos disease, Marfan's syndrome, cutis laxa, osteogenetic imperfecta, but also scoliosis, osteoporosis, scleroderma, periodontosis, as well as wound healing, especially bedsores, in addition to various forms of rheumatism, especially osteoarthritis. The value of the new compounds has also been shown in disorders that concern the circulatory system, and this applies to both veins and arteries.

Thus, e.g. the effect on the normal or pathological metabolism found in the hepatocytes of living rats is shown in isolated rat hepatocytes as described by Berry and Friend' (J. Cell. Biol. 4_3, 506-520

(1969)), which were incubated in 2 ml of physiological Krebs-Ringer solution in the presence of the new products in amounts varying from 0.5 to. 5 mg, and to which solution different hepatotoxic compounds were added, or the inhibition of lipoperoxidation by carbon tetrachloride as can be demonstrated by the method described by Comporti, Sacconi and Danzani (Enzymologia 28, 185-203 (1965)), and where the intensity of the lipoperoxidation in the presence of the new products in amounts of from 5 to 50 u<g.>per, 4 ml was judged by the amount of malonic acid dialdehyde formed. The modification of an experimental hepatitis that was induced by galactosamine, carbon tetrachloride or ethanol can be shown in rats that were previously treated orally or intra-peritoneally with the new products in doses that varied from 100 to 500 mg/kg, and this applies to both acute or chronic disorders and for prophylactic or curative treatment. In the investigation of acute disorders, the animals were killed 24 or 48 hours after the administration of the toxic substances, and the functioning of the liver was assessed by the following tests: BSP removal, the bilirubin level in the plasma, the transaminase level in the plasma, total level of triglycerides and lipids in the liver as well as in serum and the level of lipoproteins in serum. The present compounds are also capable of promoting liver regeneration and also exert an immunostimulating effect.

The ability of the new compounds to protect the connective tissue can be demonstrated by the fact that they inhibit the breakdown of collagen by collagenase in amounts of the present compound varying from 0.1 to 5 mg per 2 ml, or by the fact that they inhibit the activity of lysosomal enzymes and increase the stability of the membrane in the lysosomes in amounts of from 0.05 to 0.2 mg of the new compounds per 1 ml as described by P. Niebes and Ponard (Biochem. Pharmacol. 24, 905 (1975)) or by

■experimental lathyrism in rats that had been given toxic amino-acetonitrile orally in a dose of 100 mg/kg body weight/day or iminopropionitrile subcutaneously in a dose of 250 mg/kg body weight/day for 7 days or p-aminopropionitrile orally for one dose of 600 mg/kg body weight/day for 3 weeks and who had been given oral doses of from 100 to 500 mg/kg body weight/day of the new products for 3 weeks' before, during and after the poisoning. In doses that were administered parenterally or orally and that varied from 100 to 500 mg/kg body weight, these substances proved to be able in these animal experiments to a.a) reduce the experimental edema •which was induced by the galactosamine and dextran, b ) reduce the capillary permeability in rats, as measured by the diffusion of trypan blue (technique of V.L. Beach and B.G. Steinetz, J. Pharmacol. Exp. Ther. 131, 400 (1961)) or by skin wounds in a hamster subjected to a lesion induced by bradykinin, histamine or serontonin, c) to reduce the retroauricular venous flow in the ear of a rabbit, d) to promote tissue clearance in the ischemic paw of a dog.

The activity of the present new compounds was hitherto unknown with respect to these indications. It is currently known that (+)-cyanidan-3_ol has one liver-protective effect, but it is surprising that these new derivatives have an unsaturated and far better activity than said compound.

The present invention relates in particular to compounds of formula I, where R is

an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic hydrocarbon radical,

a radical of an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid,

a radical of an esterified or amidated carboxylic acid,

a radical of an aliphatic, aromatic or aromatic-aliphatic sulphonic acid or

a radical of an inorganic acid which has as its main atom one

sulphur, phosphorus, boron or nitrogen atom,

as well as salts of these compounds.

The present invention relates in particular to compounds of formula I, where R is

an alkyl or alkenyl radical which is unsubstituted or

■substituted with hydroxy, lower alkanoyloxy, lower alkoxy, lower alkanoyl, cyano, amino, mono- or di-lower alkylamino, lower alkyleneamino, oxa- or aza-lower alkyleneamino, amido or mono- or di-lower alkylamido groups or with halogen atoms; a cycloaliphatic radical with from 3 to 6 ring carbon atoms which may be unsubstituted or substituted with one or

more hydroxy, lower alkoxy, lower alkyl, carboxy, oxo, lower alkanoylamino,' mono- or di-lower alkylamino or

lower alkoxycarbonyl groups;

a lower cycloaliphatic-alkyl radical with. from 3 to 6 ring carbon atoms which may be unsubstituted or substituted with at least one lower alkyl group;

a phenyl or naphthyl radical which may be unsubstituted or mono- or di- or tri-substituted with hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, arriino or mono- or di-lower alkylamino groups, or, with halogen atoms;

a phenyl lower alkyl. or naphthyl-lower alkyl radical or phenyl1-lower alkeny1 or naphthy1-lower alkenyl radical which may be unsubstituted or mono-, di- or tri-substituted in the aromatic nucleus with hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, nitro,

amino, mono- or di-lower alkylamino, amido or mono- or di-lower alkylamido groups or with halogen atoms;

an unsaturated or saturated aza-, thia-, oxa-, thiaza-, oxaza- or diaza-cyclic radical which may be condensed to a phenyl nucleus and which has from 2 to 7 carbon atoms in the heterocyclic nucleus and which may be mono- or di- or poly-substituted with lower alkyl, hydroxy, lower alkoxy, nitro, carboxy, lower alkoxycarbonyl or lower alkanoyloxy groups;

a heterocyclic-lower alkyl radical where the heterocyclic part can be one of those described above, a radical of an alkanecarboxylic acid, a lower alkenecarboxylic acid, a lower alkanedicarboxylic acid, a lower alkenedicarboxylic acid

acid, a lower cycloalkane carboxylic acid which may be unsubstituted or substituted with one or more hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkyl, lower alkanoyl or oxo groups or with halogen atoms,

a benzoyl or naphthoyl radical optionally substituted with hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, nitro or amino groups or with halogen atoms,

a radical of a phenyl-lower alkanoic or naphthyl-lower alkanoic acid which may be unsubstituted or substituted in the aromatic nucleus with one or more hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, nitro, amino or mono- or di-lower alkylamino groups or with halogen atoms;

a radical of an unsaturated or saturated aza-, thia-, oxa-, thiaza-, oxazaro or diaza-cyclic acid which may be condensed to a phenyl radical;

a lower alkoxycarbonyl radical, a phenoxycarbonyl radical, a carbamoyl radical, optionally mono- or di-substituted with lower alkyl radicals or by phenyl or benzyl radicals optionally substituted in the phenyl nucleus with one or more hydroxy or lower alkoxy groups or with halogen atoms;

a radical of a lower alkylsulfonic acid or phenylsulfonic acid optionally substituted with one or more lower alkyl or lower alkoxy groups or with halogen atoms, or a radical of a phosphoric acid which may be unsubstituted or esterified by one or two lower alkyl radicals or by a

or two optionally substituted phenyl radicals,

or salts of such compounds.

The present invention relates in particular to compounds of formula I, where R is

a lower alkyl radical which may be unsubstituted or substituted with one, two or more hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, cyano, lower alkanoyl, amino, mono- or di-lower alkylamino, lower alkyleneamino or oxa- or aza-alkyleneamino groups or with chlorine or fluorine atoms ;

a cycloaliphatic radical containing 5 or 6 ring carbon atoms, and where the radical may be unsubstituted or substituted with hydroxy-lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino or mono- or di-lower alkyl amino groups;

a cycloaliphatic-C-L_^ alkyl radical, where the ring may contain 5 or 6 carbon atoms and may be substituted by at least one alkyl radical with from 1 to 4 carbon atoms;.

a phenyl radical which may be unsubstituted or mono-, di- or tri-substituted by hydroxy, C 1-1 (alkoxy, carboxy, nitro, amino or mono- or di-(C 1-4 alkyl)amino groups or by chlorine or fluorine atoms;

a benzyl, phenylethyl, or phenylpropyl radical which may be unsubstituted or mono-, di-, or tri-substituted in the phenyl ring with hydroxy, C-1-4 alkoxy, carboxy, (C 1-4 alkoxy)carbonyl, nitro, amino, mono- or di-(C ^_^alkyl)-amino, or C^^alkyl groups or by chlorine or fluorine atoms;

a tetrahydropyranyl, pyridyl, quinolinyl or pyrimidyl radical optionally substituted with one or more nitro, amino or hydroxy groups;<*>

an alkane carboxylic acid radical with from 3 to 18 carbon atoms, and which may be unsubstituted or substituted with one or more hydroxy, carboxy, (C-L-Alkoxy) carbonyl, C1-^alkyl, amino or mono- or di-( (C 1 -3 alkyl)amino groups or by chlorine or fluorine atoms;

a cycloalkanecarboxylic acid radical with from 3 to 6 ring carbon atoms which may be unsubstituted or substituted by one or more hydroxy, carboxy, lower alkoxycarbonyl, amino or mono- or di-.(C-^_^alkyl) amino groups or by chlorine or fluorine atoms;

a cycloalkanealkanoic acid radical, where the aliphatic chain may have from 1 to 4 carbon atoms and the ring may have from 3 to 6 ring carbon atoms;

a benzoyl radical which may be unsubstituted or mono-, di- or tri-substituted by hydroxy, C 1 -C 1 )-alkoxy, carboxy, (C 1 -C 1 -C 1 -C 1 ) carbonyl, C 1 -C 1 -alkanoyl, C 1 -C 2 -alkanoyloxy, nitro, amino or mono- or di-(C 1-6 alkyl) amino groups or with fluorine or chlorine atoms;

a phenylalkanoic acid radical where the aliphatic chain may contain from 1 to 4 carbon atoms and where the phenyl radical may be substituted as indicated above for the benzoyl group;

a radical of a nicotinic or isonicotinic acid;

a (C 1 -C 6 ) carbonyl radical;

a carbamoyl radical optionally mono- or di-substituted by C-1-4 alkyl groups or by phenyl groups unsubstituted or substituted by hydroxy, methoxy or ethoxy groups or by means of chlorine or fluorine atoms; or a phosphoric acid radical which is unsubstituted or mono- or

dimethyl, ethyl or phenyl substituted,

as well as salts of such compounds.

The present invention relates in particular to compounds of formula I, where R is

a lower alkyl radical which is unsubstituted or substituted with one or two hydroxy, C 1-6 hydroxy, carboxy, C 1-6 alkanoyloxy, amino, mono- or di-(C 1-6 alkyl)amino or cyano groups;

a cycloaliphatic radical of 5 or 6 ring carbon atoms which is unsubstituted or substituted with one or two hydroxy, C 1-4 alkoxy, carboxy, C 1-1 )alkanoyloxy, amino or di-lower alkylamino groups;

a cycloalkanealkyl radical where the alkyl part has from 1 to 4 carbon atoms and where the ring contains 5 or 6 carbon atoms;

a phenyl radical which is unsubstituted or mono-, di- or tri-substituted by hydroxy, methoxy, ethoxy, propoxy, amino or nitro groups;

a benzyl, phenylethyl or phenylpropyl radical which is unsubstituted or mono- or di-substituted in the phenyl ring with one or two hydroxy, methoxy, ethoxy, propoxy, carboxy, (C-^_ ^ alkoxy) carbonyl, nitro, amino or mono- or di -(C-^_^alk<y>l)amino groups or by chlorine or fluorine atoms;

a tetrahydropyranyl radical;

a pyridyl radical which is unsubstituted or substituted with a nitro, amino or hydroxy group;

an alkanecarboxylic acid radical with from 3 to 18 carbon atoms and which may be unsubstituted or substituted with one or more hydroxy, carboxy, (C^_galkoxy)carbonyl, C^_^alka-

noylamino or mono- or di-(C^_^alkyl)amino groups or with chlorine or fluorine atoms;

a cycloalkanecarboxylic acid radical with 5 or 6 ring carbon atoms, and where the radical must be unsubstituted or substituted with one, two or three hydroxy, carboxy, (C1_i(alkoxy)carbonyl, amino or mono- or di-(C^_^-. alkyl)amino groups or with chlorine or fluorine atoms;

a cycloalkane alkanoic acid radical where the alkyl chain may contain from 2 to 4 carbon atoms and where the cycloalkane moiety may contain 5 or 6 ring carbon atoms;

a benzoyl radical which is unsubstituted or mono-, di- or tri-substituted by hydroxy, C 1 -C 1 ) alkoxy, carboxy, (C 2 -C 2 ) alkoxy) carbonyl, C 3 -C 4 alkanoyl, C 1 -C 1 -alkanoyloxy, nitro, amino or mono- or di-(^alkyl)amino groups or by chlorine or fluorine atoms;

a phenylalkanoic acid radical in which the aliphatic chain has from 1 to 4 carbon atoms and in which the phenyl nucleus is unsubstituted or substituted by one or two hydroxy, C^_^-alkoxy, amino, carboxy, (C-^_1)alkoxy)carbonyl, C^_ 3-alkanoyl, 3-alkanoyloxy groups or with chlorine or fluorine atoms;

a nicotine or isonicotinic acid radical;

a (N-Alkoxy)carbonyl radical;

a carbamoyl radical optionally mono-substituted with a C 1-6 alkyl or phenyl radical;

or an unsubstituted phosphoric acid radical or a dimethyl, diethyl or monohydroxyphenyl phosphoric acid radical.

The invention relates in particular to the new compounds of formula I which are described in the examples.

The new compounds can be prepared by methods which are known per se. They can thus be prepared by, in compounds of formula II where R-^0 represents a protected hydroxy group which can easily be hydrolyzed or hydrogenated, the OR^ groups are split into hydroxy groups, and if desired, a radical R in a resulting compound is modified by reduction and/or, if desired, converting a resulting salt into the free compound or into another salt and/or, if desired, converting a resulting compound if it has a salt-forming group into a salt.

In compounds of formula II, the radical R can thus be a mono-, di- or poly-substituted lower alkyl radical, a lower alkenyl radical, an araliphatic radical which can be unsubstituted or mono-, di- or tri-substituted in

■ the aromatic nucleus, a radical of an aliphatic, aromatic or araliphatic carboxylic acid, a radical of a carboxylic acid esterified with an iaverealkyl radical, or a radical where, with the oxygen atom' bonded to R^, which may or may not form a cyclic acetal.

When is a lower alkyl radical, this can contain from 1 to 4 carbon atoms and is in particular a methyl or ethyl radical. These groups can be substituted with lower alkoxy groups, preferably a methoxy or ethoxy group or lower alkoxyethoxy groups, especially a methoxyethoxy group.

When is a lower alkenyl radical, this should contain from 2 to 5 carbon atoms and in particular allyl, metallyl, buten-2-yl or penten-2-yl can be mentioned.

When the substituent FL is an araliphatic radical, especially a benzyl radical, this can be substituted on. different ways, e.g. with one or more C^_^alkyl radicals, preferably methyl, ethyl, isopropyl and tert.butyl groups, with one or more halogen atoms, preferably chlorine, bromine or fluorine, with one or more alkoxy groups such as methoxy or ethoxy, or with a cyano group . These different substituents may or may not simultaneously occupy the ortho and para positions, preferably the para position. When the substituent in the radical. R^ is of a different order, e.g. a nitro group, then it is preferred that this should sit in the meta position.

