CA1284640C - Therapeutic compositions based on 3-alkoxyflavone derivatives, and novel 3-alkoxyflavone derivatives - Google Patents
Therapeutic compositions based on 3-alkoxyflavone derivatives, and novel 3-alkoxyflavone derivativesInfo
- Publication number
- CA1284640C CA1284640C CA000527372A CA527372A CA1284640C CA 1284640 C CA1284640 C CA 1284640C CA 000527372 A CA000527372 A CA 000527372A CA 527372 A CA527372 A CA 527372A CA 1284640 C CA1284640 C CA 1284640C
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- Prior art keywords
- hydroxy
- group
- alkoxy
- hydrogen
- alkyl
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Therapeutic compositions based on 3-alkoxyflavone deriva-tives, and novel 3-alkoxyflavone derivatives ABSTRACT OF THE DISCLOSURE
The present invention relates to therapeutic compositions based on 3-alkoxyflavone derivatives, which have in particular an antiviral activity.
Figures: none
The present invention relates to therapeutic compositions based on 3-alkoxyflavone derivatives, which have in particular an antiviral activity.
Figures: none
Description
The present invention relates to therapeutic compositions based on 3-alkoxyElavone derlvatives, which have in particular an antiviral activity.
3-Alkoxyflavone derivatives are compounds having the following basic structure:
`r in which Ro is an alkyl group.
European Patent 0 019 081 described 3-alkoxy-flavone derivatives possessing an antiviral activity.
The derivatives have a hydroxyl group or a derived group in the 5-position and a hydroxyl or alkoxy group in the 7-position, the 6-position and 8-position being unsub-stituted. These compounds are described as inhibiting the reproduction of rhinoviruses, enteroviruses, coxsackieviruses and polioviruses.
Nevertheless, some of these 3-alkoxyflavones have relatively low cytotoxic dose/active dose ratios, prohibiting any practical therapeutic application.
Others have even proved inactive.
It has now been found that certain particular classes of 3-alkoxyflavones have a substantial antiviral activity with cytotoxic dose/active dose ratios which permit therapeutic application.
The présent invention thus relates to a thera'peutic composition containing an effective amount of a compound of the formula :
R G ~ 3J R
R O
in which:
R is a C1-C4 alkyl group and 1) R1, R2, R3 and R4 are selected from the group com--prising a hydrogen atom, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a benzyloxy group, a methylenedioxy group, a C1-C4 alkanoyl group, a (C1-C4 alkoxy)carbonyloxy group, an amino group, a (C1-C4 alkyl)-amino group, a di(Cl-C4 alkyl)amino group, a (C1-C4 alkanoyl)amino group, a hydroxy group, a (C1-C4 alkanoyl)-oxy group, a glycosyloxy group, a carboxy group and a (C1-C4 alkoxy)carbonyl group, R5, R6, R8 and Rg are selected from the group comprising a hydrogen atom, a halogen atom, a hydroxy group, a C1-C4 alkoxy group, a benzyloxy group and a C1-C4 alkyl group, at least one.of the groups R1, R2, R3, R4, R5, R6, R8 ~nd R9 belng other than a hvdrogen atom, a hydrox~ grou~ or a C1-C4 alkoxy group, for example a halogen atom or a C1-C4 alkyl group, and R7 is a hydroxy or glycosyloxy group;
3-Alkoxyflavone derivatives are compounds having the following basic structure:
`r in which Ro is an alkyl group.
European Patent 0 019 081 described 3-alkoxy-flavone derivatives possessing an antiviral activity.
The derivatives have a hydroxyl group or a derived group in the 5-position and a hydroxyl or alkoxy group in the 7-position, the 6-position and 8-position being unsub-stituted. These compounds are described as inhibiting the reproduction of rhinoviruses, enteroviruses, coxsackieviruses and polioviruses.
Nevertheless, some of these 3-alkoxyflavones have relatively low cytotoxic dose/active dose ratios, prohibiting any practical therapeutic application.
Others have even proved inactive.
It has now been found that certain particular classes of 3-alkoxyflavones have a substantial antiviral activity with cytotoxic dose/active dose ratios which permit therapeutic application.
The présent invention thus relates to a thera'peutic composition containing an effective amount of a compound of the formula :
R G ~ 3J R
R O
in which:
R is a C1-C4 alkyl group and 1) R1, R2, R3 and R4 are selected from the group com--prising a hydrogen atom, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a benzyloxy group, a methylenedioxy group, a C1-C4 alkanoyl group, a (C1-C4 alkoxy)carbonyloxy group, an amino group, a (C1-C4 alkyl)-amino group, a di(Cl-C4 alkyl)amino group, a (C1-C4 alkanoyl)amino group, a hydroxy group, a (C1-C4 alkanoyl)-oxy group, a glycosyloxy group, a carboxy group and a (C1-C4 alkoxy)carbonyl group, R5, R6, R8 and Rg are selected from the group comprising a hydrogen atom, a halogen atom, a hydroxy group, a C1-C4 alkoxy group, a benzyloxy group and a C1-C4 alkyl group, at least one.of the groups R1, R2, R3, R4, R5, R6, R8 ~nd R9 belng other than a hvdrogen atom, a hydrox~ grou~ or a C1-C4 alkoxy group, for example a halogen atom or a C1-C4 alkyl group, and R7 is a hydroxy or glycosyloxy group;
2) Rl, R2, R3 and R4 are selected from the group comprising a hydroxy group and a C1-C4 alkoxy group, R5, R6,R8 and Rg are selected from the group comprising a hydrogen atom~a hydroxy group and a Cl-C4 alkoxy group, and R7 is a hydroxy, C1-C4 alkoxy o~ glycosyloxy.qroup, with the exclusion of 3,3', 4' , 5,6,7,8-heptamethoxyflavone ;
1284~
or 3) R1, R2, R3 and R4 are selected from the group com-prising a hydrogen atom, a hydroxy group and a C~-C4 . alkoxy group, three of these groups being other than hydrogen, R5 and Rg are selected from the group comprising a hydrogen atom, a hydroxy group and a C1-C4 alkoxy group, R6 and R8 are hydrogen atoms, and 10 R7 is a hydroxy, a cl-c4 a~oxy ~roU2 or ~ cos~lo~ group;
or 4) R3 and R4 are hydrogen atoms, R1 and R2 are selected from the group comprising a hydroxy group and a C1-C4 alkoxy group, R5, R6, R8 and R9 are selected from the group comprising a hydrogen atom, a hydroxy group and a C1-C4 alkoxy group, and R7 is a hydroxy , C~-C4 alkoxy or glycosyloxy group;
or 5) R~ and R4 are hydrogen atoms, R2 and R~ are selected from the group comprising a hydroxy group and a C1 -C4 alkoxy group, R5, R6, R8 and Rg are selected from the group comprising a hydrogen atom, a hydroxy group and a C~-C4 alkoxy group, and R7 is a hydroxy . C1-C4 alkoxy or glycosyloxy group;
or 6) R3 is a hydrogen atom, Rl, R2 and R4 are selected from the group comprising a hydrogen atom, a hydroxy group and a Cl-C4 alkoxy group, two of these groups being other than hydrogen, R5, R6, R8 and Rg are selected from the group comprising a hydrogen atom, a hydroxy group and a Cl-C4 alkoxy group, and R7 is a hydroxy , Cl-C4 alkoxy or glycosyloxy group;
or 7) Rl, R2, R3 and R4 are selected from the group com-prising a hydrogen atom, a hydroxy group and a C1-C4 alkoxy group, at least three of these groups being a hydrogen atom, R5, R6, R8 and Rg are selected from the group com-prising a hydrogen atom, a hydroxy group and a Cl-C4 alkoxy group, and R7 is a hydroxy , C1-C4 alkoxy or glycosyloxy 10 qroup, ora pharmaceutically acceptable salt thereof.