When R is an aliphatic alkyl radical, the aliphatic part should be a C 1-4 alkyl group, preferably a methyl or ethyl group optionally substituted with an alkoxy group, such as a methoxy group. If R is an aromatic or araliphatic alkyl radical, then the aryl moiety may be a phenyl radical substituted in various ways, and the aliphatic radical may be a C 1-2 alkyl radical.

When R-^ is an alkoxycarbonyl radical, then the alkyl part itself can be substituted with an aryl radical,

which may themselves be substituted in various ways or with halogen atoms.

When forming an acetal with the oxygen atom bound to R-^j, this can be linear or cyclic, e.g. the pyranyl group for R .

Of the radicals with formula R^ which can be mentioned

is e.g. allyl, methylallyl, ethylallyl, buten-2-yl, penten-2-yl, methoxymethyl, ethoxymethyl, methoxyethoxymethyl, acetonyl, propionylmethyl, cinnamyl, phenacyl, benzyl, 2-methylbenzy1, 4-methylbenzyl, 4-tert.-butylbenzyl, 4 -bromobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 3-nitrobenzyl, 3,5-dinitrobenzyl, 4-cyanobenzyl, 4-chloro- or bromo- or phenylphenacyl or methoxycarbonyl, ethoxycarbonyl, 2 ,2,2-trichloroethoxycarbonyl or phenoxycarbonyl.

The groups OR^ can be cleaved by hydrolysis or by hydrogenation.

The compounds can be hydrolysed under the influence of acids, but there is always a certain risk in this case that the flavanin structure may be changed, and consequently the yield will be significantly reduced. Of suitable acids, it is preferred to use p-toluenesulfonic acid, e.g. by carrying out the reaction in alcohol, then especially in methanol. Depending on the type of substituents to be hydrolysed, the reaction can take place within a few hours to several days, and can take place at room temperature or can be accelerated by heating, possibly by boiling under reflux, however with the risk of partial decomposition of the desired products.

It is also possible to cleave the OR^ groups by catalytic hydrogenation using molecular hydrogen or by transferring hydrogen in situ using a hydrogen donor such as cyclohexene. If the compound to be hydrogenated has a salt-forming group in the 3-position of the -substituent, then the free form or a salt of this group can be used.

The reaction should take place in the presence of a solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, ethyl acetate, dioxane or tetrahydrofuran. Hydrogenation can be carried out at room temperature and under normal pressure, but can also take place at elevated temperatures and/or under elevated pressure, which reduces the duration of the reaction. The reaction conditions and type of catalyst are preferably chosen so that a breakdown of the flavanic heterocyclic core is avoided and so that on the one hand the aromatic core and on the other hand the desired substituents R are not attacked. As a suitable catalyst you can use finely divided palladium or palladium on activated carbon, and the reaction is preferably carried out at room temperature and under normal pressure.

Hydrogenable groups in the radical R can be hydrogenated at the same time, especially if you use extremely reactive catalysts, such as palladium on carbon. However, it is possible to leave the groups R to remain intact by reducing the activity of these catalysts.

Compounds having a radical containing a salt-forming group, e.g. in the form of free carboxyl groups,

can, according to the reaction conditions chosen, be obtained in the free form or in the form of salts, and such forms are mutually transferable to one another. Salts of compounds containing a free carboxy group can e.g. be the metal salt,

then especially alkali metal salts, e.g. sodium or potassium salts, besides alk.ali-j ord metal salts, e.g. magnesium or calcium salts, or salts of ammonium, e.g. those with ammonia and organic bases such as tri-lower alkylamines,

e.g. trimethylamine or triethylamine, then especially non-toxic, pharmaceutically acceptable salts of the above-mentioned type. They can e.g. are produced by treating the free compounds with metal hydroxides or . carbonates or with ammonia or amines, as well as with suitable ion exchangers and organometallic compounds.

Compounds which include basic groups can also be obtained in the form of acid addition salts, as especially in the form of non-toxic pharmaceutically acceptable salts, e.g. with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic carboxylic or sulphonic acids such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic, heterocyclic-aliphatic acids, e.g. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic, cylic acid, aminosalicylic acid, embonic acid or nicotinic acid,

as well as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethylenesulfonic, phenylsulfonic, p-methylphenylsulfonic, naphthalenesulfonic, sulfaniline or cyclohexylsulfamic acids. ' Salts of these acids can e.g. are produced by treating the five compounds containing basic groups with acids or with suitable anion exchangers.

The new compounds containing basic groups can be converted to their quaternary ammonium compounds by treatment with alkylating agents such as lower alkyl halides, e.g. methyl iodide or lower alkyl sulfates or benzyl sulfates such as dimethyl sulfates.

Some of the starting compounds for the present method are known, but most are new. They can be produced by a method which is known in itself or more particularly by a new and advantageous method. Thus (+)-cyanidan-3-ol or one of its salts can be reacted with a reactive ester of an alcohol of the formula

where R^ has the same meaning as stated above, and where the radical R is introduced into the hydroxy group in the .3-position by etherification or esterification.

A reactive ester is particularly an ester with a

strong inorganic acid, then especially a hydrohalic acid, such as hydrochloric acid or hydrobromic acid or an organic sulphonic acid, preferably a lower alkanesulphonic acid, e.g. methane or ethanesulfonic acid, or a benzenesulfonic acid, optionally substituted in the benzene ring with methyl, chlorine or bromine, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid.

With this method, derivatives of (+)-cyanidan-3-ol and the 4-phenolic hydroxy groups can be produced. will then be substituted. From these tetraethers, (+)-3',4',5,7-0-tetrabenzyl-cyanidan-3-ol has already been prepared according to a method that has been strictly limited to the laboratory (K. Weinges and D. Seiler , Liebig's Ann. Chem.

7 14 193-204 (1968)) who recommends treating (+)-cyani-dan~3-ol in solution with acetone with benzyl chloride in the presence of potassium iodide and potassium carbonate, and where the whole is carried out

under nitrogen and boiling under reflux for several hours. This is the usual procedure for carrying out a benzylation,

and after separation and crystallization from ethanol, results in a mixture of (+)-3',4',5,7-0-tetrabenzyl-8-benzyl-cyanidan-3-61 and (+)-3<1> ,4',5,7-0-tetrabenzyl-cyanidan-3-ol. The latter compound can then be isolated by column chromatography in a yield of 1 to 2%, which is extremely low, and makes this method for preparing (+)-3', 4',5,7-0-tetrabenzyl- cyanidan-3_ol completely unacceptable for commercial purposes.

If, however, benzyl chloride is replaced by a

other halide selected from the group of radicals R mentioned above, then this method becomes completely acceptable, especially with substituted or unsubstituted phenacyl chlorides or bromides such as phenacyl chloride or phenacyl bromide or 4-bromophenacyl or bromide or 4-phenylphenacyl chloride or bromide. After filtering off the insoluble potassium carbonate and. evaporation of acetone, then one can only dissolve the residue for crystallization in a suitable solvent, e.g. a mixture of acetone and methanol. A good yield of the corresponding O-tetraether is obtained.

In addition to this, a new method has been found, which forms part of the present invention, and by means of which the intermediate products can be produced in very good yield. The method is characterized in that said (+)-cyanid-3-ol is reacted in an aprotic organic solvent with a high dielectric constant, with an alkaline hydride or an alkaline carbonate, whereby the tetra-alkaline salt of (+.)-cyanidan-3- ol is reacted with a reactive ester of an alcohol with the formula using a ratio of (+)-cyanidan-3-ol to said alkaline hydride to the reactive ester of 1: approx. 4.25 : approx. 4.5, or a ratio of (+)-cyanidan-3-ol to 'alkaline carbonate to reactive ester of 1 : approx. 8: approx. 6.

The alkaline hydride is more specifically sodium hydride which is used in the form of a dispersion in oil. The alkaline carbonate is preferably potassium carbonate.

Aprotic solvents with a high dielectric constant are preferably amides, such as dimethylformamide, but can also be sulfoxides such as e.g. dimethyl sulfoxide. However, dimethylformamide is the preferred solvent, firstly for economic reasons, and also because it can be recovered by simple distillation under normal pressure, besides being easier to use than dimethylsulphoxide. In addition to this, it is important that the reaction medium should be as water-free as possible. If you therefore dry the dimethylformamide on a molecular sieve, and then dry the solution of (+)-cyanidan-3-ol in dimethylformamide in the same way, the formation of secondary products is inhibited to a greater extent without the drying weakening the formation of the desired products.'

The reaction can take place in the presence of quarter- . close ammonium salts such as tetra-n-butylammonium bisulphate which are used in a ratio of 0.1 to 0.5 mol per mol of said (+)-cyanidan-3-ol, or in a carbon ether, preferably l8-crown-6, which is used in a ratio of 0.5 mol per moles of (+)-cyanidan-3-ol.

The reaction is carried out at temperatures between -25°C and +50°C. It is well known that dimethylformamide begins to decompose as low as room temperature, but not when it is in contact with basic substances, and this decomposition is avoided as far as possible by carrying out the reaction in this solvent at temperatures between - 25°C and +25°C, more particularly between -5°C and approx. 0°C. There is no danger of decomposition when using dimethylsulfoxide, and the reaction can then be carried out at temperatures lower than 50°C, preferably between +15°C and +30°C, e.g. at room temperature.

According to the present invention, after the formation of the alkali salt of (+)-cyanidan-3-ol, because this salt is not stable in the dimethylformamide/sodium hydride medium even at low temperature, the etherifying or esterifying agent must be immediately added. If this is not done, the yield of the reaction will be reduced and there will be complications in the purification of the desired products. After the etherification and esterification agent has been added, the temperature is low and should be kept for a certain period, after which it is allowed to rise slowly, e.g. to room temperature. At this stage, the reaction will be finished, and the reaction liquid can be kept for more than 15 hours in this state without changing the purification itself or impairing the quality of the desired product. It is also important to ensure adequate mixing of the medium during the reaction.

The development of the reaction can be examined by means of thin-layer chromatography on silicon dioxide gel, using chloroform or dichloromethane as the mobile phase.

After eliminating the solvent by distillation, the residue can be dissolved in a suitable solvent which can be used for crystallization of the intermediate. The proposed solvent for the crystallization of the desired products is trichlorethylene, which is very suitable. However, other solvents can be used, such as carbon tetrachloride, toluene and possibly ethyl acetate, ethanol, isopropanol or mixtures of these, e.g. carbon tetrachloride/n-hexane or acetone/methanol. However, ethyl ether and n-hexane are less suitable, and the same applies to acetone, pyridine, chloroform, dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane, the desired products being all soluble in said solvents at room temperature.

The radical R is introduced by the method which is known in itself in the intermediate products produced. Thus, e.g. a halogen derivative with the formula

used in the reaction. This is performed in the presence of a base, e.g. alkali, such as sodium or potassium hydroxide, silver oxide, sodium amide or sodium or potassium hydride. The etherification can be carried out in the presence of a non-reactive solvent such as dioxane, tetrahydrofuran or toluene, or optionally in mixtures of these solvents with each other or

with water. The reaction takes place at room temperature and can be accelerated by heating, possibly to the boiling point of the solvent used. The duration of the reaction is between a few minutes and several days, but a few hours will usually be sufficient. When the base is soda ash or pot ash in -aqueous solution and the intermediate product is in a water-immiscible

solvent, then a phase transfer catalyst, such as tetrabutylammonium bisulphate, can be used.

If R is a hydroxyalkyl or an aminoalkyl radical, then it is also possible to prepare derivatives of formula II by condensing an epoxide or an aziridine with the intermediate products in an acid or in a basic medium.

If R is an aromatic radical, the derivatives -with formula II. is produced by reacting an aromatic halide with the intermediate products. This reaction can be carried out in an inert solvent, e.g. tetrahydrofuran optionally at room temperature, in the presence of a base, such as a tertiary amine, e.g. trimethyl- or triethyl-amine, or in the presence of a fluoride, such as potassium fluoride or quaternary ammonium fluoride in the presence or absence of a crown ether, such as l8-crown-6. One. alcoholate of the intermediate products react e.g. with a halide of a heterocyclic compound. It is also possible to use an aromatic diester of phosphoric acid in the presence of catalytic amounts of a sulphonic acid, e.g. p-toluenesulfonic acid.

Intermediates of formula II where R is hydrogen can be added to olefins containing as substituents electron-withdrawing groups such as cyano, nitro, ketone or ester groups in the presence of a base, and the reagents can, e.g. be dissolved in an inert water-immiscible solvent, and

■ the base can be a 50% aqueous sodium carbonate solution, and as a phase transfer catalyst one can e.g. use benzyltrimethylammonium hydroxide.

A derivative of an acid-with the formula

such as an acid halide, alkyl anhydride or alkyl cyanide which can be formed in situ, is preferably used for the introduction of the radical R into the intermediates. A basic solvent

such as pyridine can be used in the presence or absence of a tertiary aliphatic amine, such as triethylamine and/or pyridine, or a mixture of solvents of which at least one is basic, or an inert or basic solvent, and preferably an alkaline catalyst. This reaction also applies to N-substituted isocyanates.

The esters of a mineral acid or a sulphonic acid with the intermediate products can be prepared by reacting the latter with a halide of said acid, or with a mineral polyacid which is suitable for esterification and where one or two hydroxy groups are respectively substituted or blocked, after which they be-, protecting groups can be eliminated by hydrolysis or hydrogenation, separately or together with the radicals R, which protect the aromatic hydroxy groups on said (+)-cyanidan-3-ol. These esters of mineral acids can also be prepared more directly using the anhydrides.

As a result of the close relationship between the new compounds in free form and in the form of their salts, it is understood in the above and in what follows that the free compounds also include the salts, and references to the salts also include the free compounds.

The substituents R can be chiral and the new compounds can thus be in the form of pure stereoisomers or in the form of mixtures of stereoisomers. The latter can, on the basis of physical-chemical differences between the components in the mixture, be dissolved in a known manner into pure stereoisomers, e.g. by means of chromatography, e.g. by thin-layer chromatography or by another suitable process. The most active of the stereoisomers are preferably isolated.

The above methods can be carried out using well-known methodology, and can be carried out in the absence of or in the presence of diluents or solvents, and if necessary under cooling or heating, under elevated pressure and/or in an inert gaseous atmosphere, such as in a nitrogen atmosphere.

The invention also relates to methods for carrying out the process where a compound produced as an intermediate product at any step of the process is used as starting material and the remaining steps of said process are carried out, or the latter is interrupted at one of its steps, or where the starting compound is formed under the reaction conditions or is used in the form of a. reactive derivative. In such cases, one should preferably use starting compounds that result in compounds that are particularly valuable.

The pharmacologically acceptable compounds according to the present invention can e.g. used for the manufacture of pharmaceutical preparations containing an effective amount

of the active substance in a mixture with solid or liquid, mineral or organic carriers or diluents of the type used in pharmacy and which are suitable for enteral or parenteral administration. The preparations are preferably used in the form of tablets or gelatin capsules and contain the active substance together with diluents such as lactose, dextrose,

sucrose, mannitol, sorbitol, cellulose and/or glycine, and/or lubricants such as silicon dioxide, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and/or polyethylene glycol, and the tablets may also contain binders such as magnesium silicate, an aluminum silicate, starch such as corn starch, wheat starch, rice starch or arrowroot, gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, drying agents such as starch, galactan, alginic acid or a salt thereof such as sodium alginate and/or effervescent mixtures or adsorbents, dyes, taste-correcting additives and/or sweeteners. The injectable preparations are preferably aqueous isotonic solutions or suspensions, and the suppositories are more particularly emulsions or suspensions in oil. The pharmaceutical preparations can be sterilized and/or contain auxiliary substances such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizing agents, salts to regulate the osmotic pressure and/or buffers. The present pharmaceutical preparations can, if desired, also contain other pharmacologically valuable substances which are produced in a manner known per se, e.g. by carrying out ordinary mixing, granulation or preparing coated preparations, and these can contain from 0.1 to 75 more especially from approx. 1 to approx. 50% of it

active substance.

Compounds according to the present invention can be administered in doses from 1 to 1000 mg, preferably from 1 to 500 mg per unit dose.

The invention also relates to the new intermediate products. formula II where OR^ and OR have the same meanings as stated above, except for the compound in which all the radicals R^

is benzyl and R is hydrogen or methyl.

The invention further relates to new starting compounds of formula II, where OR^ has the same meaning as stated above and OR is a free hydroxy group.

The following examples illustrate the invention. All temperatures are given in °C.

Example 1

A suspension of 12 g of palladium chloride (PdCl2) in 1800 ml of methanol was placed in a 3 liter round-bottomed flask and a hydrogenation was then carried out for 2 hours at room temperature, and 2400 ml of hydrogen was used. The methanol was poured off, and the palladium catalyst was washed four times with 800 ml of fresh methanol, which eliminates the hydrochloric acid that had formed, as well as traces of soluble PdClg that had not reacted. The methanol was then replaced with ethyl acetate and washed three times with 500 ml of this solvent.- After site washing, a thin layer of ethyl acetate was placed over the catalyst to prevent spontaneous ignition of this on contact with air.

A solution of 40 g-( + ) 3 ' , 4 ' , 5, 7-0-tetra-benzyl-3-0-methyl-cyanidan-3-ol in 1600 ml of ethyl acetate was added to this newly prepared suspension of palladium black ,

and the mixture was hydrogenated for 3 hours and the hydrogen consumption was 6600 ml. Said catalyst was then removed by filtration, and the filtrate evaporated to dryness under a vacuum at 40°C. The residue was dissolved in 2000 ml of water, and the water evaporated under a weak vacuum at 40°C until a volume of approx. 100 ml. This azeotropically removes the ethyl acetate and the toluene formed by the removal of the benzyl groups, is repeated three times until a final volume of 100 ml was obtained which was dried by lyophilization. The yield is quantitative and consists of 18.5 g of (+) 3-0-methyl-cyanidan-3-ol. Melting point: 118-120°C. W29+2.76 in EtOH (c = 0.5).

Example 2

A suspension of 6.0 g of palladium chloride in 900 ml of methanol was hydrogenated in a 2000 ml flask for 1 hour at room temperature, and 1100 ml of hydrogen was used. After pouring off the methanol, the mixture was washed three times with 200 ml of methanol and then three times with 200 ml of ethyl acetate.

A solution of 21.2 g of (+) 3',4',5,7-0-tetra-benzyl-3-0-butyl-cyanidan-3-ol in 900 ml of ethyl acetate was then added, and the mixture was hydrogenated in 5 hours at room temperature, and the hydrogen consumption was 3250 ml. The palladium was removed by filtration and the filtrate evaporated under a medium vacuum at 40°C. The residue was dissolved in 500 ml of water and then evaporated to a volume of 50 ml. This was repeated four times to azeotropically remove the ethyl acetate and the toluene formed during the hydrogenation. After the last evaporation step, the residue was dried under 10 mm Hg at 60°C to constant weight. The yield of (+) 3_0-butyl-cyanidan-3-ol was quantitative and amounted to 10.4 g. "Melting point: 103-104°C.

Example 3'

The method was used as in example 2, except that 21.6 g of (+) 3',4',5,7-0-tetra-benzyl-3-0-butyryl-cyanidan-3-ol were used.

After the residue' had been dried to constant weight as in example 2, it was dissolved in a mixture of 5500 ml of water and 1100 ml of ethanol at room temperature and then filtered, after which the filtrate was concentrated in a medium vacuum at 40°C to a volume of 2500 ml, and the result was a paste-like oil. The solution was poured off and left at 4°C for 3 days, and the white precipitate that had formed was filtered off, washed with cold water and dried under 10 mm Hg over P2°5 at 50°C to constant weight. The yield of (+) 3~0-butyryl-cyanidan-3-ol is 7.3 g, i.e. 67.6 Melting point: 112-113°C.

Example 4

The procedure was as in example 2, except that 22.5 g of (+) 3'34',5,7-0-tetrabenzyl-3-0-(3,3_dimethylbutanoyl)-cyanidan-3-ol were used. The yield was (+) 3-0-(3,3-dimethylbutanoyl)-cyanidan-3-ol is quantitative, and amounted to 11.6 g. Melting point: Il8-120<Q>C.

Example 5

The procedure was as in example 2, except

from using 22 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-(3-carboxypropionyl)-cyanidan-3-ol..

After the ethyl acetate and toluene were azeotropically removed with water, the residue was dissolved in 1000 mL of water, evaporated until slightly cloudy (ca. 500 mL), filtered, after which the filtrate was lyophilized to constant weight. The yield of (+) 3-0-(3-carboxypropionyl)-cyanidan-3-ol is practically quantitative and amounted to approx. 11.7 g.

Melting point': 102-106°C.

Example 6

The procedure is as in example 1, except

from the fact that 50 g of ( + ) 3 ' , 4 ' , 5, 7-0-tetrabenzy I-.3-0-decanoyl-cyanidan-3-01 were used.

After the ethyl acetate was evaporated, the residue was . dried in vacuum at 40°C and dissolved in 300 ml of ethanol, and the solution was evaporated to 50 ml. after which 250 ml of ethanol and 250 ml of water were added. The solution was evaporated

to 50 ml, and 500 ml of water was added, after which the solvent was driven off under a weak vacuum by 40°C. The residue was dried to constant weight under high vacuum above

P20. The yield of ( + ) 3-0-decanoyl-cyanidan-3-ol is 26 g,

i.e. 94.3 Melting point: 71-74°C.

Example 7

26.6g'(+) 3',4',5,7-0-tetrabenzyl-3-0-palmi-toyl-cyanidan-3-ol was dissolved in 900 ml of ethyl acetate (solvent

ning was accelerated by heating) in a 2000 ml round bottom flask.

16.0 g of 10% palladium on activated carbon was added and the mixture was hydrogenated. The palladium and activated carbon were removed by filtration and the filtrate evaporated to dryness. The residue was taken up in a mass which was dissolved in 400 ml of hot methanol. 1500 ml of water was added to the methanol solution with stirring, and this was continued overnight at room temperature and then for 48 hours in an ice bath. The precipitate formed was filtered off and dried under high vacuum over ^2^5

at room temperature. The yield of (+) 3_O-palmitoyl-cyanidan-3-ol is 12.4 g, i.e. 78.2%. Melting point: 67-69°C.

Example 8

The procedure was as in Example 2, and palladium black was prepared by hydrogenating a suspension of 18 g of palladium chloride in 900 ml of ethyl acetate, after which 40 g of a solution of (+) 3',4',5,7-0-tetrabenzyl -3-O-tetrahydro-phthalyl-cyanidan-3-ol in 1800 ml of ethyl acetate was hydrogenated as described in Example 1. After the organic solvent (ethyl acetate and toluene) had been removed azeotropically with water, the residue was dried to constant weight at room temperature under a high vacuum above P2°5' The yield of (+) 3-0-(2-carboxy-cyclohexanecarbonyl)-cyanidan-3-ol is 22.2 g, i.e. quantitative. Melting point: 138-140°C.

Example 9

A suspension of 30 g of palladium chloride in 4.5 liters of methanol was hydrogenated in a 10 liter round bottom flask. The reaction lasts for an hour and consumes 4.92 liters of hydrogen. The catalyst was washed, first four times with 1 liter of methanol and then four times with 1 liter of ethyl acetate. A solution of 113 g of ( + ) 3' ,4',5,7-0-tetrabenzyl-3-0-benzoyl-cyanidan-3-ol in 4

liter of ethyl acetate was added to the catalyst impregnated with ethyl acetate, and the mixture hydrogenated for approx. lg hour. The Pd catalyst was filtered off, the filter was washed with 250 ml of ethyl acetate, and all the ethyl acetate was combined and distilled under a weak vacuum at 40°C. The residue was dissolved in 5 liters of water, and the resulting suspension stirred for 30 minutes at room temperature, after which the water was driven off under a medium vacuum at 40°C to a volume of approx. 500 ml. This was repeated twice and the suspension was finally evaporated to dryness. The residue was dried to constant weight over silica gel under high vacuum. The yield of (+) 3-0-benzoyl-cyanidan-3-ol is quantitative and amounted to 59 g. Melting point: 132-135°C (amorphous product).

Example 10

The procedure was as in example 9, except

from using 115.8 g of ( + ) .3',4',5,7-0-tetrabenzyl-3-0-(4-fluorobenzoyl)-cyanidan-3-ol. The yield is 61.5 g of (+) 3-O-(4-fluorobenzoyl)-cyanidan-3-ol, i.e. 99.5%. Melting point: 131-133°C.

Example 11

As in Example 9, palladium black was prepared from a suspension of 40 g of palladium chloride in 4.5 liters of methanol, and the methanol was replaced by ethyl acetate, after which a solution of 130 g of (+) 3',4',-5, 7-O-tetrabenzyl-3-O-(3,4-dibenzyloxybenzoyl)-cyanidan-3-ol in 5.5 liters of ethyl acetate, and the mixture was hydrogenated. After ethyl acetate and toluene were removed azeotropically with water, the residue was dissolved in 500 ml of water and the solution lyophilized to constant weight. The yield of (+) 3_0-protocatechyl-cyanidan-3-ol is quantitative and amounts to 57.5 g. Melting point: 166-168°C.

Example 12

The procedure is as in example 2, except that 24.5 g of (+) 3',4',5,7"0-tetrabenzyl-3-0-(acetyl-salicylyl)-cyanidan-3-ol were used. The yield of (+) 3-O-(acetylsalicyyl)-cyanidan-3-ol is quantitative and amounts to 13.5 g.

Melting point: ll8-119°C. u

Example 13

The procedure is as in example 1: Palladium black was prepared from 24 g of palladium chloride in 3.6 liters of methanol, after which 64 g (+.X 3' , 4 ' , 5, 7_0-tetrabenzyl-3-0-(2 -carboxybenzoyl)-cyanidan-3-ol in 3.5 liters of ethyl acetate. After filtering off the catalyst and evaporating the ethyl acetate and toluene, the residue was dissolved

in 2 liters of ethanol and the solution evaporated to approx. 100 ml. This was repeated twice, after which the residue was dried under high vacuum at 40°C to constant weight. The yield of (+) 3-O-(2-carboxybenzoyl)-cyanidan-3-ol is quantitative and amounts to 35 g. Melting point: 139-142°C.

Example 1, 4

Palladium black was prepared as in Example 1, after which the methanol was replaced by ethyl acetate and 30.8 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-(N-phenylcarbamoyl) was hydrogenated )-cyanidan-3-ol in 1600 ml of ethyl acetate. After filtering off the catalyst, the ethyl acetate was evaporated to a volume of approx. 50 ml, and 250 ml of water was added and the pH was adjusted to 6 using an aqueous solution of 1N NaOH. Evaporation to dryness in vacuo was carried out at 40°C, after which addition was made

500 ml of water and evaporated three times, finally the residue was dissolved in 1 liter of ethanol which was distilled off, and the whole thing was repeated. The product was then dissolved in a mixture of 300 ml. ethanol and 300 ml of water, evaporated and then dissolved in 500 ml of water and evaporated to 100 ml. The precipitate formed was filtered off and dried to constant weight at 40°C in vacuum. The yield of (+) 3-O-(N-phenylcarbamoyl)-cyanidan~3^ol is 15.0 g, i.e.

91.6%. Melting point: l89-200°C.

Example 15

The procedure is the same as in example 2 except that 18.2 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-methane-sulfonyl-cyanidan-3-ol were used and hydrogenation was carried out in 600 ml of ethyl acetate. The solvents were distilled off at room temperature, and the residue dried at the same time under high vacuum. It was then dissolved in 500 ml of ethanol at room temperature, and distilled to approx. 50 ml under high vacuum at 0°C. It was repeated twice and the product was dried at 35°C for 15 minutes in vacuum and

■ the residue dried to constant weight under high vacuum at room temperature. The yield of (+) 3-0-methanesulfonyl-cyanidan-3-ol is quantitative and amounts to 9.2 g. The substance decomposes slowly even at room temperature, and it was stored for several days in a freezer at -30°C.

Example 16

As in example 7, a solution of 40 g of (+) 3'-4',5,7-0-tetrabenzyl-3-0-(4-methylbenzenesulfonyl)-cyanidan-3-ol in 1.8 liters of ethyl acetate was hydrogenated in a 3000 ml round bottom flask over 20 g of 10% palladium on activated carbon. The hydrogenation takes 2\ hours. The palladium and carbon were filtered off and the filtrate evaporated to dryness in vacuum at room temperature, after which 1.7 liters of ethanol were added and a distillation was carried out at 0°C under high vacuum. When the volume was approx. 100 ml, 800 ml of ethanol was added and distilled at 0°C under high vacuum. The residue was then heated to 35°C for 15 minutes under high vacuum and kept at room temperature under said vacuum until a constant weight was obtained. The yield of (+) 3-O-(4-methylbenzenesulfonyl)-cyanidan-3-ol is quantitative and amounts to 22 g.

The product was stored in a deep freezer at -30°C

to avoid decomposition.

Example 17

•A suspension of 29 g of palladium chloride in 2.9 liters of methanol was hydrogenated in a 10 liter round bottom flask. The methanol with added hydrochloric acid was poured off, and the palladium black was first washed three times with 300 ml of methanol and then three times with 300 ml of ethyl acetate. A solution of 54.5 g of (+)-3',4',5,770-tetrabenzyl-3-0-(2-cyanoethyl)-cyanidan-3-ol in 2.9 liters of ethyl acetate was then added, and the whole was hydrogenated. After removal of the catalyst by filtration, the solvent was evaporated in a medium vacuum and the residue dissolved in 1.5 liters of water, and the mixture evaporated on a rotary evaporator (Rotavapor) at 40°C under a medium vacuum to 500 ml. This was repeated twice more and the final fraction of 500 ml was lyophilized to constant weight. Said (+) 3-O-(2-cyanoethyl)-cyanidan-3-ol was obtained in a yield of 25 g, i.e. 94%.

Example 18

56 g (+> 3',4',5,7-0-tetrabenzyl-3-0-(2-cyano-ethyl)-cyanidan-3-ol, 4 liters of absolute ethanol and 100 ml of chloroform were placed in a 10 liter round flask Under exclusion

of air, the mixture was heated to 60°C until complete dissolution was obtained, then cooled to room temperature and argon bubbled through it. Under argon, 25 g of 10% palladium on activated carbon was added and a hydrogenation was carried out. 12 liters of hydrogen were used. The hydrogen was then replaced with nitrogen, the catalyst filtered off and the filtrate evaporated to dryness in a medium vacuum. The residue was mixed with 1 liter of ethyl acetate, and the resulting suspension stirred for 30 minutes at 40°C. The solvent was then evaporated to approx. 200 ml, the whole cooled to 0°C.

filtered and the precipitate washed with ethyl acetate. The treatment with ethyl acetate was repeated twice. Finally, the precipitate was washed twice with ethyl acetate, then twice with methylene chloride and then dried under high vacuum for 24 hours at room temperature. The product was dissolved in 2 liters of water, and the solution was evaporated to 200 ml by distillation under medium pressure, after which 1.8 liters of water were added and evaporated in the same way to 200 ml. The final solution was lyophilized to constant weight. The hydrochloride of (+) 3-0-

(3-Aminopropyl)-cyanidan-3-ol was obtained in a yield of 21 g, i.e. 68.4%. Melting point (with decomposition): 195°C.