In the above definition, the expression "a halogen atom" denotes a chlorine, bromine, iodine or fluorine atom.
Pharmaceutically acceptable salts are the addition salts which the compounds form with pharma-ceutically acceptable acids, as well as the salts which the compounds containing an acid group (COOH) form with pharmaceutically acceptable bases.
The expression "addition salts with pharma-ceutically acceptable acids" denotes salts which givethe biological properties of the free bases without having any undesirable effects. In particular, these salts can be those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, with metal salts con-taining acid hydrogens, such as disodium orthophosphate and monopotassium sulphate, and with organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, tartaric acid and pamoic acid.
Likewise, the expression "salts with pharma-ceutically acceptable bases" denotes salts which do not modify the biological properties of the free acids. In particular, these salts can be those formed with in-organic bases such as sodium hydroxide, potassium ~284~
-- 5 ~
hydroxide, lithium hydroxide, calcium hydroxide andmagnesium hydroxide, or with organic baseS such as glucamine, N-methylglucamine, N~N-dimethylglucamine~
ethanolamine, diethanolamine, morpholine, N-methyl-morpholine and tris(hydroxymethyl)methylamine.
To the knowledge of the Applicant Company, thecompounds of the formula I belonging to the class defined under 1) are novel compounds.
The compounds belonging to the classes defined under 2) to 7) are products of natural origin or derivatives of products of natural origin.
The Applicant Company has also found that 3,3', 4',5,6,7,8-heptamethoxyflavone has an antiviral activity.
The compound was described in US-A-3 867 541 as havina an aggregation-inhibiting activity, with no suggestion of a viral activity. The invention also relates to the use of this compound for the manu-facture of a pharmaceutical composition for treating viral diseases.
In general terms, the 3-alkoxyflavones used in the present invention can be obtained by one of the following processes:
1) Alkylation of 3-hydroxyflavones according to the following scheme:
~3 ~ ~ 7 III
l RZ
~284640 3 ~ J ~ ~ 37 in which Z is a nucleus-repelling group.
Methyl sulphate, methyl iodide or diazomethane may be mentioned as examples of methylating agents.
2) Synthesis by the Allan-Robinson method (J. Chem. Soc.
125, 2192, 1924), in which o-hydroxyaryl ketones are condensed with aromatic acid anhydrides according to the following scheme:
A2~CO-CH2_oQ ~ ~ ~ >
X XI
2 ~
In this method, any hydroxy groups present can be protected, if necessary, and deprotected after the reaction.
~Z846~0 As a variant, using the same type of reaction, it is possible to prepare a 3-hydroxyflavone and then carry out an alkylation as described in 1.
3) The Algar-Flynn-Oyamada oxidation metho~ (J. Algar, J.P. Flynn, Proc. Roy. Irish Acad. 423, 1, 1934; B.
Oyamada, J. Chem. Soc. Japan 55, 1256, 1934), which consists in oxidizing chalcones with hydrogen peroxide in an alkaline medium, this being followed by an alkylation reaction as described in 1, according to the following scheme:
~3 ~ IIH ~R~ II
Rl I
j alkylat~on 3~ ~ 7 ~za4~o In this method, any hydroxy~ groups present can be protected and deprotected at the end.
4) The nuclear reduction of an ester, for example according to the following reaction scheme:
HO = R7 XIV
Rl O
l~ ClY
R4 R ~ R6 ~ `1~ )--2 ~ OR I ~ R
1H2 /Raney Ni ~2 ~ ; R7 XVI
1;2B46~0 Y being, for example, a p-toluenesulphonyl radical.
5) Nuclear oxidation, for example with persulphate, according to the following scheme:
~3 = ~7 Rl O
oxidation ~ /
~3 ~ ; ~ ~7 Rl O
A number of 3-alkoxyflavones which can be used in the present invention are present in plants and can be obtained by extraction.
The extraction method is as follows:
The leaves of the plants are macerated with 80~ ethanol at room temperature for 2 hours, with stirring. After maceration, the leaves are filtered off and the filtra-tion residue is percolated with the same solvent. The filtrate and the percolation liquid are combined and concentrated in vacuo (at a temperature below 40C) to give a thick extract. The extract is partitioned between 90% methanol and hexane (or a 40-60 petroleum ether).
The methanol phase is separated off and evaporated to dryness. The residue obtained is partitioned between l2s464al water (pH 5) and ethyl acetate. The etHyl acetate phase is separated off and evaporated to dryness. The residue obtained is subjected to countercurrent chroma-tography, dropwise, using a chloroform/water/methanol mixture (7:8:13) as the eluent by the descending tech-nique. The effluent is monitored at 355 nm and by thin layer chro~atography or by high performance liquid chromatography, and the antiviral activity of the fractions is tested. The fractions with antiviral activity are evaporated and then chromatographed on Sephadex~LH 20 using methanol as the eluent, and the eluate is monitored as before. The active fractions are chromatographed on a column of silica gel impregna-ted with 5% of water, a hexane/ethyl acetate/acetic acid mixture (5:3:1) being used as the developer in accordance with the "dry column" technique. This gives the pure active 3-alkoxyflavones.
The examples which follow illustrate the prepara-tion of the compounds of the formula I.
Example: Preparation of 4'-hydroxy-3-methoxyflavone (Algar-Flynn-Oyamada method) a) Preparation of 2'-hydroxy-4-benzyloxychalcone A solution of 2-hydroxyacetophenone (25 mmol) and benzyloxybenzaldehyde (25 mmol) in 25 ml of ethanol is cooled with ice. A 50% solution of potassium hydroxide (25 ml) is added slowly and the mixture is stirred for 4 days at room temperature. The solution is again cooled with ice and acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water and recrystallized from ethanol (yield: 59%). M.p. = 112-113C.
Other chalcones are prepared in the same way:
* 7`~ /c ~
l;~B4~
Table I
Yield M.p. (C) %
2'-hydroxy-4-benzyloxy-6'-methoxy-chalcone S0 111-112 2'-hydroxy-4-benzyloxy-5'-methoxy-chalcone 50 142-143 2'-hydroxy-4-benzyloxy-4'-methoxy-chalcone 35 123-124 2'-hydroxy-3'-methoxy-4-benzyloxy-chalcone ~ 45 152-153 2'-hydroxy-4,5'-dibenzyloxychalcone 59 121-122 2'-hydroxy-4,4'-dibenzyloxychalcone 55 134-136 2'-hydroxy-4-benzyloxy-5'-chloro-chalcone 88 100-102 2'-hydroxy-4-benzyloxy-4'-chloro-chalcone 40 140-141 2'-hydroxy-4,6'-dimethoxychalcone 58 98-100 2'-hydroxy-4,5'-dimethoxychalcone 78 63-64 2'-hydroxy-3',4-dimethoxychalcone 74 118 2'-hydroxy-4-methoxy-6'-benzyloxy-chalcone 55 75-76 2'-hydroxy-4-methoxy-5'-benzyloxy-chalcone 72 89-92 2'-hydroxy-4-methoxy-5'-chlorochalcone40 191-192 2'-hydroxy-4-methoxy-4'-chlorochalcone68 128-129 2'-hydroxy-4-chloro-6'-methoxychalcone50 116-111 2'-hydroxy-4,5'-dichlorochalcone 60 188-189 2'-hydroxy-4,4'-dichlorochalcone 80 150-151 2'-hydroxy-4-benzyloxy-5'-methyl-chalcone 53 139 2'-hydroxy-4-benzyloxy-4'-methyl-chalcone 52 144-145 2'-hydroxy-4-benzyloxy-4'-fluoro-chalcone 75 119-120 lZ846410 2'-hydroxy-3'-methyl-4-benzyloxy-5'-chlorochalcone 85 153-154 2'-hydroxy-4-chloro-4'-methylchalcone 55 145 , b) Preparation of 3-hydroxy-4'-benzyloxyflavone A 10% solution of potassium hydroxide in water (15 ml) and a solution of hydrogen peroxide (100 vol., 2 ml) are added to a boiling solution of the chalcone described in a (3 mmol) in ethanol ~15 ml). After 15 minutes, the solution is poured into a mixture of ice and hydrochloric acid and the precipitate formed is filtered off. It is washed with water and recrystallized from an ethanol/acetone mixture (yield: 42%). M.p. =
176C.