Example 19

An approx. 55% dispersion of 5.0 g sodium hydride

in oil was added to a 500 ml round bottom flask equipped with a condenser and closed with a calcium chloride tube, a dropping funnel with a pressure equaliser,

a nozzle for supplying nitrogen, a thermometer and a stirring mechanism. A strong stream of nitrogen was passed through for 5 minutes

and then reduced so that 60 ml of anhydrous tetrahydrofuran was added dropwise through the dropping funnel. The mixture was heated to approx. 40°C using an external oil bath and with stirring

7.5 ml (17 g) of freshly distilled methyl iodide added dropwise. 52.0 g of (+) 3',4',5,7-0-tetra-benzyl-cyanidan-3-ol in 170 ml of anhydrous tetrahydrofuran was then added dropwise over the course of one hour. The mixture was stirred for 1 hour and kept at 40°C.

It was then cooled to room temperature, 200 ml of water was added

and the mixture stirred for 15 minutes. The reaction mixture was then filtered and the filtrate placed in a rinsing funnel containing 200 ml of toluene and 200 ml of water. The organic phase was separated and washed with 50 ml of water and the aqueous phase extracted twice with 400 ml of methylene chloride. The organic fractions were combined, dried over magnesium sulfate and evaporated under a medium vacuum at 40°C. The residue was dried overnight at 15 mm Hg at 45°C and weighed 51 g-

The dry residue was dissolved at 100°C in 510 ml of methoxyethanol, filtered hot, and the filtrate was cooled slowly with stirring. After 8 hours, the precipitate formed was filtered off, washed with 30 ml of cold methoxyethanol and dried in vacuum at 50°C overnight. The yield of (+) 3',4',5,7-0-tetrabenzyl-3_0-methyl-cyanidan-3_ol is 45.5 g, i.e. 85.5

■Melting point: 124-125°C.

Example 20

1.5 liters of a 50% aqueous solution of NaOH,

a solution of 52 g of (+) 3',4',5,7-0-tetrabenzy1-cyanidan-,3-ol in 1.5 liters of butyl chloride and 6.8 g of tetrabutylammonium hydrogen sulfate was added to a 6 liter round bottom flask equipped with mechanical stirrer and cooler. The mixture was heated to 50°C

and held at this temperature for 2 hours and 45 minutes below

vigorous stirring. After cooling to room temperature, two phases were separated, and the organic phase was washed three times with 300 ml of water and dried over magnesium sulfate. After filtration, the butyl chloride was distilled off and recovered. The residue was recrystallized twice in 3.2 liters of absolute ethanol. After drying, (+) 3',4',5,7-0-tetrabenzyl-3-0-butyl-cyanidan-3-ol was obtained in a yield of 40.0'g, i.e. 70.8%.

Melting point: 55-56°C.

Example 21

A solution of 52 g of (+) 3',4',5,7-0-tetra-benzyl-cyanidan-3-ol in 360 ml of anhydrous pyridine was added to a 500 ml 4-necked round bottom flask equipped with a dropping funnel with a pressure equalizer , a cooler, closed with calcium chloride tubes, a nozzle for supplying nitrogen and a magnetic stirrer.' 17 g of butyryl chloride was then added under nitrogen and vigorous stirring. The mixture was reacted at room temperature with stirring for 5 hours and then completely poured into 500 ml of water containing ice. The mixture was stirred for one hour and the oily. layer separated. This was mixed first with 500 ml of an aqueous solution of 1N NaHCO-j and then twice with 500 ml of water. The fixed product

was filtered off, washed with water and dried in vacuo. Recrystallization was carried out from 3 liters of ethanol and 400 ml of acetone. After drying (+) 3',4',5,7-0-tetrabenzyl-3~0-butyryl-cyanidan-3-ol was obtained in a yield of 52.4 g, i.e. 91%• Melting point: 92- 93°C.

Example 22

The procedure is as in example 21, but 21.5 g of 3,3-dimethylbutanoyl chloride was used. The reaction time is one hour. After washing with water, 56 g of crude product was obtained, this was dissolved in 400 ml of acetone and 3 liters of ethanol which was added dropwise and the solution was then set aside for crystallization for 6 days. (+) 3',4',5,7-0-tetrabenzyl-3_0-(3,3-dimethylbutanyl)-cyanidan-3-ol was obtained in a yield of 50.6 g, i.e. 84.6%. Melting point: 58°C.

■ Example 23

52 g (>) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol, 400 ml of triethylamine, 80 ml of pyridine and 16 g of succinic anhydride were added to a 1 liter round bottom flask equipped with a condenser, closed with calcium chloride tube. The mixture was refluxed for one hour, after which the solvent was removed under medium

vacuum at 40°C. The residue was washed twice with 300 ml of water, acidified to pH 3 with HCl, then twice with distilled water. Recrystallization was carried out twice with 3 liters of ethanol. (+) 3',4',5,7-0-tetrabenzyl-3-0-(3-carboxy-propionyl)-cyanidan-3-ol was obtained in a yield of 47.3 g, i.e. 8l.8 %. Melting point: 95-96°C.

Example 24

The procedure is the same as in example 21 except

from using a 1 liter round bottom flask and 104 g of (+) 3',4',5-7-0-tetrabenzyl-cyanidan-3-ol in 720 ml of pyridine in the presence of 6l g of capric chloride. The mixture was kept at 50°C for 11 hours with stirring and then poured into 3 liters of ice and water and mixed for one hour. The precipitate was filtered off, first washed twice with 1 liter of aqueous solution of 1N NaHCO-^ and then

twice with 1 liter of water and dried in vacuum at room temperature above P2°5*Finally, the mixture was recrystallized in

1.4 liters of methoxyethanol. (+) 3',4',5,7-0-tetra-benzyl-.3-0-decanoyl-cyanidan-.3-ol was obtained in a yield of 121.7 g, i.e. 94.5 Melting point: - 88-89°C.

Example 23

The procedure is as in example 21, using 44 g of palmitoyl chloride and keeping the reaction medium at 90°C

for 2 hours. The resulting (+) 3',4',5,7-0-tetrabenzyl-3-0-palmitoyl-cyanidan-3-ol was purified by dissolving under heat in 80 ml of acetone, after which 3 liters of ethanol was added dropwise to the solution. The yield of the desired substance was 68.4 g, i.e. 96.2%. Melting point: 57-59°C.

Example 26

The procedure is as in example 23, but 24.5 g of tetrahydrophthalic anhydride was used. The reaction mixture was refluxed for 45 minutes and the solvent removed by distillation under a medium vacuum at 40°C. The residue was dissolved in 600 ml of methylene chloride and extracted twice with 500 ml of 2N HCl and twice with 500 ml of distilled water. The methylene chloride solution was dried over MgSO 4

. and the solvent evaporated. The residue was recrystallized

in a mixture of carbon tetrachloride and petroleum ether. (+) 3',4',5,7-0-tetrabenzyl-3-0-tetrahydrophthalyl-cyanidan-3-ol was obtained in a yield of 55.2 g, i.e. 86%. Melting point: 67-68°C.

Example 27

The procedure is as in Example 21, except that 22.5 g of benzyl chloride was used, and the mixture was kept at 80°C for 6 hours. The separated product was, after washing with NaHCO 3 and water, recrystallized in a mixture of 7 liters of ethanol and 1.25 liters of acetone. (+) 3',4',5,7-0-tetra-benzyl-3_0-benzoyl-cyanidan-3-ol was obtained in a yield of 50.1 g, i.e. 83%. Melting point: 115-116°C.

Example 28

The procedure is as in Example 21, except that 25.4 g of 4-fluorobenzoyl chloride was used, and the mixture was kept at room temperature for 7 hours. The finished product was dissolved in 3.5 liters of acetone under heating and precipitated by adding 800 ml of water. Upon cooling, (+)3'_4',5,7_0-tetrabenzyl-3_0-(4-fluorobenzoyl)-cyanidan-3-ol was precipitated in

"a yield of 52.2 g, i.e. - 84.4%. Melting point: 154°C.

Example 29

Procedure as in Example 21", except

that a solution of 56.6 g of 3,4-dibenzyloxybenzoyl chloride in 130 ml of pyridine was used. The mixture was stirred at room temperature for 2 hours and 45 minutes. The final product was recrystallized twice from acetone. (+) 3',4',5,7_0-tetraben-syl-3-0-(3,4-dibenzyloxybenzoyl)-cyanidan-3-ol was obtained

in a yield of 56.5 g, i.e. 73 Melting point: 162-163°C.

Example 3' 0

The procedure is as in example 21, except that a solution of 32 g of acetylsalicylic chloride in 180 ml of pyridine was added and the mixture was stirred for 2 hours at

65°C. After washing with NaHCOy and water, the crude product was recrystallized first from 8 liters of ethanol and then from a mixture of 5 liters of ethanol and 1.2 liters of acetone. The yield of (+) 3',4'-5,7-0-tetrabenzyl-3-0-(acetylsalicylicyl)-cyanidan-3-ol is 44.8 g, i.e. 69%. Melting point: 136-137°C.

Example - 31

260 g (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol, 89 g phthalic anhydride, 3 liters triethylamine and 1 liter pyridine

was added to a 4-necked 6 liter round-bottomed flask equipped with a mechanical stirrer, a condenser closed with calcium chloride stirrers, a nozzle for the supply of nitrogen and a thermometer. Under nitrogen, the mixture was refluxed (92°C) for 9 hours and then cooled to room temperature and filtered. The mixture was evaporated to . dryness in a medium vacuum at 40°C in a rotary evaporator (Rotavapor), and the oily residue was dissolved in 500 ml of methylene chloride and extracted twice with 500 ml of aqueous 2N HCl and then twice with 500 ml of water. The organic solution was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was recrystallized from 2.5 liters of toluene and 1.6 liters of naphtha. It crystallized

product was dried to constant weight under high vacuum at room temperature. The yield of (+) 3',4',5,7-0-tetrabenzyl-3-0-(2-carboxybenzoyl)-cyanidan-3-ol is 221.6 g, i.e. 69.4%. Melting point: 127-129°C.

Example 32

Procedure as in example 21 except that a 1 liter round bottom flask and 65 g of (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol in 800 ml of pyridine were used. The mixture was kept at 100 °C under nitrogen and 17.1 ml (18.7 g) of N-phenylisocyanate were added dropwise. The mixture was left for one hour at 100°C, cooled to room temperature, filtered and 6 liters of water added with vigorous stirring. The white precipitate was washed with 6 liters of water. and dried under a medium vacuum at 60°C for 2 days. It was recrystallized from 8 liters of acetone, which gave 60.7 g, and after concentration to approx. 2 liters gave a further 16.2 g. The yield of (+) 3',4',5,7-0-tetra-

benzyl-3-0-(N-phenylcarbamoyl)-cyanidan-3-ol is thus 76.9 g, i.e. 100%. Melting point.: 204°C.

Example 53

A solution of 65 g of (+) 3',4',5,7-0-tetra-benzyl-cyanidan-3-pl in 500 ml of pyridine and 25 ml of triethylamine was added to a 3-necked 750 ml round bottom flask fitted with a magnetic tubes, a calcium chloride tube, a separating funnel and a nozzle for supplying nitrogen. A stream of nitrogen was passed through the flask, and the mixture cooled to -15°C and then 23 g of methanesulfonyl chloride was added dropwise over 30 minutes. The reaction mixture was stirred for 30 minutes at -15°C, and then completely poured into 2.5 liters of ice water. The precipitate was filtered off and mixed with 1 liter of water and then filtered and dried in vacuum over ^2^5" The product was recrystallized from 2 liters of n-butanol, filtered and washed with 250 ml of methanol and then again with 500 ml of methanol. The substance was dried in vacuum over ^ 2^ 5 at room temperature The yield of (+)3',4',5,7-0-tetrabenzyl-3-0-methane-sulfonyl-cyanidan-3-ol is 60.5 g, i.e. 83%• Melting point: l-38-139°C.

Example 34

158 g of (+) 3 ' , 4 ' ,5,7-0-tetrabenzyl-cyanidan-3-ol and 250 ml of pyridine were added to a 4-necked 500 ml round bottom flask equipped with a condenser closed with a calcium chloride tube, a nozzle for supplying nitrogen, an immersion thermometer and a magnetic stirrer. The mixture was heated to 90°C and (+) 3'-,4'-5,7_0-tetrabenzyl-cyanidan-3-ol was added to the solution.

67 g of 4-methylbenzenesulfonyl chloride were then added while heating, and the solution was kept at 90°C under nitrogen and stirring for 4 hours. The mixture was then cooled to -30°C i

2\ hour and a precipitate was obtained. 1.5 liters of water was added and the mixture was mixed and filtered off and washed with an aqueous 1N NaHCO3 and then with water until the filtrate became neutral. The precipitated substance was recrystallized from 5 liters of chloroform and 20 liters of isopropanol. The yield of ('+) 3',4'-5,7-0-tetrabenzyI-3-0-(4-methylbenzenesulfonyl)-cyanidan-3-ol is 162.9 g, i.e. 84.3 Melting point: 173- 174°C.

Example 35

'A solution of 300 g (+) 3',4',5,7-0-tetra-benzyl-cyanidan-3-ol in 3 liters of toluene was first added, then

became 4.5 liters of a 50% aqueous solution of NaOH and then finally 16 g of Triton B were added while stirring to a 20 liter round flask equipped with a separatory funnel and a mechanical stirrer.

With stirring, 82 g of acrylonitrile were added; dropwise" over the course of 45 minutes. The mixture was vigorously stirred for 2 hours at room temperature, 30 g of acrylonitrile was added and stirring continued overnight. A third of 100 g of acrylonitrile was then added to the reaction mixture. Stirring was continued for a further 2 hours , after which the toluene phase was isolated and washed three times with 1 liter of 0.1N hydrochloric acid and then with 2 liters of water. The toluene phase was dried over magnesium sulfate and the toluene evaporated. The residue was dissolved in 1.8 liters of acetone, and the acetone solution completely while stirring over in 5.4 liters of boiling ethanol. Upon cooling, (+) 3',4',5,7-0-tetrabenzyl-3-0-(2-cyanoethyl)-cyanidan-3-ol was precipitated. It was filtered and dried Yield: 318 g, i.e. 98% Melting point: 100-101°C.

Example 36

A 3-necked 500 ml round bottom flask was equipped with a nozzle for the supply of nitrogen, a dropping funnel with a pressure equaliser, a calcium chloride tube and a magnetic stirrer. 52 g of 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol, 260 ml of anhydrous dioxane and 130 mg of p-toluenesulfonic acid were added to the flask. 26 ml (24 g) of dihydropyran was added dropwise with stirring. Stirring was continued at room temperature for 2 hours, after which the mixture was filtered and the filtrate evaporated to dryness under a medium vacuum. The residue was dissolved in 500 ml of chloroform, and the solution was washed twice with 300 ml of aqueous 1N NaHCO 3 , then with 300 ml of distilled water. The chloroform solution was dried over magnesium sulfate, filtered and evaporated. The residue was dried under high vacuum at room temperature. Said (+) 3',4',5,7_0-tetrabenzyl-3~0-tetrahydropyranyl-cyanidan-3-ol was obtained in the form of a mixture of the two diastereoisomeric forms in a yield of 56 g, i.e. 95.3 %.