Other 3-hydroxyflavones are prepared in the same way:
Table II
Yield M.p. (C) %
3-hydroxy-4'-benzyloxy-5-methoxy-flavone 30 165-166 3-hydroxy-4l-benzyloxy-6-methoxy-flavone 60 180-181 3-hydroxy-4'-benzyloxy`-7-methoxy-flavone 34 169 3-hydroxy-4'-benzyloxy-8-methoxy-flavone 38 203 3-hydroxy-4'-benzyloxy-6-chloroflavone 72 203-204 3-hydroxy-4'-benzyloxy-7-chloroflavone 62 ~250 3-hydroxy-4',6-dimethoxyflavone 65 182-183 3-hydroxy-4',8-dimethoxyflavone 34 212-214 3-hydroxy-4'-methoxy-6-benzyloxy-flavone 70 162-164 3-hydroxy-4'-methoxy-7-chloroflavone 55 190-191 ~284640 3-hydroxy-4',6-dichloroflavone 58 216-217 3-hydroxy-4',7-dichloroflavone 50 199-200 3-hydroxy-4'-benzyloxy-6-methylflavone 62 213 3-hydroxy-4'-benzyloxy-7-methylflavone 50 157-158 3-hydroxy-4'-benzyloxy-7-fluoroflavone 44 178-179 3-hydroxy-4'-benzyloxy-6-chloro-8-methylflavone 50 218-219 3-hydroxy-4'-chloro-7-methy,lflavone 61 197-198 c) Preparation of 3-methoxy-4'-benzyloxyflavone Potassium carbonate (3 mmol) and dimethyl sulphate (2 mmol) are added to an acetone solution of the 3-hydroxyflavone obtained in b (1 mmol). The mixture is heated under reflux for 12 hours. The solvent is evaporated off. Water is added until the precipitate has dissolved. The precipitate is filtered off and re-crystallized from ethanol (yield: 63~).
Other 3-methoxy-4'-benzyloxyflavones are pre-pared in the same way:
Table III
Yield Solvent M.p. (C) 3-methoxy-4'-benzyloxyflavone 63 EtOH 112 3,5-dimethoxy-4'-benzyloxy-flavone 72 MeOH 120-122 3,6-dimethoxy-4'-benzyloxy-flavone 60 MeOH 135-136 3,7-dimethoxy-4'-benzyloxy-flavone 72 MeOH 149-151 3,8-dimethoxy-4'-benzyloxy-flavone 60 MeOH/ 170-171 - acetone '3-methoxy-4'-benzyloxy-6-chloroflavone 92 MeOH 142-143 1~84~1D
3-methoxy-4'-benzyloxy-7-chloroflavone 70MeOH/ 131-132 acetone 3-methoxy-4'-benzyloxy-6-methylflavone 85 MeOH 133-134 3-methoxy-4'-benzyloxy-7-methylflavone 78MeOH/H20 123-124 3-methoxy-4'-benzyloxy-7-fluoroflavone 87 MeOH 132-133 3-methoxy-4'-benzyloxy-6- 92MeOH/ 126-127 chloro-8-methoxyflavone acetone 3,4'-dimethoxy-6-benzvloxyflavone 72 MeOH/ 117-118 acetone 3-methoxy-4',6-dichloroflavone88 MeOH/ 168-169 acetone 3-methoxy-4',7-dichloroflavone78 MeOH/ 171-172 acetone 3-methoxy-4'-chloro-7-methyl- 72 acetone/ 144-145 flavone MeOH
3,4',6-trimethoxyflavone 60MeOH 137-138 3,4',8-trimethoxyflavone 58EtOH 131-133 3,4'-dimethoxy-6-chloroflavone76 MeOH/ 135-136 acetone 3,4'-dimethoxy-7-chloroflavone80 MeOH/ 171-172 acetone d) Preparation of 4'-hydroxy-3-methoxyflavone 3-Methoxy-4-benzyloxyflavone (1 mmol) is heated under reflux in a mixture of concentrated hydrochloric acid (2 ml) and concentrated acetic acid (2 ml) for 3 hours. After dilution with water, the precipitate formed is filtered off and recrystallized from ethanol (yield:
72%). M.p. = 232-233C.
- Other 3-methoxyflavones are prepared in the same way:
~2846~L0 Table IV
Yield Solvent M.p. (C) %
3,5-dimethoxy-4'-hydroxyflavone81 EtOH./H20 206-208 3,6-dimethoxy-4'-hydroxyflavone82 EtOH 229-230 3,7-dimethoxy-4'-hydroxyflavone68 MeOH 224-226 3,8-dimethoxy-4'-hydroxyflavone72 MeOH 226-227 3-methoxy-4'-hydroxy-6-chloro-flavone 80EtOH 254-255 3-methoxy-4'-hydroxy-7-chloro- 85EtOH/ 266-267 10 flavone acetone 3-methoxy-4'-hydroxy-6-methyl-flavone 75MeOH 228-230 3-methoxy-4'-hydroxy-7-methyl-flavone 70MeOH 219-220 15 3-methoxy-4'-hydroxy-7-fluoro-flavone 69MeOH 228-229 3-methoxy-4'-hydroxy-6-chloro- 60MeOH/ 292-293 8-methylflavone acetone The compounds which are used in the present invention inhibit the reproduction of picornaviruses, including hepatitis A virus, rhabdoviruses and other viruses which cause human or animal diseases.
The results of an in vitro study of the antiviral activity of the compounds used in the present invention, towards certain picornavirusesj will be given below in Table V.
. The antiviral activity has been expressed as the viral strength reduction factor by the method known as EPTT (end point titration technique) (cf. Vanden Lerghe et al., Lloydia, 1978, 41, 463).
1~84~0 ___ ~O~ ê
_ ~ ~o ~o~o ~o o o ~o~o ~o o ~ ~ e ~ ~ 2 ~
o ~ ._ l .~
o o o ;~
~2a4640 Furthermore, the 50% lethal dose (LD50), the 90% and 99% effective doses (EDgo and EDg9) and the 90% and 99% therapeutic indices (TIgo and TIg9) were determined using the following methods:
a) Preparation of the compounds The compounds were prepared at a dose of 1 mg/ml in a maximum volume of 0.1 ml of dimethyl sulphoxide, the volume being made up to 12 ml by the addition of a maintenance medium M-2. The dilutions were made up with the maintenance medium M-2.
b) Determination of the antiviral activity by the method known as the "end point titration technique"
Monolayers of VER0 cells in microdishes were infected with 10-fold dilutions of the virus ~polio type I). After absorption of the virus onto the cells (60 minutes, 37C), the compounds ln the medium M-2 are added to the infected cultures. The dishes were incubated at 37C for a sufficient time to allow the cytopathogenic effect (CPE) to appear. The antiviral activity was determined on the basis of this effect.
The viral strength reduction factor is calculated for each dilution as the ratio of the dilution of the virus with no cytopathogenic effect to the dilution of the virus ~ compound with no cytopathogenic effect.
The 90% effective dose, EDgo, is the dose at which 90~ of the viruses are inhibited.
The 99% effective dose, EDg9, is the dose at which 99~ of the viruses are inhibited.
c) Determination of the lethal dose The LD50 is the concentration at which 50% of the growth of the normal cells is inhibited. This was determined using a suspension of 5 105 VER0 cells in 10 ml of E199 medium to which 6% of calf serum (CS) and gentamycin (20 micrograms/ml) have been added. The compounds were added to give final concentrations of 1~84~
200, 100, 75, S0, 25, 10, 5, 3, 2, 1, ~,1 an-1 0,01 micro~rams~ml~
d) Calculation of the therapeutic index The TI90 and TIg9 ar~ the value of the LD50 divided by EDgo and ED99 respectively.
The results are given in Table VI:
Ta~le VI
Compound LD50 ED90 TI 9D ~Dg g TIg9 3-methoxy-4'-hydroxyflavone 10 3 3.3 6 1.66 3,6-dimethoxy-4'-hydroxy-flavone 200 7 29 25 8 3-methoxv-4'-hydroxy-6-chloroflavone 100 2 50 6 17 3-methoxy-4~-hydroxy-6- 1 methylflavone 75 1 75 1 5 ¦15 15 3-methoxy-4',6-dihydroxy-flavone 3 0.5 6 2 1,.5 3,4'-dimethoxy-6-hydroxy-flavone 200 100 2 200 1 3,4',6-trimethoxyflavone 100 2 50 50 2 20 3-methoxy-4'-hydroxy-7- I !
chloroflavone 100 5 20 ' 7 14.3 3-methoxy-4'-hydroxy-7-methylflavone 25 0.5 50 2 l12.5 3-methoxy-4'-hydroxy-7-fluoroflavone 20 1 20 6 j3.2 3,7-dimethoxy-4'-hydroxy- l flavone 25 1 1 25 ¦ 5 ! 5 3-methoxy-4'-chloro-7- l methyIflavone 10 10 1 20 O.S
30 3,5-dimethoxy-4'-hydroxy-flavone 150 S ¦ 30 10 15 3,8-dimethoxy-4'-hydroxy-flavone 25 10 2.5 20 1.2 12846~0 3,4',6-trimethoxy-5,7-di-h-droxyflavone 5C l 50 lO 5 3,6-dimethoxy-4',5,7-tri-hydroxyflavone 20 0.5 40 1 20 3,6,7-trimethoxy-4',5-di-hydroxyflavone 100 0.5 200 5 20 3,3',4',6,7,8-hexamethoxy-5-hydroxyflavone 200 20 10 25 8 3,3',4',5,6,7,8-hepta-methoxyflavone 200 20 10 25 8 3,3',4',5,6,7-hexamethoxy-10 flavone 200 100 2 200 1 3-methoxy-4'-benzyloxyflavon~ 100 30 3.3 100 1 The therapeutic compositions according to the invention can therefore be used in both curative and preventive capacities.
The therapeutic compositions according to the invention can be administered topically, orally or parenterally to humans or animals.
They can be in the form of solid, semi-solid or liquid preparations. Examples which may be mentioned are tablets, gelatin capsules, suppositories, injectable solutions or suspensions, ointments, oil-based or water-based eye lotions, mouthwashes and nose and ear solutions, as well as delayed-action forms.
In these compositions, the active principle is generally mixed with one or more of the usual pharma-ceutically acceptable excipients which are well known to those skilled in the art.
~2B4640 The therapeutic compositions which can be administered topically can contain in particular from 0.1 to 5% by weight of active principle.
The therapeutic compositions which can be administered orally or parenterally can contain in par-ticular from 1% to 60% by weight of active principle.
The amount of active principle administered obviously depends on the patient being treated, the method of administration and the severity of the disease.
However, for oral or parenteral administration, it is possible to administer about 100 to 1000 mg -3 to 6 times per day. For topical administration, it is possible to administer from 0.1 to 100 micrograms/cml 3 to 6 times per day.
1284~
or 3) R1, R2, R3 and R4 are selected from the group com-prising a hydrogen atom, a hydroxy group and a C~-C4 . alkoxy group, three of these groups being other than hydrogen, R5 and Rg are selected from the group comprising a hydrogen atom, a hydroxy group and a C1-C4 alkoxy group, R6 and R8 are hydrogen atoms, and 10 R7 is a hydroxy, a cl-c4 a~oxy ~roU2 or ~ cos~lo~ group;
or 4) R3 and R4 are hydrogen atoms, R1 and R2 are selected from the group comprising a hydroxy group and a C1-C4 alkoxy group, R5, R6, R8 and R9 are selected from the group comprising a hydrogen atom, a hydroxy group and a C1-C4 alkoxy group, and R7 is a hydroxy , C~-C4 alkoxy or glycosyloxy group;
or 5) R~ and R4 are hydrogen atoms, R2 and R~ are selected from the group comprising a hydroxy group and a C1 -C4 alkoxy group, R5, R6, R8 and Rg are selected from the group comprising a hydrogen atom, a hydroxy group and a C~-C4 alkoxy group, and R7 is a hydroxy . C1-C4 alkoxy or glycosyloxy group;
or 6) R3 is a hydrogen atom, Rl, R2 and R4 are selected from the group comprising a hydrogen atom, a hydroxy group and a Cl-C4 alkoxy group, two of these groups being other than hydrogen, R5, R6, R8 and Rg are selected from the group comprising a hydrogen atom, a hydroxy group and a Cl-C4 alkoxy group, and R7 is a hydroxy , Cl-C4 alkoxy or glycosyloxy group;
or 7) Rl, R2, R3 and R4 are selected from the group com-prising a hydrogen atom, a hydroxy group and a C1-C4 alkoxy group, at least three of these groups being a hydrogen atom, R5, R6, R8 and Rg are selected from the group com-prising a hydrogen atom, a hydroxy group and a Cl-C4 alkoxy group, and R7 is a hydroxy , C1-C4 alkoxy or glycosyloxy 10 qroup, ora pharmaceutically acceptable salt thereof.
In the above definition, the expression "a halogen atom" denotes a chlorine, bromine, iodine or fluorine atom.
Pharmaceutically acceptable salts are the addition salts which the compounds form with pharma-ceutically acceptable acids, as well as the salts which the compounds containing an acid group (COOH) form with pharmaceutically acceptable bases.
The expression "addition salts with pharma-ceutically acceptable acids" denotes salts which givethe biological properties of the free bases without having any undesirable effects. In particular, these salts can be those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, with metal salts con-taining acid hydrogens, such as disodium orthophosphate and monopotassium sulphate, and with organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, tartaric acid and pamoic acid.
Likewise, the expression "salts with pharma-ceutically acceptable bases" denotes salts which do not modify the biological properties of the free acids. In particular, these salts can be those formed with in-organic bases such as sodium hydroxide, potassium ~284~
-- 5 ~
hydroxide, lithium hydroxide, calcium hydroxide andmagnesium hydroxide, or with organic baseS such as glucamine, N-methylglucamine, N~N-dimethylglucamine~
ethanolamine, diethanolamine, morpholine, N-methyl-morpholine and tris(hydroxymethyl)methylamine.
To the knowledge of the Applicant Company, thecompounds of the formula I belonging to the class defined under 1) are novel compounds.
The compounds belonging to the classes defined under 2) to 7) are products of natural origin or derivatives of products of natural origin.