The product is in the form of a caked mass, so that

is not possible to determine the melting point.

Example 37

A suspension was prepared in 1 liter of freshly distilled dimethylformamide of 92.8 g of a 55% dispersion of sodium hydride in oil (51 g NaH) under nitrogen. The suspension was cooled to between -5°C and 0°C using an external cooling bath.

A solution of 145 g of (+)-cyanidan-3-OH in

2 liters of freshly distilled dimethylformamide were added at a in such a way that the suspension remained between -5 and 0°C (addition time approx. one hour). Hydrogen was evolved and removed

with nitrogen circulation.

When the addition of (+)-cyanidan-3-ol was finished, the reaction was left at low temperature for 15 minutes and the evolution of hydrogen gas then practically stopped. In the course of 1 hour, 267.5 ml, i.e. 385 g of benzyl bromide were then added in such a way that the temperature remained in the aforementioned range. This temperature was further held there for 30 minutes, after which it was slowly allowed to rise to room temperature.

The dimethylformamide was recovered by distillation in vacuum at 60°C, and the oily residue was dissolved in 3 liters of trichloroethylene. The organic solution was washed three times with 3 liters of distilled water and then filtered to remove impurities in the suspension.

By concentration and cooling to 5°C several times, 159 g of practically pure (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol was obtained, which was crystallized. Dividend:

51%..The product•is in the form of white needles.

Melting point: l44-l45°C.

Example 58

The procedure was carried out as described in Example 37, except that the dimethylformamide was dried on a molecular sieve (4 Å, 2 mm) and that the solution of (+)-cyanidan-3-ol in dimethylformamide was dried in a similar manner. Mån obtained (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol in a yield of 55%.

Example 39

The procedure was as in Example 37, but the benzyl bromide was replaced with 2.25 mol of benzyl chloride. After the reaction medium had been raised to room temperature, this temperature was maintained for 10 hours with stirring before the dimethylformamide was distilled off. The yield of (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol is 57%•

Example 40

A solution of 1.45 g of (+)-cyanidan-3-ol in 20 ml of freshly distilled dimethyl sulfoxide was added slowly with stirring at room temperature to a suspension in 10 ml of freshly distilled dimethyl sulfoxide, kept under nitrogen, consisting of 0.93 g of a 55% dispersion of sodium hydride in oil (0.51 g NaH). Hydrogen was evolved and removed by nitrogen circulation. After stirring for one hour at room temperature, the evolution of hydrogen had stopped, and the sodium salt of (+)-cyanidan-3-ol had partially deposited on the wall of the flask. 2.68 ml (3.85 g) of benzyl bromide was then added dropwise, and a slight exothermic reaction was obtained. 30 minutes later the mixture becomes clear and is then stirred for one hour at room temperature. The solution was then poured dropwise, while stirring, into 300 ml of cold 10% aqueous solution of sodium chloride. The precipitate formed was filtered off, dried in vacuum at 80°C and then recrystallized from 40 ml of carbon tetrachloride. 196 g of (+) 3'j4',5,7_0-tetrabenzyl-cyanidan-3_ol were obtained, i.e. a yield of 60.3

Example 4l

The procedure as in Example 37, except that 416 g of ct-bromo-o-xylene were used instead of benzyl bromide. After removal of the dimethylformamide, the residue was dissolved in chloroform. The solution was washed with distilled water, filtered and evaporated. The residue was recrystallized from a mixture of benzene and petroleum ether (6:3 volume/volume). (+) 3'j4',537-0-tetra-(2-methylbenzyl)-cyanidan-3-ol was obtained in a yield of 51%. Melting point: 88-90°C.

Example 42

Procedure as in example'37 except

that 4l6 g of oe-bromo-p-xylene was used instead of benzyl bromide. The residue after removal of the dimethylformamide was dissolved in chloroform. The solution was washed with water, filtered and evaporated and then recrystallized from carbon tetrachloride. (+) 3',4',5,7-0-tetra-(4-methylbertzyl)-cyanidan-3-ol was obtained in a yield of 40%. Melting point: 66-70°C.

Example 43

Procedure as in Example 37 except

that 562 g of 2-bromobenzyl bromide was used instead of benzyl bromide. After removal of the dimethylformamide, the residue was dissolved in chloroform. The solution was washed with water, filtered and evaporated and then recrystallized from a mixture of chloroform and carbon tetrachloride (40:55 v/v).. The yield of (+) 3',4',5,7-0-tetra-(2 -bromobenzyl)-cyanidan-3-ol was 74%. Melting point: 155-157°C.

Example 44

The procedure was as in example 37 except

from using 18l g of methyl chloromethyl ether instead of benzyl bromide. The residue obtained after removal of the dimethylformamide was dissolved in chloroform, washed three times with water and then evaporated. Recrystallization was first ex-

conducted from n-hexane and then from a mixture of methanol and water (1:1 v/v). (+) 3',4',5,7-0-tetra(methoxymethyl)-cyanidan-3-ol was obtained in a yield of 40%.

Melting point: 92-93°C.

Example 45

The procedure is the same as in example 37 except

from the fact that 272 g of allyl bromide was used instead of benzyl bromide. The final solution of dimethylformamide was poured over a mixture of water and crushed ice, and the white precipitate was separated by centrifugation and dissolved in chloroform. The chloroform solution was washed three times with water and then evaporated. The residue was recrystallized from n-hexane. The yield of (+) 3',4',5,7-0-tetra-allyl-cyanidan-3-ol is 28%. Melting point: 78.5 - 80°C.

Example 46

The procedure is the same as in example 37 except

from using 244 g of ethyl chloroformate instead of benzyl bromide. The distillation residue of the dimethylformamide solution was dissolved in chloroform and this was washed several times with water and then evaporated. The residue was dissolved in a mixture of methanol and water (15:5, volume/volume), and the impurities were

field. After standing for several days in the cold, the overlying liquid was distilled off and (+) 3',4',5,7~0-tetra(ethoxycarbonyl)-cyanidan-3_ol was recovered in a yield of 52%. Melting point: approx. 65°C.

Example 47

1.45 g of (+)-cyanidan-3-ol was dissolved in 50 ml of anhydrous acetone, after which 6.91 g of anhydrous potassium carbonate was added, and the mixture was refluxed under nitrogen. A resolution of 6.26. g of p-bromophenacyl bromide in 30 ml of anhydrous acetone was then added and refluxing was continued with stirring for 3 hours. After cooling was

the salts filtered off, and the solution evaporated to dryness and the residue dissolved in 50 ml of chloroform. The chloroform solution was washed three times with 50 ml of water and the chloroform evaporated, whereby 6.23 g of a yellow powdery residue was obtained. This

was dissolved in approx. 1000 ml of ether. The insoluble part so

as well as some crystals that had formed on cooling were filtered off. The ether solution was then concentrated to 150 ml, and this gave 2.9 g of (+ ) 3' , 4' , 5, 7-0-tetra-(4-bromoenacyl)-cyanidan-3-ol, i.e. a dividend of 53.8%. The product can be recrystallized from ethanol. Melting point: 127-129°C.

Example 48

A 3-necked 500 ml round-bottomed flask was equipped with a condenser closed with a calcium chloride tube, a nozzle for the supply of nitrogen which also enables the application of a vacuum, a separatory funnel with a pressure equalizer and a magnetic stirrer. A stream of nitrogen was passed through, after which 5.4 g of a 55% suspension of NaH in oil was added. This was washed twice with 50 ml of anhydrous hexane to remove the oil, and said NaH was dried in vacuo. A solution of 32.5 g of (+)'3',41,5,7-0-tetrabenzyl-cyanidan-3-ol in 200 ml of anhydrous THF was then added. The mixture was boiled under reflux. for 2 hours and then cooled in an ice bath. A solution of 9 g of methoxymethyl chloride in 40 ml of anhydrous THF was then added dropwise over the course of 45 minutes. The mixture was then stirred over an ice bath for 2 hours, and the solution sucked through a glass filter under nitrogen and then filtered through Cellite. The filtrate was evaporated to dryness at room temperature in a rotary evaporator (Rotavapor). The residue was recrystallized twice from a mixture of 200 ml of acetone and 500 ml of propan-2-ol. Yield: 25.1 g (72.3%) of (+) 3',4',5,7-0-tetra-benzy1-3-0-methoxymethyl-cyanidan-3-ol.

Melting point: 108-110°C.

Example 49

A suspension of 7.15 g of palladium chloride in 2.4 liters of methanol was hydrogenated in a 5 liter round bottom flask. The main amount of the methanol was poured off, and the palladium was washed four times with 4 liters of methanol and four times with 200 ml of ethyl acetate. After the last decanting, the palladium was deposited under a thin layer of ethyl acetate. A solution of 20 g

(+ ) 3 ' , 4 ' , 5, 7_0-tetrabenzyl-3-0-methoxymethyl-cyanidan--3-ol in 2,<1>! liters of ethyl acetate were then added, and the hydrogenation consumes 3.6 liters of hydrogen and lasts for 5 hours. The catalyst was filtered off and washed twice with 200 ml of ethyl acetate. The combined ethyl acetate solutions were evaporated to dryness, 700 ml of ethanol was added to the residue and the mixture evaporated to approx. 100 ml and the whole thing repeated once, then twice with 700 ml of water. The residue was dried to constant weight in vacuo at room temperature. The yield of (+) 3-0-methoxymethyl-cyanidan-3-ol is quantitative. Melting point: 106-109°C.

Example 50

42.5 g (37.9 ml) of boron trifluoride etherate in 50 ml of diglyme recently distilled over sodium was added to a 3-necked round-bottomed flask A, equipped with a nozzle for the supply of nitrogen, a dropping funnel and an evacuation tube. A solution of 7.65 g of sodium borohydride in 250 ml of diglyme was then placed in the dropping funnel.

Another round-bottomed flask B with four necks was fitted with a dropping funnel, a downward-directed filter tube connected to the evacuation nozzle of flask A, an independent nozzle for the supply of nitrogen, and a condenser, the upper end of which was connected to a washing flask containing acetone by means of a U- tube containing blue silica gel. A solution of 28 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-(2-cyanoethyl)-cyanidan-3~ol in 500 ml of anhydrous THF freshly distilled over sodium was then placed in the latter flask B. The two flasks A and B were equipped with a magnetic stirrer, and the contents of flask A were vigorously stirred while the contents of flask B were gently stirred. A stream of dry nitrogen was passed through washing in succession flask A, flask B, the cooler in flask B, the U-tube and the washing flask and thence out into the hood. The solution of sodium borohydride was added dropwise to flask A over the course of 15 hours, and on contact with the boron trifluoride, borohydride BjHg is produced, which is carried with the nitrogen stream into flask B where it reduces the 2-cyanoethyl group to 3-aminopropyl. The mixture was allowed to react for 5 hours after the addition of matric borohydride was complete. 100 ml of absolute ethanol was then added through the dropping funnel in flask B, gases are evolved, but the evolution stops after a couple of minutes. The reaction mixture in flask B was then distilled in vacuum in a rotary evaporator (Rotavapor) at a temperature below 30°C. The residue was dissolved in 200 ml of boiling butan-2-ol and left overnight at 4°C, whereby an oil is formed. The butan-2-ol was poured off, and this treatment with butan-2-ol • was repeated four times.

The combined butanol extracts were evaporated in

a rotary evaporator, and the residue dried under high vacuum over Po2 0r b for 24 hours to constant weight. The yield of (+) 3'-4',5,7_0-tetrabenzyl-3-0-(3-aminopropyl)-cyanidan-3-ol is 12.9 g, i.e. 45.6%. Melting point: 93-95°C.

Example 51

A suspension in 700 ml of freshly distilled dimethylformamide of 65.5 g of a 55% dispersion of sodium hydride in oil (36 g NaH) was prepared under nitrogen and with vigorous stirring. The suspension was cooled to between -5 and 0°C using a cooling bath. A solution of 650 g of ( + ) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol in 3800 ml of freshly distilled dimethylformamide was slowly added to the cooled suspension in such a way that the temperature remained within said area. 15 minutes after the supply, 178.5 ml,.;i.e. 257 g of benzyl bromide added during 45 minutes so that the temperature remained below 0°C. This temperature was then maintained for approx. 30 minutes, and was then raised to room temperature with stirring. The dimethylformamide was removed by distillation under a medium vacuum at 60°C in a rotary evaporator, and the residue was then dissolved in 3 liters of chloroform at room temperature, washed three times with 2 liters of distilled water, filtered and then evaporated. The residue was dissolved in 1750 ml of hot benzene and petroleum ether

(BP 30-45°C) was slowly added while heating and stirring until the mixture becomes turbid (approx. 1 liter of petroleum ether is necessary). Practically pure (+) 3,3',4',5,7-0-pentabenzyl-cyanidan-3-0I was obtained by cooling in a yield of 710 g,

.ie 96. 56 - Melting point: 119-121°C.

Example 52

0.96 g of a 55% dispersion of sodium hydride in oil (0.53 g NaH) was added to a 3-necked 50 ml round-bottomed flask fitted with a 25 ml dropping funnel with pressure equaliser, a nitrogen-

feed tube and a condenser closed with a calcium chloride tube, and the whole dried under heating in a stream of nitrogen. While cooling, while maintaining a gentle stream of nitrogen, 10 mL of freshly distilled dimethylsulfoxide was added and the mixture was stirred at room temperature using a magnetic stirrer. A solution of 1.45 g (+) cyanidan-3-ol in 15 ml of freshly distilled dimethylsulfoxide was then added dropwise from the dropping funnel with stirring at room temperature. Hydrogen was developed.

30 minutes after the addition of the solution, was added

a solution of 2.74 mL (2.99 g) of methoxyethoxymethyl chloride i

10 ml of freshly distilled dimethylsulfoxide, which occurs at

using the dropper. 30 minutes after this, the entire solution is completely saturated with sodium chloride over 150 ml of water and the pH is adjusted to 7. A brownish-black caked precipitate is obtained, and this was extracted three times with 100 ml of toluene. The toluene solution was washed three times with 50 ml of water, after which the toluene was evaporated. 2.88 g of an oily brown-red residue was obtained. The oil was extracted ten times with 100 ml of n-hexane under reflux. The combined n-hexane solutions give, after cooling, 1.53 g (+) 3',4',5,7-■ O-tetra(methoxyethoxymethyl)-cyanidan-3"-ol in the form of a yellowish oil. Decomposition by 150°C/0.02 mnrHg..