The Applicant Company has also found that 3,3', 4',5,6,7,8-heptamethoxyflavone has an antiviral activity.
The compound was described in US-A-3 867 541 as havina an aggregation-inhibiting activity, with no suggestion of a viral activity. The invention also relates to the use of this compound for the manu-facture of a pharmaceutical composition for treating viral diseases.
In general terms, the 3-alkoxyflavones used in the present invention can be obtained by one of the following processes:
1) Alkylation of 3-hydroxyflavones according to the following scheme:
~3 ~ ~ 7 III
l RZ
~284640 3 ~ J ~ ~ 37 in which Z is a nucleus-repelling group.
Methyl sulphate, methyl iodide or diazomethane may be mentioned as examples of methylating agents.
2) Synthesis by the Allan-Robinson method (J. Chem. Soc.
125, 2192, 1924), in which o-hydroxyaryl ketones are condensed with aromatic acid anhydrides according to the following scheme:
A2~CO-CH2_oQ ~ ~ ~ >
X XI
2 ~
In this method, any hydroxy groups present can be protected, if necessary, and deprotected after the reaction.
~Z846~0 As a variant, using the same type of reaction, it is possible to prepare a 3-hydroxyflavone and then carry out an alkylation as described in 1.
3) The Algar-Flynn-Oyamada oxidation metho~ (J. Algar, J.P. Flynn, Proc. Roy. Irish Acad. 423, 1, 1934; B.
Oyamada, J. Chem. Soc. Japan 55, 1256, 1934), which consists in oxidizing chalcones with hydrogen peroxide in an alkaline medium, this being followed by an alkylation reaction as described in 1, according to the following scheme:
~3 ~ IIH ~R~ II
Rl I
j alkylat~on 3~ ~ 7 ~za4~o In this method, any hydroxy~ groups present can be protected and deprotected at the end.
4) The nuclear reduction of an ester, for example according to the following reaction scheme:
HO = R7 XIV
Rl O
l~ ClY
R4 R ~ R6 ~ `1~ )--2 ~ OR I ~ R
1H2 /Raney Ni ~2 ~ ; R7 XVI
1;2B46~0 Y being, for example, a p-toluenesulphonyl radical.
5) Nuclear oxidation, for example with persulphate, according to the following scheme:
~3 = ~7 Rl O
oxidation ~ /
~3 ~ ; ~ ~7 Rl O
A number of 3-alkoxyflavones which can be used in the present invention are present in plants and can be obtained by extraction.
The extraction method is as follows:
The leaves of the plants are macerated with 80~ ethanol at room temperature for 2 hours, with stirring. After maceration, the leaves are filtered off and the filtra-tion residue is percolated with the same solvent. The filtrate and the percolation liquid are combined and concentrated in vacuo (at a temperature below 40C) to give a thick extract. The extract is partitioned between 90% methanol and hexane (or a 40-60 petroleum ether).
The methanol phase is separated off and evaporated to dryness. The residue obtained is partitioned between l2s464al water (pH 5) and ethyl acetate. The etHyl acetate phase is separated off and evaporated to dryness. The residue obtained is subjected to countercurrent chroma-tography, dropwise, using a chloroform/water/methanol mixture (7:8:13) as the eluent by the descending tech-nique. The effluent is monitored at 355 nm and by thin layer chro~atography or by high performance liquid chromatography, and the antiviral activity of the fractions is tested. The fractions with antiviral activity are evaporated and then chromatographed on Sephadex~LH 20 using methanol as the eluent, and the eluate is monitored as before. The active fractions are chromatographed on a column of silica gel impregna-ted with 5% of water, a hexane/ethyl acetate/acetic acid mixture (5:3:1) being used as the developer in accordance with the "dry column" technique. This gives the pure active 3-alkoxyflavones.
The examples which follow illustrate the prepara-tion of the compounds of the formula I.
Example: Preparation of 4'-hydroxy-3-methoxyflavone (Algar-Flynn-Oyamada method) a) Preparation of 2'-hydroxy-4-benzyloxychalcone A solution of 2-hydroxyacetophenone (25 mmol) and benzyloxybenzaldehyde (25 mmol) in 25 ml of ethanol is cooled with ice. A 50% solution of potassium hydroxide (25 ml) is added slowly and the mixture is stirred for 4 days at room temperature. The solution is again cooled with ice and acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water and recrystallized from ethanol (yield: 59%). M.p. = 112-113C.
Other chalcones are prepared in the same way:
* 7`~ /c ~
l;~B4~
Table I
Yield M.p. (C) %
2'-hydroxy-4-benzyloxy-6'-methoxy-chalcone S0 111-112 2'-hydroxy-4-benzyloxy-5'-methoxy-chalcone 50 142-143 2'-hydroxy-4-benzyloxy-4'-methoxy-chalcone 35 123-124 2'-hydroxy-3'-methoxy-4-benzyloxy-chalcone ~ 45 152-153 2'-hydroxy-4,5'-dibenzyloxychalcone 59 121-122 2'-hydroxy-4,4'-dibenzyloxychalcone 55 134-136 2'-hydroxy-4-benzyloxy-5'-chloro-chalcone 88 100-102 2'-hydroxy-4-benzyloxy-4'-chloro-chalcone 40 140-141 2'-hydroxy-4,6'-dimethoxychalcone 58 98-100 2'-hydroxy-4,5'-dimethoxychalcone 78 63-64 2'-hydroxy-3',4-dimethoxychalcone 74 118 2'-hydroxy-4-methoxy-6'-benzyloxy-chalcone 55 75-76 2'-hydroxy-4-methoxy-5'-benzyloxy-chalcone 72 89-92 2'-hydroxy-4-methoxy-5'-chlorochalcone40 191-192 2'-hydroxy-4-methoxy-4'-chlorochalcone68 128-129 2'-hydroxy-4-chloro-6'-methoxychalcone50 116-111 2'-hydroxy-4,5'-dichlorochalcone 60 188-189 2'-hydroxy-4,4'-dichlorochalcone 80 150-151 2'-hydroxy-4-benzyloxy-5'-methyl-chalcone 53 139 2'-hydroxy-4-benzyloxy-4'-methyl-chalcone 52 144-145 2'-hydroxy-4-benzyloxy-4'-fluoro-chalcone 75 119-120 lZ846410 2'-hydroxy-3'-methyl-4-benzyloxy-5'-chlorochalcone 85 153-154 2'-hydroxy-4-chloro-4'-methylchalcone 55 145 , b) Preparation of 3-hydroxy-4'-benzyloxyflavone A 10% solution of potassium hydroxide in water (15 ml) and a solution of hydrogen peroxide (100 vol., 2 ml) are added to a boiling solution of the chalcone described in a (3 mmol) in ethanol ~15 ml). After 15 minutes, the solution is poured into a mixture of ice and hydrochloric acid and the precipitate formed is filtered off. It is washed with water and recrystallized from an ethanol/acetone mixture (yield: 42%). M.p. =
176C.