Example 53

A solution of 52 g of (+) 3',4',5,7-0-tetraben-zyl-cyanidan-3-ol in 300 ml of anhydrous pyridine was added to a 4-necked 50 ml round-bottomed flask equipped with a dropping funnel with a pressure equaliser, a cooler closed with a calcium chloride tube, a nozzle for supplying nitrogen and a magnetic stirrer. With stirring under nitrogen, 18 g of ethyl chloroformate was added dropwise through the dropping funnel, and the mixture was kept at 60°C for 7 hours. It was then cooled and mixed with 500 ml of a mixture of water and ice. The precipitate formed was filtered off and mixed with 500 ml of anhydrous 0.5 M NaHCO 3 . The precipitate was filtered off, washed with water and dried in vacuum overnight. It was then dissolved in 550 ml of acetone, filtered and the filtrate heated under gentle reflux in 3.3 liters of ethanol. After the mixture had been left at room temperature for 2 days, the precipitate was filtered off and recrystallized from a mixture of 250 ml of acetone and 1.5 liters of ethanol. After drying, one got

( + ) 3'',4',5,7-0-tetrabenzyl-3_0-ethoxycarbonyl-cyanidan-3-ol in a yield of 42 g, i.e. 73 Melting point: 33-84°C..

Example 34

A palladium catalyst was prepared from 4 g of palladium chloride as in example 1.- A solution of 15 g (0.021 mol) of ( + ) 3',4 *,5,7-0-tetrabenzyl-3-0-ethoxycarbonyl-cyanidan- 3-ol in 600 ml of ethyl acetate was then added. Hydrogenation was carried out for 2 hours and 2.33 liters were consumed

•hydrogen. The catalyst was filtered off, washed twice with 200 ml of ethyl acetate and the combined ethyl acetate solutions were evaporated to dryness. 500 ml of ethanol was added to the residue and evaporated to approx. 50 ml, after which 200 ml of ethanol and 250 ml of water were added and the whole evaporated to 50 ml

and again 500 ml of water was added and the whole thing evaporated

50 ml. This was repeated, and the precipitate was filtered off

and dried under high vacuum to constant weight. One achieved

7.4 g (97%) of (+) 3_O-ethoxycarbonyl-cyanidan-3-ol. Melting point: 123-124°C.

Example 55

A solution of 65 g of (+) 3',4',5,7-0-tetra-benzyl-cyanidan-3-ol in 350 ml of anhydrous pyridine was added to a 3-necked 750 ml round-bottomed flask equipped with a dropping funnel with pressure equalization , a cooler closed with calcium chloride tubes, a nozzle for supplying nitrogen and a magnetic stirrer. The solution was heated to 60°C and, under nitrogen, 31 g of phenylacetyl chloride were added dropwise. The mixture was left under the same conditions for 6 hours and then cooled and poured into 1 kg of crushed ice. The mixture was allowed to stand until the ice had melted, then the water was poured off to isolate the caked precipitate. This was washed twice with 1 liter of aqueous IN NaHCO^ and

so twice with 1 liter of water. It was dried in vacuum overnight and the product recrystallized from 1.2 liters of methoxyethanol. After drying (+) 3',4',5,7~0-tetrabenzyl-3-0-phenylacetyl-cyariidan-3-ol was obtained in a yield of 57.4 g (75%). - Melting point: 83-85°C.

Example 56

6.5 g (+) 3<1>,4',5,7_0-tetrabenzyl-cyanidan-3-ol, 1.9 g 2,4-dinitrofluorobenzene, 3.g potassium fluoride, 500 mg

18-crown-6 and 100 ml of anhydrous tetrahydrofuran were added to a 2-necked 250 ml round bottom flask equipped with a condenser closed with a calcium chloride tube, a nozzle for supplying nitrogen and a magnetic stirrer. The mixture was refluxed under nitrogen for 24 hours. After cooling, 250 ml of toluene was added, and the mixture was washed four times with 300 ml of a saturated aqueous solution of NaCl. The organic phase was dried over magnesium sulfate and the solvents removed by evaporation in vacuo. The residue was washed twice with 25 ml of petroleum ether (BP. 30-45°C), dissolved in 65 ml of chloroform and then slowly added with 325 ml of boiling absolute ethanol. The mixture was cooled and the oil was decanted off. It was washed with a little ethanol and dried under high vacuum for 24 hours. 5.1 g (62%) of solid (+) 3' , 4' , 5,7-0-tetrabenzyl-'3-0-(2,4-dinitrophenyl)-cyanidan-3-ol were obtained. Melting point: 6l-62°C.

Example 57

400 mg of a 55% dispersion of sodium hydride in oil was added to a 3-necked 50 ml round bottom flask equipped with a condenser, closed with calcium chloride tubing, a nozzle for the supply of nitrogen, a membrane closure and a magnetic stirrer. A strong stream of nitrogen was passed through for 5 minutes, after which the nitrogen supply was reduced and 5 ml of anhydrous tetrahydrofuran freshly distilled over sodium was added. The mixture was kept at 40°C

and using a syringe, a solution of 0.5 ml of recently distilled methyl iodide in 10 ml of anhydrous tetrahydrofuran was first added, after which a solution of 2.3 g of 3',4',5,7,-0-tetramethoxymethyl was added -cyanidan-3-ol in 10 ml of anhydrous tetrahydrofuran. The mixture was stirred at 40°C for one hour and then filtered. 20 ml of toluene and 40 ml of water were added, and the whole was stirred and then set aside for separation of the organic phase, which was again washed with 10 ml of water. The combined aqueous phases were extracted with 30 ml of methylene chloride. The combined organic extracts were then dried over magnesium sulfate, filtered and then evaporated in a rotary evaporator to give an oil which did not solidify. This was dissolved in 55 ml of methanol and treated with activated carbon and, after evaporation of the methanol, the oil was extracted twice with 25 ml of petrol

ether (BP 50-70°C) under heating. The combined petroleum ether fractions were evaporated in a rotary evaporator at room

temperature, and the remaining oil consisting of (+) 3',4'-5,7-0-tetra(methoxymethyl)-3-0-methyl-cyanidan-3-ol was dried under high vacuum to constant weight.

IR (Nujol) S (cm<-1>): 2920, l6l5, 1590, 1507, 1494 , 1440, 1400, 1260, 1220, 1155, 1070, 1000, 920, 822.'

Example 58

A 1 liter round bottom flask was equipped with a stirrer, a thermometer, a condenser closed with a silica gel tube, a nozzle for supplying nitrogen and a 250 ml dropping funnel, and the apparatus was dried at 100°C in vacuum overnight. It was then heated in a thermostatically controlled oil bath. 110 g of dry potassium carbonate were then added under a gentle stream of nitrogen, followed by 250 ml of dry dimethylformamide. A solution of 29.0 g of (+)-cyanidan-3-ol in 250 ml of dry dimethylformamide was dried overnight on a molecular sieve (4 Å).

and was then added, after which: 71.25 ml of benzyl bromide diluted in 100 ml of dry dimethylformamide was added. The mixture was kept at 100°C for 5 hours while stirring and passing nitrogen. The suspension was filtered hot, and the filtrate evaporated in vacuo in a rotary evaporator at 80°C and then dissolved in 250 ml of chloroform. The chloroform solution was filtered and transferred to a 1 liter separatory funnel where it was washed three times with 250 ml of water and then dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in 750 ml of carbon tetrachloride under reflux. The caked brown residue was separated and set aside for crystallization by stirring at normal temperature with cooling from time to time in a refrigerator. 31.2 g of a product identical to that stated in example 37. Melting point: 144-145°C.

Example 59

Palladium black was prepared from 15 g of palladium chloride as in example 1. A solution of 40 g of (+) 3',4',5,7-0-tetrabenzyl-3-O-phenylacetyl-cyanidan-3-ol was then added in 2.25 liters of ethyl acetate. The mixture was hydrogenated in

3 hours and 1.25 liters of hydrogen were used. The catalyst was filtered off and washed twice with 300 ml of ethyl acetate, and the combined ethyl acetate solutions were evaporated to dryness under reduced pressure. 500 ml of ethanol was added to the residue and evaporated under reduced pressure to approx. 50 ml, and this was repeated once. 250 ml of ethanol and 250 ml of water were added and evaporated to 50 ml. 500 ml of water was added and evaporated again to 50 ml, after which 500 ml of water was added again and evaporated under reduced pressure. The residue was dried to constant weight under high vacuum overnight to give (+) 3-O-phenylacetylcyanidan-3-ol. Melting point: 102-103°C.

Example 60

A solution of 24.8 g of nicotinoyl chloride i

100 ml of anhydrous pyridine was added to a 3-necked 250 ml round bottom flask equipped with a dropping funnel with pressure equaliser, a condenser closed with a calcium chloride tube, a nozzle for the supply of nitrogen and a magnetic stirrer. 56 g of (+) 3',4',5,7_0-tetra-benzyl-cyanidan-3-ol in four portions, one of 26 g and three of 10 g were added dropwise with stirring and under nitrogen,

and there was an hour between each addition. The mixture was kept at 60°C for 20 hours. After cooling, the solution was poured into 1 kg of ice and left there until the ice had melted. The liquid ran off completely and a lumpy precipitate was obtained. This was washed twice with water, twice with IN sodium bicarbonate, and twice with water. The insoluble part, which was still a kind of cake, was dried in vacuum overnight. 120 ml of acetone was added, and the mixture was stirred for 10 minutes and left for 2 hours at -30°C. The precipitate was filtered off and again treated with acetone in the same way. The product was recrystallized from 950 ml of methoxyethanol, and 1.9 liters of absolute ethanol. '(+) 3',4',5,7-0-tetrabenzyl-3-0-nicotinoyl-cyanidan-3-ol was produced. Melting point: 137-138°C.

Example 6l

1.5 g (+ ) 3' ,4-' ,5,7-0-tetrabenzyl-3-0-nicotinoyl-cyanidan-3-ol. were hydrogenated in the presence of 100 ml of anhydrous ethanol, 300 mg of trifluoromethanesulfonic acid and 1, 0 g 10% palladium on activated carbon at 50°C. The reaction lasted for 5 hours and 500 ml of hydrogen was used. The mixture was cooled, then filtered and the filtrate evaporated to dryness. 100 ml of distilled water was added and evaporated to a volume of approx. 10 ml. This was repeated three times and the product was flash lyophilized. Mon

.got a quantitative yield of.(+) 3-0-(3-piperidylcarbonyl)-

cyanidan-3-ol trifluoromethanesulfonate. (Mixture of 2 diastereo-lisomers. ) Melting point: 125-130 C (not sharp).

Example 62

5.2 g of (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol and 200 ml of toluene were added to a 500 ml round bottom flask equipped with a condenser and a stirrer. The mixture was kept at 90°C until a solution was obtained, after which 200 ml of a 50% solution of sodium hydroxide, 2.7 g of tetrabutylammonium bisulphate and 3.0 g of 2-cyclohexylethyl bromide were added. The temperature was kept at 90°C for 10 hours with vigorous stirring, after which 1.5 g of 2-cyclohexylethyl bromide was added. The temperature was kept at 90°C for 15 hours with stirring, and the mixture was then set aside to cool. Two phases separated and the organic phase was washed three times with 250 ml of water. The toluene was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in 60 ml of absolute ethanol at 60°C, stirred for 15 minutes and the insoluble part filtered off in the heat. This precipitate became dried in vacuum and then recrystallized from 80 ml of methoxyethanol. (+) 3',V,5,7-0-tetrabenzy1-3-0-(2-cyclohexylethyl1)-cyanidan-3-ol was prepared. Melting point: 110°C.

Example 63

1.0 g of (+) 3',V,5,7-0-tetrabenzyl-3-0-(2-cyclohexylethyl)-cyanidan-3-ol dissolved in 90 ml of ethyl acetate was hydrogenated in the presence of 400 mg of 10 % palladium on activated carbon. 180 ml of hydrogen were consumed. The mixture was filtered and the solvent and toluene were evaporated. The oily residue was dissolved in 100 ml of ethanol, evaporated to near dryness and 100 ml of ethanol again added and evaporated again. 50 ml of ethanol and 50 ml of water were added, and the mixture was evaporated. The residue was dissolved in 150 ml of water which was evaporated to dryness and the residue was dried over phosphorus pentaoxide under high vacuum to constant weight. A quantitative yield of (+) 3-O-(2-cyclohexylethyl)-cyanidan-3-ol was obtained. Melting point: 99-102°C.

Example Sk

65 g ( + )■ 3 ' , 4 ' ,5,7-0-tetrabenzyl-cyanidan-3~ol

and 2 liters of toluene were added to a 6 liter round bottom flask equipped with a condenser and a mechanical stirrer. Heating■was carried out until

a solution was obtained, after which 1.5 liters were added

50% sodium hydroxide solution, 3-4 g of tetrabutylammonium bisulphate and 40 g of 3-phenyl-propyl bromide. The mixture was kept at 50°C with stirring for 48 hours, and then cooled to room temperature. The two phases were separated, and the organic phase was washed three times with 1 liter of water. The toluene phase was dried over magnesium sulfate and evaporated. The oily residue was washed with 200 ml of petroleum ether and then with 150 ml of anhydrous ethanol. The product was recrystallized from 600 ml of methoxyethanol. (+) 3',4',5,7-0-tetrabenzyl-3-0-(3-phenylpropyl)-cyanidan-3-ol was produced. Melting point: 96-97°C

Example 65

40.0 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-(3-phenylpropyl)-cyanidan-3-ol dissolved in 3 liters of ethyl acetate was hydrogenated in the presence of 16 g of 10% palladium on activated carbon. The reaction lasts for 6 hours and 6.2 liters of hydrogen were used. The mixture was filtered and the solvent and toluene evaporated. 250 ml of water was added and the mixture was stirred and evaporated in vacuo until the solid coagulated. Filtration was carried out, the precipitate washed with water.-After drying to constant weight (+) 3-0-(3-phenylpropyl)-cyanidan-3-ol was produced. Melting point: 190-192°C.

Example 66

52 g of 3',4',5,7-O-tetrabenzy 1-cyanidan-3-ol and 500 ml of toluene were added to a 3 liter round bottom flask equipped with a condenser and a mechanical stirrer. The mixture was heated until the solution was obtained, after which 187 g of propyl chloride, 750 ml of a 50% sodium hydroxide solution and 6.8 g of tetrabutylammonium bisulphate were added. The mixture was held at 50°C for 24 hours, then cooled to room temperature. Of the two phases, the organic phase was washed three times with 500 ml of a saturated aqueous solution of sodium chloride. It was then dried over magnesium sulphate until the solvent had evaporated. 100 ml of carbon tetrachloride was added and the whole evaporated to dryness. The product was recrystallized from a mixture of 1.8 liters of ethanol and 0.3 liters of acetone. (+) 3',4',5,7-0-tetrabenzyl-3-O-propyl-cyanidan-3-ol was produced. Melting point: 92z93°C

Example 67

Palladium black was prepared from 12 g of palladium chloride as described in Example 1. A solution of 41.6 g of (+) 3<1>,4',5,7-0-tetrabenzyl-3-0-propyl-cyanidan- 3-ol in 1.8 liters of ethyl acetate was then added. Hydrogenation was then carried out for 6 hours, 6.25 liters of hydrogen were used. The catalyst was filtered off and washed twice with 200 ml of ethyl acetate. The combined organic solutions were then evaporated to dryness. 500 ml of water was added<p>g evaporated under reduced pressure to a volume of approx. 50 ml. This was repeated three times, after which the product was lyophilized. A quantitative yield of (+) 3-0-propyl-cyanidan-3-ol was obtained. Melting point: 94-96°C.

Example 68

A solution of 65.0 g of (+) 3',4',5,7-0-tetra-benzyl-cyanidan-3-ol in 500 ml of anhydrous pyridine was added to a 4-necked 1 liter round bottom flask equipped with a condenser closed with a calcium chloride tube, a drop funnel with pressure equaliser, a stirrer and a nozzle for supplying nitrogen. 34.5 g of diethyl chlorophosphate was then added dropwise under nitrogen. The mixture was stirred under nitrogen at room temperature for .8 hours. It.

was then completely poured into 1 liter of ice water. The water was poured off the caked mass, and this was washed five times with 500

ml of water each time and then left in vacuum overnight at 40°C after which it solidified. The product was recrystallized from

720 ml of carbon tetrachloride and 2.8 liters of petroleum ether. Diethyl phosphate and 2R,3S 3',4',5,7-tetrabenzyloxy-flavan-3-yl phosphate were produced after drying under high vacuum to constant weight. Melting point: 96°C.

Example 69

The palladium catalyst was prepared from 13 g of palladium chloride as described in example 1. A solution of 30.0 g of diethyl phosphate and 2R,3S 3',4'-5,7-tetrabenzyloxy-flavan-3-yl-phosphate was then added in 1, 3 liters of ethyl acetate. Hydrogenation was carried out for 3 hours and 3.9 liters of hydrogen were used. The catalyst was filtered off and washed twice with 200 ml of ethyl acetate. The combined solutions were evaporated to dryness. 750 ml of water was added to the residue and evaporated under reduced pressure to approx. 100 ml. This was repeated twice and the product was then lyophilized. Diethyl phosphate and 2R,3S 3',4',5,7-tetrahydroxy-flavan-3-yl phosphate were produced. Melting point: 121-123°C.

Example 70

1.30 g of (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol, 100 ml of toluene, 100 ml of a 50% aqueous sodium hydroxide solution, 500 mg of dimethyl sulfate and 68 mg of tetrabutylammonium bisulfate were added to a 500 ml round bottom flask fitted with a condenser and a mechanical stirrer. The mixture was kept at 50°C for one hour with vigorous stirring and was then cooled to room temperature and two phases were obtained. The organic phase was washed three times with 100 ml of water and then dried over magnesium sulfate before evaporation of the solvent. The residue was recrystallized from 13 ml of methoxyethanol. (+) 3',4',5,7-0-tetrabenzyl-3-0-methyl-cyanidan-3-ol was produced, identical to the product from example 19 - Melting point: 124-125°C,

Example 71

500 mg palladium catalyst, 120 ml ethanol,

650 mg (+ ) 3 ' , 4',5,7_0-tetrabenzyl-cyanidan-3-ol and 60 ml

The cyclohexene was placed in a 250 ml round bottom flask. While stirring, the mixture was refluxed for 4 hours. Thin-layer chromatography over silicon dioxide gel Merck 60' (mobile phase: ethyl acetate/chloroform/formic acid 5:5:1 v/v/v) shows that the removal of the benzyl group is quantitative. At room temperature, the palladium catalyst was removed by filtration and the filtrate distilled under reduced pressure. The residue was recrystallized from water and is (+)-cyanidan-3-ol. Melting point: 207-210°C.

Example 72

A 4-necked 500 ml round bottom flask was fitted with

an efficient mechanical stirrer, a 250 ml dropping funnel, a calcium chloride tube and a tube for supplying nitrogen. The entire apparatus was dried and nitrogen was circulated through it before adding 100 ml of anhydrous DMF. This was cooled to -3°C and 9.28 g of a 55% dispersion of NaH in oil was added. While stirring, first a solution of 14.5 g of (+)-cyanidan-3-ol in 200 ml of anhydrous DMF and then 1.698 g of tetra-n-butylammonium bisulphate were added and the stirring was continued for a

hour at 0°C. In the course of 15 minutes, a solution of 25.9 ml of benzyl chloride in 25 µl of anhydrous DMF was then added, and the mixture was stirred for 30 minutes at 0°C, and during stirring the temperature was allowed to rise to room temperature, where the mixture set aside, for 24 hours with vigorous stirring. The mixture was then filtered and the filtrate evaporated under reduced pressure to give a residue which was dissolved in 250 ml of chloroform. The chloroform solution was washed four times with 250 ml

distilled water, and after drying over anhydrous magnesium sulfate and filtration, the chloroform was evaporated under reduced pressure. The residue was washed with 50 ml of hexane and then dried to constant weight. A mass of 37.4 g was dissolved under heat in 500 ml of carbon tetrachloride, and the solution was filtered while hot and cooled to room temperature and then successively concentrated to 350 and 150 ml. 23.6 g of ( + ) 3' ,4',5,7-0-tetrabenzyl-cyanidan-3-ol were produced, identical to the product from example 37-

Example 73

The procedure is as in Example 58, except that after the addition of the solution of (+)-cyanidan-3-O1 in DMF, 13.22 g of 18-crown-6 was used and 69 ml of benzyl chloride was substituted for benzyl bromide. The mixture was then kept at 60°C for 20 hours with vigorous stirring.

45.5 g of ( + ) 3 ' , 4 ' ,.5 , 7-0-tetrabenzyl-cyanidan-3-ol, is identical to the product from example 37-

Example 74

The procedure is as in example 73, except

from that ...18-crown-6 was replaced by 16.98 g of tetra-n-butyl-ammonium bisulphate.

44.5 g ( + ) were produced. 3' , 4 • , 5, 7-0-tetra-benzyl-cyanidan-3'-ol, identical to the product from example 37.

Example 75

130 g of (+) 3',4',5,7_0-tetrabenzyl-cyanidan-3-ol, 250 g of 1-chloroheptane and 25 g of tetrabutylammonium bisulphate were added to a 5 liter round bottom flask equipped with a condenser and a mechanical stirrer. 3.75 L of a 50% N.aOH solution was then added, and the mixture was kept at 50°C with vigorous stirring for 6 hours. It was cooled to room temperature, 1.25 liters of dichloromethane was added and two phases were formed. The organic phase was

washed three times with 750 ml of water, dried over magnesium sulfate, after which the solvent was evaporated. 4 liters of petroleum ether (boiling point 40-60°C) were then added to the residue, and the mixture stirred overnight. It was then cooled to -20°C for \ hour,

and the solid was filtered off and washed with 500 ml of petroleum ether. After drying, recrystallization was carried out twice from a mixture of 1.5 liters of ethanol and 400 ml of ethyl acetate. After drying to constant weight in vacuum, 132 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-heptyl-cyani-dan-3-ol were produced. Melting point: 65°C.

Example 76

52 g (+ ) 3' ,4',5,7-0-tetrabenzyl-cyanidan-3-ol and 650 ml of toluene were added to a 3-neck round-bottomed flask equipped with a condenser and a mechanical stirrer. The mixture was heated until a solution was obtained, after which 115 g of 1-chlorododecane, 27 g of tetrabutylammonium bisulphate and 750 ml

of a 50% NaOH soln. The mixture was kept at 50°C

for four days under vigorous stirring, and was then cooled to room temperature. Two phases were obtained, and the organic phase was washed three times with 500 ml of water. It was then dried over magnesium sulfate and the solvent evaporated. The residue was mixed twice with 500 ml of petroleum ether (boiling point 40-60°C). After filtration and drying, the product was recrystallized from 800 ml of acetone and 3.2 liters of ethanol. After drying to constant weight in vacuum, 54 g of (+) 3',4',5,7-0-tetra-benzyl-3-0-dodecyl-cyanidan-3-ol were obtained. Melting point: 9.8-99°C.

Example 77

A mixture of 26 g of (+) 3',4',5,7-0-tetrabenzyl-cyanidan-3-ol, 73 g of 1-chlorohexadecane and 5 g of tetrabutylammonium bisulfate was added to a 1 liter round bottom flask equipped with a condenser and mechanical stirring. 750 ml of a 50% aqueous NaOH solution was then added and the mixture was kept at 50°C with vigorous stirring for 24 hours. It was then cooled to room temperature and 250 ml of dichloromethane was added. The two phases were separated, and the organic phase was washed with 250 ml of water. The solvent was evaporated, and 375 ml of ethanol were added and stirring was then carried out for 2 hours. The mixture was cooled to -10°C, the solid precipitate was filtered off and washed with 50 ml of ethanol and dried in vacuo. The product was recrystallized from 300 ml of ethanol and 70 ml of ethyl acetate and then dried to constant weight in vacuo.

A total of 30 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-hexa-decyl-cyanidan-3-ol was obtained. Melting point: 88-89°C.

Example 78

52 g (+) 3',4',5,7_0-tetrabenzyl-cyanidan-3-ol, . .162 g of 1-chlorooctadecane and. 10 g of tetrabutylammonium bisulphate was added to a 3 liter round bottom flask equipped with a mechanical stirrer and cooler. 1.5 liters of a 50% NaOH solution were added and the mixture was kept at 50°C for 28 hours with vigorous stirring. It was then cooled to room temperature, 500 ml of dichloromethane was added and two phases were obtained. The organic phase was washed with 500 ml of water. An emulsion formed, and the two phases were separated by filtration on a phase separator paper. The organic phase was dried over magnesium sulfate and then the solvent was evaporated. 750 ml of ethanol was added and stirring was carried out for 2 hours. The solid was filtered off and washed with 100 ml of ethanol. The product was recrystallized twice from a mixture of 600 ml of ethanol and 260 ml of ethyl acetate. After drying to constant weight in vacuum, 60 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-octadecylin-cyanidan-3-ol were obtained. Melting point 86°C.

Example 79

56 g of (+) 3 ' , V ,5,7-0-tetrabenzyl-3-0-heptyl-cyanidan-3-ol dissolved in 2.25 liters of ethyl acetate was hydrogenated in a 5 liter round bottom flask in the presence of 40 g of 10% palladium on activated carbon. The catalyst was filtered off and washed twice with 300 ml of ethyl acetate. The combined solutions were evaporated to dryness, and the residue treated with 250 ml of water,

which was then evaporated to approx. 50 ml. This was repeated twice before evaporation to dryness, after which the residue

was dried to constant weight under h<zSyvacuum over Po0r.

25

A total of 25 g of (+) 3_0-heptyl-cyanidan-3-ol was obtained.

Melting point: 157-159°C

Example 80

40 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-dodecyl-cyanidan-3-ol dissolved in 3 liters of ethyl acetate was hydrogenated in a 6 liter round bottom flask in the presence of 20 g of 10 ■% palladium on activated carbon. The reaction lasts for 6 hours and 6.2 liters of hydrogen were consumed. The catalyst was filtered off and washed twice with 300 ml of ethyl acetate. The combined solutions were evaporated to dryness, and the oily residue dissolved in 1 liter of ethanol. The solvent was evaporated to approx. 50 ml, after which 1 liter of water was added and evaporated again to approx. 50 ml.'One liter of water was then again added and evaporated to approx. 100 ml, after which the solid was filtered off and washed with water. After drying to constant weight under high vacuum over P2°, 21.5 g of (+) 3-0-dodecyl-cyanidan-3-ol were obtained. Melting point: 158-160 oC.

Example 8l

26.3 g of (+) 3',4',5,7-0-tetrabenzyl-3-O-hexa-decyl-cyanidan-3-ol dissolved in 1.5 liters of ethyl acetate was hydrogenated in a 3 liter round bottom flask in presence of 16 g of 10% palladium on activated carbon. The catalyst was filtered off and washed twice with 100 ml of ethyl acetate. The combined solutions were evaporated to dryness, after which the residue was treated with 5 g of activated carbon in 100 ml of ether for one hour. The mixture was filtered, and the filtrate evaporated to dryness, after which the residue was treated in 60 ml of water and the water then evaporated to approx. 10 ml. This was repeated twice, after which the mixture was evaporated to dryness and the residue dried to constant weight under high vacuum above ^ 2°^' 10.5 g ( + ) were obtained. 3-O-hexadecyl-cyanidan-3-ol. Melting point: 152-154°C.

Example 82

83.7 g of (+) 3',4',5,7-0-tetrabenzyl-3-0-octa-decyl-cyanidan-3-ol dissolved in 4.5 liters of ethyl acetate was hydrogenated in an 8 liter round bottom flask in the presence of 48 g of 10% palladium on activated carbon. The catalyst was filtered off and washed twice with 400 ml of ethyl acetate. The combined solutions were evaporated to dryness. The residue was recrystallized from 260 ml of chloroform containing 4% methanol. The solid was treated in 100 ml of water, after which the water was evaporated to approx. 25 ml. This was repeated twice, and the water was then evaporated, and the solid dried to constant weight under high vacuum over f^^R"r'^an ^ikk 34.1 g ( + ) 3_0-octadecyl-cyanidan-3- etc. Melting point: 162-164 oC.

Example 83

A solution of 52 g of ( + ) .3' ,4' , 5, 7-0-tetrabenzy 1-cyanidan-3-ol. in 300 ml of dichloromethane, - 150 ml of a 50% aqueous solution of NaOH and 6.8 g of tetrabutylammonium bisulphate were added to a 750 ml round bottom flask equipped with a condenser and a mechanical stirrer. The mixture was refluxed for 24 hours with vigorous stirring, then cooled to room temperature and two phases were separated. The organic phase was washed three times with 300 ml of water and then dried over magnesium sulfate. The solvent was evaporated and the residue recrystallized from a mixture of 2.4 liters of ethanol and 1.2 liters of acetone. 39 g of di(3',4',5,7-0-tetrabenzyl-cyanidan-3-yloxy)-methane were obtained. Melting point: 103-104°C.

Example 84

Palladium black was prepared from 5 g of palladium chloride as described in example 1. A solution of 31.0 g of di(3',4',5,7-0-tetrabenzyl-cyanidan-3-yloxy)methane was then added in 700 ml of ethyl acetate. Hydrogenation was carried out

for 3 hours and 4.8 liters of hydrogen were used. The catalyst was filtered off, washed twice with 100 ml of ethyl acetate,

and the combined organic solutions were evaporated to dryness. 1 liter of water was neutralized to pH 7 with several drops of pyridine then added to the residue. The mixture was concentrated to approx. 100 ml under reduced pressure. This was repeated twice, after which 900 ml of clean water was added and this again. 'evaporated to approx. 200 ml. The mixture was then lyophilized and 12.9 g of di(cyanidan-3-yloxy)methane was obtained.

Melting point: l62-l65°C.

Example 85

In the same way as described in the previous examples, the following compounds were prepared:

( + ) 3,3',4' , 5 , 7-0-pent α-(methoxyrnethy1)-cyanidan-3-01,

(+) 3,3',4',5,7-0-pentaallyl-cyanidan-3-ol,

(+) 3',4',5,7-0-tetra-(trimethylsilyl)-cyanidan-3-O1,

(+) 3' ,4' ,5,7-0-tetrabenzyl-3-0-(3-(N,N-dimethylamino,)propyl] -

cyanidan-3-ol,

(+) 3-O-(3-(N,N-dimethylamino)-propyl]-cyanidan-3-ol in the form of

its hydrochloride,

(+) 3',4',5,7-0-tetrabenzyl-3-0-[4-(4,4-ethylenedioxy-p-

fluoro-enyl)-butyl l -cyanidan-3-ol,

3-0- 4-(4,4-ethylenedioxy-p-fluorophenyl]-butyl -

cyanidan-3-ol,

(+) 3',4'35,7-0-tetrabenzyl-3-0-(233-dihydroxypropyl)-cyanidan-3-ol and .(+) 3-0-(2,3-dihydroxypropyl)-cyanidan- 3-o1.