Other 3-hydroxyflavones are prepared in the same way:
Table II
Yield M.p. (C) %
3-hydroxy-4'-benzyloxy-5-methoxy-flavone 30 165-166 3-hydroxy-4l-benzyloxy-6-methoxy-flavone 60 180-181 3-hydroxy-4'-benzyloxy`-7-methoxy-flavone 34 169 3-hydroxy-4'-benzyloxy-8-methoxy-flavone 38 203 3-hydroxy-4'-benzyloxy-6-chloroflavone 72 203-204 3-hydroxy-4'-benzyloxy-7-chloroflavone 62 ~250 3-hydroxy-4',6-dimethoxyflavone 65 182-183 3-hydroxy-4',8-dimethoxyflavone 34 212-214 3-hydroxy-4'-methoxy-6-benzyloxy-flavone 70 162-164 3-hydroxy-4'-methoxy-7-chloroflavone 55 190-191 ~284640 3-hydroxy-4',6-dichloroflavone 58 216-217 3-hydroxy-4',7-dichloroflavone 50 199-200 3-hydroxy-4'-benzyloxy-6-methylflavone 62 213 3-hydroxy-4'-benzyloxy-7-methylflavone 50 157-158 3-hydroxy-4'-benzyloxy-7-fluoroflavone 44 178-179 3-hydroxy-4'-benzyloxy-6-chloro-8-methylflavone 50 218-219 3-hydroxy-4'-chloro-7-methy,lflavone 61 197-198 c) Preparation of 3-methoxy-4'-benzyloxyflavone Potassium carbonate (3 mmol) and dimethyl sulphate (2 mmol) are added to an acetone solution of the 3-hydroxyflavone obtained in b (1 mmol). The mixture is heated under reflux for 12 hours. The solvent is evaporated off. Water is added until the precipitate has dissolved. The precipitate is filtered off and re-crystallized from ethanol (yield: 63~).
Other 3-methoxy-4'-benzyloxyflavones are pre-pared in the same way:
Table III
Yield Solvent M.p. (C) 3-methoxy-4'-benzyloxyflavone 63 EtOH 112 3,5-dimethoxy-4'-benzyloxy-flavone 72 MeOH 120-122 3,6-dimethoxy-4'-benzyloxy-flavone 60 MeOH 135-136 3,7-dimethoxy-4'-benzyloxy-flavone 72 MeOH 149-151 3,8-dimethoxy-4'-benzyloxy-flavone 60 MeOH/ 170-171 - acetone '3-methoxy-4'-benzyloxy-6-chloroflavone 92 MeOH 142-143 1~84~1D
3-methoxy-4'-benzyloxy-7-chloroflavone 70MeOH/ 131-132 acetone 3-methoxy-4'-benzyloxy-6-methylflavone 85 MeOH 133-134 3-methoxy-4'-benzyloxy-7-methylflavone 78MeOH/H20 123-124 3-methoxy-4'-benzyloxy-7-fluoroflavone 87 MeOH 132-133 3-methoxy-4'-benzyloxy-6- 92MeOH/ 126-127 chloro-8-methoxyflavone acetone 3,4'-dimethoxy-6-benzvloxyflavone 72 MeOH/ 117-118 acetone 3-methoxy-4',6-dichloroflavone88 MeOH/ 168-169 acetone 3-methoxy-4',7-dichloroflavone78 MeOH/ 171-172 acetone 3-methoxy-4'-chloro-7-methyl- 72 acetone/ 144-145 flavone MeOH
3,4',6-trimethoxyflavone 60MeOH 137-138 3,4',8-trimethoxyflavone 58EtOH 131-133 3,4'-dimethoxy-6-chloroflavone76 MeOH/ 135-136 acetone 3,4'-dimethoxy-7-chloroflavone80 MeOH/ 171-172 acetone d) Preparation of 4'-hydroxy-3-methoxyflavone 3-Methoxy-4-benzyloxyflavone (1 mmol) is heated under reflux in a mixture of concentrated hydrochloric acid (2 ml) and concentrated acetic acid (2 ml) for 3 hours. After dilution with water, the precipitate formed is filtered off and recrystallized from ethanol (yield:
72%). M.p. = 232-233C.
- Other 3-methoxyflavones are prepared in the same way:
~2846~L0 Table IV
Yield Solvent M.p. (C) %
3,5-dimethoxy-4'-hydroxyflavone81 EtOH./H20 206-208 3,6-dimethoxy-4'-hydroxyflavone82 EtOH 229-230 3,7-dimethoxy-4'-hydroxyflavone68 MeOH 224-226 3,8-dimethoxy-4'-hydroxyflavone72 MeOH 226-227 3-methoxy-4'-hydroxy-6-chloro-flavone 80EtOH 254-255 3-methoxy-4'-hydroxy-7-chloro- 85EtOH/ 266-267 10 flavone acetone 3-methoxy-4'-hydroxy-6-methyl-flavone 75MeOH 228-230 3-methoxy-4'-hydroxy-7-methyl-flavone 70MeOH 219-220 15 3-methoxy-4'-hydroxy-7-fluoro-flavone 69MeOH 228-229 3-methoxy-4'-hydroxy-6-chloro- 60MeOH/ 292-293 8-methylflavone acetone The compounds which are used in the present invention inhibit the reproduction of picornaviruses, including hepatitis A virus, rhabdoviruses and other viruses which cause human or animal diseases.
The results of an in vitro study of the antiviral activity of the compounds used in the present invention, towards certain picornavirusesj will be given below in Table V.
. The antiviral activity has been expressed as the viral strength reduction factor by the method known as EPTT (end point titration technique) (cf. Vanden Lerghe et al., Lloydia, 1978, 41, 463).
1~84~0 ___ ~O~ ê
_ ~ ~o ~o~o ~o o o ~o~o ~o o ~ ~ e ~ ~ 2 ~
o ~ ._ l .~
o o o ;~
~2a4640 Furthermore, the 50% lethal dose (LD50), the 90% and 99% effective doses (EDgo and EDg9) and the 90% and 99% therapeutic indices (TIgo and TIg9) were determined using the following methods:
a) Preparation of the compounds The compounds were prepared at a dose of 1 mg/ml in a maximum volume of 0.1 ml of dimethyl sulphoxide, the volume being made up to 12 ml by the addition of a maintenance medium M-2. The dilutions were made up with the maintenance medium M-2.
b) Determination of the antiviral activity by the method known as the "end point titration technique"
Monolayers of VER0 cells in microdishes were infected with 10-fold dilutions of the virus ~polio type I). After absorption of the virus onto the cells (60 minutes, 37C), the compounds ln the medium M-2 are added to the infected cultures. The dishes were incubated at 37C for a sufficient time to allow the cytopathogenic effect (CPE) to appear. The antiviral activity was determined on the basis of this effect.
The viral strength reduction factor is calculated for each dilution as the ratio of the dilution of the virus with no cytopathogenic effect to the dilution of the virus ~ compound with no cytopathogenic effect.
The 90% effective dose, EDgo, is the dose at which 90~ of the viruses are inhibited.
The 99% effective dose, EDg9, is the dose at which 99~ of the viruses are inhibited.
c) Determination of the lethal dose The LD50 is the concentration at which 50% of the growth of the normal cells is inhibited. This was determined using a suspension of 5 105 VER0 cells in 10 ml of E199 medium to which 6% of calf serum (CS) and gentamycin (20 micrograms/ml) have been added. The compounds were added to give final concentrations of 1~84~
200, 100, 75, S0, 25, 10, 5, 3, 2, 1, ~,1 an-1 0,01 micro~rams~ml~
d) Calculation of the therapeutic index The TI90 and TIg9 ar~ the value of the LD50 divided by EDgo and ED99 respectively.
The results are given in Table VI:
Ta~le VI
Compound LD50 ED90 TI 9D ~Dg g TIg9 3-methoxy-4'-hydroxyflavone 10 3 3.3 6 1.66 3,6-dimethoxy-4'-hydroxy-flavone 200 7 29 25 8 3-methoxv-4'-hydroxy-6-chloroflavone 100 2 50 6 17 3-methoxy-4~-hydroxy-6- 1 methylflavone 75 1 75 1 5 ¦15 15 3-methoxy-4',6-dihydroxy-flavone 3 0.5 6 2 1,.5 3,4'-dimethoxy-6-hydroxy-flavone 200 100 2 200 1 3,4',6-trimethoxyflavone 100 2 50 50 2 20 3-methoxy-4'-hydroxy-7- I !
chloroflavone 100 5 20 ' 7 14.3 3-methoxy-4'-hydroxy-7-methylflavone 25 0.5 50 2 l12.5 3-methoxy-4'-hydroxy-7-fluoroflavone 20 1 20 6 j3.2 3,7-dimethoxy-4'-hydroxy- l flavone 25 1 1 25 ¦ 5 ! 5 3-methoxy-4'-chloro-7- l methyIflavone 10 10 1 20 O.S
30 3,5-dimethoxy-4'-hydroxy-flavone 150 S ¦ 30 10 15 3,8-dimethoxy-4'-hydroxy-flavone 25 10 2.5 20 1.2 12846~0 3,4',6-trimethoxy-5,7-di-h-droxyflavone 5C l 50 lO 5 3,6-dimethoxy-4',5,7-tri-hydroxyflavone 20 0.5 40 1 20 3,6,7-trimethoxy-4',5-di-hydroxyflavone 100 0.5 200 5 20 3,3',4',6,7,8-hexamethoxy-5-hydroxyflavone 200 20 10 25 8 3,3',4',5,6,7,8-hepta-methoxyflavone 200 20 10 25 8 3,3',4',5,6,7-hexamethoxy-10 flavone 200 100 2 200 1 3-methoxy-4'-benzyloxyflavon~ 100 30 3.3 100 1 The therapeutic compositions according to the invention can therefore be used in both curative and preventive capacities.
The therapeutic compositions according to the invention can be administered topically, orally or parenterally to humans or animals.
They can be in the form of solid, semi-solid or liquid preparations. Examples which may be mentioned are tablets, gelatin capsules, suppositories, injectable solutions or suspensions, ointments, oil-based or water-based eye lotions, mouthwashes and nose and ear solutions, as well as delayed-action forms.
In these compositions, the active principle is generally mixed with one or more of the usual pharma-ceutically acceptable excipients which are well known to those skilled in the art.
~2B4640 The therapeutic compositions which can be administered topically can contain in particular from 0.1 to 5% by weight of active principle.
The therapeutic compositions which can be administered orally or parenterally can contain in par-ticular from 1% to 60% by weight of active principle.
The amount of active principle administered obviously depends on the patient being treated, the method of administration and the severity of the disease.
However, for oral or parenteral administration, it is possible to administer about 100 to 1000 mg -3 to 6 times per day. For topical administration, it is possible to administer from 0.1 to 100 micrograms/cml 3 to 6 times per day.
Claims (10)
1. A therapeutic composition having an antiviral activity containing an effective amount of a compound selected from the compounds of the general formula in which :
R is C1 - C4 alkyl and l) R1, R2, R3 and R4 are selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1 - C4 alkyl,C1 - C4 alkoxy,benzyloxy, methylenedioxy,C1 - C4 alka-noyl,(C1 - C4 alkoxy)carbonyloxy, amino, (C1-C4alkyl)amino, di(C1-C4 alkyl)amino,hydroxy, (C1-4 alkanoyl)oxy, glycosyloxy,car-boxy and (C1-C4 alkoxy)carbonyl, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy and C1-C4 alkyl, at least one of the groups R1, R2, R3, R4, R5, R6, R8 and R9 being other than hydrogen, hydroxy or C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy and glycosyloxy ;
R is C1 - C4 alkyl and l) R1, R2, R3 and R4 are selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1 - C4 alkyl,C1 - C4 alkoxy,benzyloxy, methylenedioxy,C1 - C4 alka-noyl,(C1 - C4 alkoxy)carbonyloxy, amino, (C1-C4alkyl)amino, di(C1-C4 alkyl)amino,hydroxy, (C1-4 alkanoyl)oxy, glycosyloxy,car-boxy and (C1-C4 alkoxy)carbonyl, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy and C1-C4 alkyl, at least one of the groups R1, R2, R3, R4, R5, R6, R8 and R9 being other than hydrogen, hydroxy or C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy and glycosyloxy ;
2) R1, R2, R3 and R4 are selected from the group consist-ing of hydroxy. and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group cons-isting of hydroxy, C1-C4 alkoxy and glycosyloxy, with the exclusion of 3,3', 4',5,6,7,8-heptamethoxyflavone; or
3) R1, R2, R3 and R4 are selected from the group consist-ing of hydrogen, hydroxy and C1-C4 alkoxy, three of these groups being other than hydrogen, R5 and R9 are selected from the group consisting of hydro-gen, hydroxy and C1-C4 alkoxy, R6 and R8 are hydrogen and R7 is selected from the group consisting of hydroxy , C1-C4 alkoxy and glycosyloxy;
or
or
4) R3 and R4 are hydrogen, R1 and R2 are selected from the group consisting of hydroxy and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy, or
5) R1 and R4 are hydrogen, R2 and R3 are selected from the group consisting of hydroxy and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy;
or
or
6) R3 is hydrogen, R1, R2 and R4 are selected from the group consisting of hydro-gen, hydroxy and C16C4 alkoxy, two of these groups being other than hydrogen, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy, or
7) R1, R2, R3 and R4 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, at least three of these groups being hydrogen, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy, and a pharmaceutically acceptable salt thereof, and a therapeutically acceptable excipient.
2. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R1, R2 , R3 and R4 are selected from the group consisting of hydrogen, halogen,nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, benzyloxy, methyleredioxy, C1-C4 alkanoyl, (C1-C4 alkoxy)carbonyloxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, (C1-C4 alkanoyl)amino, hydroxy (C1-C4 al-kanoyl)oxy, glycosyloxy, carboxy and (C1-C4 alkoxy)carbonyl, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy and C1-C4 alkyl, al least one of the groups R1, R2, R3, R4, R5, R6, R8 and R9 being other than hydrogen, hydroxy or C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy and glycosyloxy.
3. A composition as claimed in claim 1 containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R1, R2, R3 and R4 are selected from the group consisting of hydroxy and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy,and glycosyloxy, with the exclusion of 3,3', 4', 5, 6,7 8-heptamethoxy-flavone.
4. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which R is C1-C4 alkyl, R1,R2; R3 and R4 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, three of these groups being other than hydrogen, R5 and R9 are selected from the group consisting of hydro-gen, hydroxy and C1-C4 alkoxy, R6 and R8 are hydrogen, and R7 is selected from the group consisting of hydroxy and glycosyloxy.
5. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R3 and R4 are hydrogen, R1 and R2 are selected from the group consisting of hydroxy and C1-C4 alkoxy R5, R6 R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
6. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4alkyl, R1 and R4 are hydrogen, R2 and R3 are selected from the group consisting of hydroxy and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
7. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R3 is hydrogen, R1, R2 and R4 are selected from the group consisting of hydro-gen, hydroxy and C1-C4 alkoxy, two of these groups being other than hydrogen, R5 R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
2. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R1, R2 , R3 and R4 are selected from the group consisting of hydrogen, halogen,nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, benzyloxy, methyleredioxy, C1-C4 alkanoyl, (C1-C4 alkoxy)carbonyloxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, (C1-C4 alkanoyl)amino, hydroxy (C1-C4 al-kanoyl)oxy, glycosyloxy, carboxy and (C1-C4 alkoxy)carbonyl, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy and C1-C4 alkyl, al least one of the groups R1, R2, R3, R4, R5, R6, R8 and R9 being other than hydrogen, hydroxy or C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy and glycosyloxy.