Claims (31)

1. New O-substituted derivatives of (+)-cyanidan-3-ol, characterized by formula I where R represents an optionally substituted hydrocarbon radical; an alkyl radical of an organic carboxylic acid containing at least 2 carbon atoms, of a carboxylic acid, or of an organic sulphonic acid, or a radical of an inorganic acid containing at least one oxygen atom, with the exception of a glucosidic radical, as well as salts of the above-mentioned derivatives. 2. Compounds of formula I according to claim 1, characterized in that R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, • aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic hydrocarbon radical, a radical of an aliphatic, cycloaliphatic, cycloaliphatic- .aliphatic, aromatic, aromatic-aliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid; a radical of an amidated or esterified carboxylic acid; a radical of an aliphatic, aromatic or aromatic-aliphatic sulphonic acid; or a radical of an inorganic acid having as its main atom a sulphur, phosphorus, boron or nitrogen atom; as well as salts of the above-mentioned derivatives. 3. Compound with formula I according to claim 1, characterized in that R is an alkyl or alkenyl radical which is unsubstituted or substituted with hydroxy, lower alkanoyloxy, lower alkoxy, lower alkanoyl, cyano, amino, mono- or di-lower alkylamino, lower alkyleneamino, oxa- or, aza-lower alkyleneamino, amido or mono- or di-lower alkylamido groups or with halogen atoms ; a cycloaliphatic radical with from 3 to 6 ring carbon atoms and where the radical may be unsubstituted or substituted with one or more hydroxy, lower alkoxy, lower alkyl, carboxy, oxo, lower alkanoylamino, mono- or di-lower alkylamino or lower alkoxycarbonyl groups; a lower cycloaliphatic alkyl radical having from 3 to 6 ring carbon atoms, and which may be unsubstituted or substituted with at least one lower alkyl group; a phenyl or naphthyl radical which may be unsubstituted or mono-, di- or tri-substituted with hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino or mono- or di-lower alkylamino groups, or with halogen atoms; a phenyl-lower alkyl or naphthyl-lower alkyl radical' • or phenyl-lower alkenyl or naphthyl-lower alkenyl radical which may be unsubstituted or mono-, di- or tri-substituted in the aromatic nucleus with hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, hitro,' amino, mono- or di-lower alkylamino, amido or mono- or di-lower alkylamido groups or with halogen atoms; a saturated or unsaturated aza-, thia-, oxa-, thiaza-, oxaza- or diaza-cyclic radical which may be fused to a phenyl ring and which has from 2 to 7 carbon atoms in the heterocyclic ring, and which may be mono-, di- or poly-substituted with lower alkyl, hydroxy, lower alkoxy, nitro, carboxy, lower alkoxycarbonyl or lower alkanoyloxy groups, a heterocyclic-lower alkyl radical where the heterocyclic part can be one of the groups mentioned above, a radical of an alkanecarboxylic acid, lower alkenecarboxylic acid, a lower alkenedicarboxylic acid, a lower alkenedicarboxylic acid or a lower cycloalkanecarboxylic acid which may be unsubstituted or substituted with one or more hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkyl, lower alkanoyl or oxo groups or with halogen atoms, a benzoyl or naphthoyl radical optionally substituted with hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, ■lower oxycarbonyl, nitro, or amino groups or' with halogen atoms, a radical of a phenyl-lower-alkano.in or naphthyl-lower-alkanoic acid which may be unsubstituted or substituted in the aromatic nucleus with one or more hydroxy, lower-alkoxy, carboxy, lower-alkoxycarbonyl, lower-alkanoyl, lower-alkanoyloxy, nitro, amino or mono- or di-lower-alkylamino groups" or with halogen atoms; a radical of an unsaturated or saturated aza-, thia-, oxa-, thiaza-, oxaza- or diaza-cyclic acid which may be condensed to a phenyl radical; a lower alkoxycarbonyl radical, a phenoxycarbonyl radical, a carbamoyl radical, optionally mono- or di-substituted with • lower alkyl radicals or with phenyl or benzyl radicals optionally substituted in the phenyl nucleus with one or more hydroxy or lower alkoxy groups or with halogen atoms; a radical of a lower alkylsulfonic acid or phenylsulfonic acid optionally substituted with one or more lower alkyl or lower alkoxy groups or with halogen atoms; or' a radical of a phosphoric acid which may be unsubstituted or substituted by one or two. lower alkyl radicals or with one or two optionally substituted phenyl radicals; as well as salts of the above-mentioned derivatives. 4. Compounds of formula I according to claim 1, characterized in that R is a lower alkyl radical which may be unsubstituted or substituted with one, two or more hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, cyano, lower alkanoyl, amino, mono- or di-lower alkylamino, lower alkyleneamino or oxa- or aza-alkyleneamino groups or with chlorine or fluorine atoms; a cycloaliphatic radical containing 5 or 6 ring carbon atoms and where the radical may be unsubstituted or substituted with hydroxy-lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino or mono- or di-lower alkylamino groups; a cycloaliphatic C 1 -3 alkyl radical, the ring of which may contain 5 or 6 carbon atoms and which may be substituted with at least 1 alkyl radical of from 1 to 4 carbon atoms; a phenyl radical which is unsubstituted or mono-, di- or tri-substituted with hydroxy, C 1-4 alkoxy, carboxy-nitro, amino or mono- or di-(C 1-6 alkyl) amino groups or with chlorine or fluorine atoms; a benzyl, phenylethyl or phenylpropyl radical which is unsubstituted or mono-, di- or tri-substituted in the phenyl ring by hydroxy, C 1 -C 6 alkoxy, carboxy, (C 1 -C 1 ) alkoxy)carbonyl, nitro, ■ amino, mono- or di-(C-^_ ^alkyl) amino, or^ alkyl groups or with chlorine or fluorine atoms; a tetrahydropyranyl, pyridyl, quinolinyl or pyrimidyl radical optionally substituted with one or more nitro, amino or hydroxy groups; a. alkanecarboxylic acid radical containing from 3 to 18 carbon atoms and which may be unsubstituted or substituted with one or more hydroxy, carboxy, (C-^ _^ alkoxy)-carbonyl, C^ _^ alkyl, amino or mono- or di- (C 1 -alkyl)amino groups or with chlorine or fluorine atoms; a cycloalkanecarboxylic acid radical with from 3 to 6 ring carbon atoms and where the radical may be unsubstituted or substituted with one or more hydroxy, carboxy, lower alkoxycarbonyl, amino or mono- or di-(C-^_i(alkyl) amino groups or with chlorine or fluorine atoms; a cycloalkanealkanoic acid radical, wherein the aliphatic chain has from 1 to 4 carbon atoms and the ring has from 3 to 6 ring carbon atoms; a benzoyl radical which may be unsubstituted or mono-, di- or tri-substituted by hydroxy, C-L-i)- alkoxy, carboxy, (C-l-i)-carbonyl, C-L-i-alkanoyl, C-i-alkanoyloxy, nitro, amino or mono- or di-(C ^_^ -alkyl)amino groups or-with fluorine or chlorine atoms, a phenylalkanoic acid radical where the aliphatic chain may contain from 1 to 4 carbon atoms and where the phenyl radical may be substituted as indicated above for the benzoyl group; .a radical of a nicotine or isonicotinic acid; a (C 1 -C 6 ) carbonyl radical, a carbamoyl radical optionally mono- or di-substituted with C 1 -3 alkyl groups or with phenyl groups substituted or unsubstituted with hydroxy, methoxy or ethoxy groups or with chlorine or fluorine atoms; or a phosphoric acid radical which is unsubstituted or mono- or dimethyl, ethyl or phenyl substituted; or salts of the above derivatives. 5. Compounds of formula I according to claim 1-, characterized in that R is a lower alkyl radical which may be unsubstituted or substituted with one or two hydroxy, 1-4 alkoxy, carboxy, 1-4 alkanoyloxy, amino, mono- or di-(C 1-4 alkyl)amino or cyano groups; a cycloaliphatic radical containing 5 or 6 ring carbon atoms which is unsubstituted or substituted with one or two hydroxy, C 1 - 4 alkoxy, carboxy, C 1 - 4 alkanoyloxy, amino, or di-lower alkylamino groups; a cycloalkanealkyl radical wherein the alkyl radical contains from 1 to 4 carbon atoms and wherein the ring contains 5 or 6 carbon atoms; a phenyl radical which is unsubstituted or mono-, di- or tri-substituted with -hydroxy, methoxy, ethoxy, propoxy, amino or nitro groups; a benzyl,-phenylethyl or phenylpropyl radical which is unsubstituted or mono- or di-substituted in the phenyl ring with one or two hydroxy, 'methoxy, ethoxy, propoxy, carboxy, (C1_^ alkoxy)carbonyl, nitro, amino or mono- or di-(C1_^ alkyl)amino groups or with chlorine or fluorine atoms, a tetrahydropyranyl radical; a pyridyl radical which is unsubstituted or substituted with a nitro, amino or hydroxy group; an alkanecarboxylic acid radical containing from 3 to 18 carbon atoms, and where the radical is unsubstituted or substituted by one or more hydroxy, carboxy, (C-L_galkoxy)carbonyl, C-^alkanoyl, amino or mono-or di-(C^ _^ alkyl) amino groups or with chlorine or fluorine atoms; a cycloalkane carboxylic acid radical with 5 or 6 ring carbon atoms which are unsubstituted or substituted' with one, two or three hydroxy, carboxy, (C^_^alkyl)-carbonyl, amino or mono- or di-(C 1_^alkyl)amino groups or with chlorine or fluorine atoms; a cycloalkane alkanoic acid radical where the alkyl chain may contain from 2 to 4 carbon atoms and where the cycloalkane moiety may contain 5 or 6 ring carbon atoms; a benzoyl radical which is unsubstituted or mono-, di- or tri-substituted by hydroxy, C-^_^alkyloxy, carboxy, (C-j^ .alkyl)carbonyl, ^alkanoyl, C^^ alkanoyloxy, nitro, amino or mono- or di-(C 2 -alkyl) - amino groups or with chlorine or fluorine atoms; a phenylalkanoic acid radical where the aliphatic chain contains 1 to 4 carbon atoms and where the phenyl nucleus is unsubstituted or substituted- by one or two hydroxy, C1 _^ alkoxy, amino, carboxy, (C^ _^ alkoxy)carbonyl, C1 _^ alkanoyl or C- L_1) alkanoyloxy group.r or with chlorine or fluorine atoms; a nicotinic or isohycotinic acid radical; a (C^_^Alkoxy)carbonyl radical; a carbamoyl radical optionally mono-substituted with .et C1_i| alkyl or phenyl radical; or an unsubstituted phosphoric acid radical or a dimethyl-, .diethyl or monohydroxypheny1 phosphoric acid radical. 6. Chemical compound according to claim 1, characterized by being (+) 3-0-methyl-cyanidan-3-ol. 7. Chemical compound according to claim 1, characterized by being (+) 3_0-butyl-cyanidan-3-ol. 8. Chemical compound according to claim 1, character- terized by being .( + ) 3-0-butyry 1-cyanidan-3-ol. 9. Chemical compound according to claim 1, characterized by being (+) 3-O-(3,3-dimethylbutanoyl)-cyanidan-3-o1. 10. Chemical compound according to claim 1, k a r a k-. terized by being (+) 3~ 0-(3~ carboxy-propionyl)-cyanidan-3-o1. 11. Chemical compound according to claim 1, characterized by being (+) 3-0-decanoyl-cyanidan-3-ol. 12. Chemical compound according to claim 1, characterized by being (+)'3-O-palmitoyl-cyanidan-3-ol. 13- Chemical compound according to claim 1, characterized by being (+) 3-0-(2-carboxycyclohexanecarbonyl)-cyanidan-3-ol. 14. Chemical compound according to claim 1, characterized by being (+) 3-0-bénzoyl-cyanidan- 3-ol. 15- Chemical compound according to claim 1, characterized by being (+) 3~ 0-(4-fluorobenzoyl)-cyanidan-3-ol. 16. Chemical compound according to claim 13 characterized by - being (+) 3~ 0-protocatechyl-cyanidan-3-ol. 17- Chemical compound according to claim 1, character k-, characterized by being '( + ) 3-O-(acetylsalicylicyl)-cyanidan-3-ol. 18. Chemical compound according to claim 1, characterized by . to be (+) 3_O-(2-carboxybenzoyl)-cyanidan-3-ol. 19. Chemical compound according to claim 1, characterized by being (+) 3-0-(N-phenylcarbamoyl)-cyanidan-3-ol. 20. Chemical compound according to claim 1. c a r a k- teris e., r t by being (+ ) 3-0-methanesulfonyl-cyanidan-3-ol. 21. Chemical compound according to claim 1, characterized by being (+) 3~ 0-(4-methylbenzene-sulfony 1)-,c"yani dan- 3-01. 22. Chemical compound according to claim 1, characterized by being (+) 3-O-(2-cyanoethyl)-cyanidan-3-ol. 23. Chemical compound according to claim 1, character- terized by being (+) 3-O-(3-aminopropyl)-cyanidan-3-ol. 24. Chemical compound according to claim 1, characterized by being (+") 3-O-methoxymethyl-cyanidan-3-ol. 25. Chemical compound according to claim 1, characterized by being .( + ) 3~ 0-ethoxycarbonyl-cyanidan-3-ol. 26. Medicinal preparations, characterized by containing one or more of the compounds according to claims 1 to 25. 27.. Therapeutic method, characterized by using one or more of the compounds according to claims 1 to 25- 28. Process for the preparation of O-substituted derivatives of (+)-cyanidan-3-ol of formula I where R represents an optionally substituted hydrocarbon radical, an alkyl radical of an organic carboxylic acid containing at least 2 carbon atoms, of a carboxylic acid or of an organic sulphonic acid; or a radical of an inorganic acid containing at least one oxygen atom with the exception of a glucosidic radical] as well as salts of the above-mentioned derivatives, characterized in that in a compound of formula II where RO represents a protected hydroxy group that can easily be hydrolyzed or hydrogenated, cleaves the O^ R groups into hydroxy groups and, if desired, modifies a radical R in the resulting compound by reduction and/or if desired, converts a resulting salt into a free compound or into another salt and/or if if desired, converts a resulting compound into a salt if said compound contains a salt-forming group. 29. Process for the preparation of (+)-cyanidan-3-ol derivatives with formula II according to claim 28, where R has same meaning as stated above and R represents hydrogen, characterized by reacting (+)-cyani-dan-3-ol in an aprotic organic solvent with a high dielectric constant, with an alkaline hydride, after which ■reacts the prepared tetra-alkaline salt of (+)-cyanidan-3-ol with a reactive ester of an alcohol with the formula HO-R, as one. uses a ratio of (+)-cyanidan-3-0I to alkaline hydride to active ester of approx. 1: approx. 4.25 : approx..4.5. 30. Process for the preparation of derivatives of (+)-cyanidan-3-ol with formula II, according to claim 28, where R1 has the same meaning as stated above and R represents hydrogen, characterized by reacting (+)-cyanidan -3-ol in an aprotic organic medium with a high dielectric constant, with an alkaline carbonate, after which the prepared tetra-alkaline salt of (+)-cyanidan-3~ol is reacted with a reactive ester of an alcohol with the formula HO- R, using a ratio of (+)-cyanidan-.3_ol to alkaline carbonate to reactive ester of 1: approx. 8: approx. 6. 31. New O-substituted derivatives of (+)-cyanidan- 3-pl, characterized by the formula where OR has the same meaning as stated in one of claims 1 to 5 or represents hydrogen, and OR^ represents a protected hydroxy group which can easily be hydrolyzed or hydrogenated, with the exception of those compounds where all the radicals R^ are benzyl radicals and R is a hydrogen atom or a methyl group.