3. A composition as claimed in claim 1 containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R1, R2, R3 and R4 are selected from the group consisting of hydroxy and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy,and glycosyloxy, with the exclusion of 3,3', 4', 5, 6,7 8-heptamethoxy-flavone.
4. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which R is C1-C4 alkyl, R1,R2; R3 and R4 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, three of these groups being other than hydrogen, R5 and R9 are selected from the group consisting of hydro-gen, hydroxy and C1-C4 alkoxy, R6 and R8 are hydrogen, and R7 is selected from the group consisting of hydroxy and glycosyloxy.
5. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R3 and R4 are hydrogen, R1 and R2 are selected from the group consisting of hydroxy and C1-C4 alkoxy R5, R6 R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
6. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4alkyl, R1 and R4 are hydrogen, R2 and R3 are selected from the group consisting of hydroxy and C1-C4 alkoxy, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
7. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl, R3 is hydrogen, R1, R2 and R4 are selected from the group consisting of hydro-gen, hydroxy and C1-C4 alkoxy, two of these groups being other than hydrogen, R5 R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
8. A composition as claimed in claim 1, containing an effective amount of a compound of the formula:
in which:
R is C1-C4 alkyl R1, R2, R3 and R4 are selected from the group consisting of hydrogen. hydroxy and C1-C4 alkoxy, at least three of these groups being hydrogen, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
in which:
R is C1-C4 alkyl R1, R2, R3 and R4 are selected from the group consisting of hydrogen. hydroxy and C1-C4 alkoxy, at least three of these groups being hydrogen, R5, R6, R8 and R9 are selected from the group consisting of hydrogen, hydroxy and C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy, C1-C4 alkoxy and glycosyloxy.
9. Use of 3,3',4',5,6,7,8-heptamethoxyflavone for the manufacture of a pharmaceutical composition for treating viral diseases.
10. A co~pound selected from the compounds of the for-mula:
in which R is C1-C4 alkyl, R1, R2 , R3 and R4 are selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, benzyloxy, methylenedioxy, C1-C4 alkanoyl, (C1-C4 alkoxy)carbonyloxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, (C1-C4 alkanoyl)amino, hydroxy, (C1-C4alkanoyl) oxy, glycosyloxy, carboxy and (C1-C4 alkoxy)carbonyl), R5, R6, R8 and R9 are selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy and C1-C4 alkyl, at least one of the groups R1, R2, R3, R4, R5, R6, R8 and R9 being other than hydrogen, hydroxy or C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy and glycosyloxy, and their pharmaceutically acceptable salts.
in which R is C1-C4 alkyl, R1, R2 , R3 and R4 are selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, benzyloxy, methylenedioxy, C1-C4 alkanoyl, (C1-C4 alkoxy)carbonyloxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, (C1-C4 alkanoyl)amino, hydroxy, (C1-C4alkanoyl) oxy, glycosyloxy, carboxy and (C1-C4 alkoxy)carbonyl), R5, R6, R8 and R9 are selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy and C1-C4 alkyl, at least one of the groups R1, R2, R3, R4, R5, R6, R8 and R9 being other than hydrogen, hydroxy or C1-C4 alkoxy, and R7 is selected from the group consisting of hydroxy and glycosyloxy, and their pharmaceutically acceptable salts.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8600644A FR2593066B1 (en) | 1986-01-17 | 1986-01-17 | THERAPEUTIC COMPOSITIONS BASED ON 3-ALKOXYFLAVON DERIVATIVES AND NEW 3-ALKOXYFLAVON DERIVATIVES. |
| FR8600644 | 1986-01-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1284640C true CA1284640C (en) | 1991-06-04 |
Family
ID=9331224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000527372A Expired - Fee Related CA1284640C (en) | 1986-01-17 | 1987-01-15 | Therapeutic compositions based on 3-alkoxyflavone derivatives, and novel 3-alkoxyflavone derivatives |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0233105B1 (en) |
| JP (1) | JPS62223179A (en) |
| AT (1) | ATE59777T1 (en) |
| CA (1) | CA1284640C (en) |
| DE (1) | DE3767175D1 (en) |
| DK (1) | DK24687A (en) |
| FR (1) | FR2593066B1 (en) |
| PT (1) | PT84130B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5539112A (en) * | 1992-02-14 | 1996-07-23 | Kyowa Hakko Kogyo Co., Ltd. | 5-aminoflavone derivatives |
| IL118657A0 (en) * | 1996-06-14 | 1996-10-16 | Arad Dorit | Inhibitors for picornavirus proteases |
| WO1998027080A1 (en) * | 1996-12-19 | 1998-06-25 | Agrevo Uk Limited | Chromones useful as fungicides |
| IL122591A0 (en) | 1997-12-14 | 1998-06-15 | Arad Dorit | Pharmaceutical compositions comprising cystein protease inhibitors |
| CN1837202B (en) * | 2006-04-25 | 2010-08-18 | 中国人民解放军第二军医大学 | Flavonols with blood-fat-lowering effect |
| WO2018194172A1 (en) * | 2017-04-21 | 2018-10-25 | 土田 裕三 | Compound or salt thereof, antiviral agent, and pharmaceutical composition |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3541M (en) * | 1964-05-12 | 1965-09-13 | Laroche Navarron Lab | Drug has natriuretic properties based on a new flavone. |
| GB1139041A (en) * | 1966-05-25 | 1969-01-08 | Beecham Group Ltd | Chlorflavonin |
| US3661890A (en) * | 1970-03-10 | 1972-05-09 | Us Agriculture | Preparation of quercetin derivatives |
| US3867541A (en) * | 1972-05-03 | 1975-02-18 | Ralph C Robbins | Compositions and methods for disaggregating blood cells |
| FR2187320A1 (en) * | 1972-06-09 | 1974-01-18 | Cortial | Flavoured extracts of birch - with cytolytic activity |
| GB1461777A (en) * | 1973-06-08 | 1977-01-19 | Fisons Ltd | 2-phenyl-4-oxo-4h-1-benzopyran derivatives |
| NZ193316A (en) * | 1979-04-10 | 1984-07-31 | Hoffmann La Roche | 3-alkoxyflavone derivatives and pharmaceutical compositions |
| JPS5899414A (en) * | 1981-12-10 | 1983-06-13 | Jun Okuda | Inhibitor of aldose reductase |
-
1986
- 1986-01-17 FR FR8600644A patent/FR2593066B1/en not_active Expired
-
1987
- 1987-01-15 CA CA000527372A patent/CA1284640C/en not_active Expired - Fee Related
- 1987-01-16 JP JP62007955A patent/JPS62223179A/en active Pending
- 1987-01-16 PT PT84130A patent/PT84130B/en not_active IP Right Cessation
- 1987-01-16 EP EP87400107A patent/EP0233105B1/en not_active Expired - Lifetime
- 1987-01-16 AT AT87400107T patent/ATE59777T1/en not_active IP Right Cessation
- 1987-01-16 DE DE8787400107T patent/DE3767175D1/en not_active Expired - Fee Related
- 1987-01-16 DK DK024687A patent/DK24687A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK24687D0 (en) | 1987-01-16 |
| PT84130B (en) | 1989-02-28 |
| JPS62223179A (en) | 1987-10-01 |
| ATE59777T1 (en) | 1991-01-15 |
| DE3767175D1 (en) | 1991-02-14 |
| FR2593066B1 (en) | 1989-06-30 |
| PT84130A (en) | 1987-02-01 |
| EP0233105B1 (en) | 1991-01-09 |
| EP0233105A1 (en) | 1987-08-19 |
| DK24687A (en) | 1987-07-18 |
| FR2593066A1 (en) | 1987-07-24 |
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