CA1117957A - 6-carboxy-flavone derivatives and process for their preparation - Google Patents
6-carboxy-flavone derivatives and process for their preparationInfo
- Publication number
- CA1117957A CA1117957A CA000289123A CA289123A CA1117957A CA 1117957 A CA1117957 A CA 1117957A CA 000289123 A CA000289123 A CA 000289123A CA 289123 A CA289123 A CA 289123A CA 1117957 A CA1117957 A CA 1117957A
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- Prior art keywords
- methyl
- carboxy
- isopropoxy
- flavone
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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Abstract
Abstract of the Disclosure This invention relates to compounds which have the following formula (I) (I) wherein R, is a) carboxy or b) -COOR4, wherein R4 is C1-C12 alkyl or C3-C4 alkenyl; R2 is a') C1-C6 alkyl, which m?? be unsubstituted or substituted by C1-C2 alkoxy, or b') C3-C4 alkenyl; R3 ?? C1-C4 alkyl, and the pharmaceuti-cally acceptable salts with bases. It also relates to a process for the preparation of these compounds by the cyclization of a compound of formula (II)
Description
~ ~7~3St7 The present invention relates to 6-carboxy-flavone deri-vatives, to a process for their preparation and ~o pharmaceutical compositions containing them.
- The compounds of the invention have the following formula ~I) O
5' wherein ` 1 a) carboxy or b) -COOR4, wherein R4 is Cl C12 alkyl or C3-C4 alkenyl;
R2 is a') Cl-C6 alkyl, which may be unsubstituted or substituted by Cl-C2 alkoxy, or b') C3-C4 alkenyl;
. R3 is Cl-C4 alkyl-! The present invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I) with bases.
In the compounds of the invention, the alkyl, alkenyl and alkoxy groups may be branched or straight chain.
Preferably, the compounds of the present invention are those compounds wherein Rl is carboxy or carbalkoxy of 1 to 6 carbon atoms ~O in the alkoxy groupJ and R2 is a Cl-C6 alkyl. More preferably, R2 is a Cl-C4 alkyl, most preferably methyl or isopropyl, or 2-ethoxy-ethyl.
R4 is most preferably Cl-C6 alkyl, in particular ethyl, isopropyl, t-butyl or hexyl, and R3 is preferably methyl or propyl. Preferably R
is carboxy. Preferably R3 is in the 3', 4' or 5' position on the phenyl ring, most preferably in the 5'-position.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides or with organic bases, such as lysine, triethyl-amine, triethanolamine, dibenzylamine~ `
- 1- ~ ''` ' methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethyl-piperidine, N,N-diethylaminoethylamine, N-ethyl~orpholine, ~-phenethylamine, N-benzyl-~--phenethylamine, N-benzyl-N,N-dimethylam~le and the other acceptable organic amines.
Examples of particularly preferred compounds of the invention are:
6-carboxy-2'-isopropoxy-3'-methyl-flavone;
6-carboxy-2'-isopropoxy-4'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-ethyl-flavone;
10 6- OE boxy-2'-isopropoxy-3'-propyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl-flavone;
6-carboxy-2'-isopropoxy-5'-isopropyl-flavone;
6-carboxy-2'-methoxy-3'-methyl-flavone;
6-carboxy-2'-methoxy-5'-methyl-flavone;
6-carboxy-2'-methoxy-3'-propyl-flavone;
6-car~oxy-2'-(2"-ethoxy-ethoxy)-3'-methyl-flavone;
6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone;
as well as the pharmaceutically ac oeptable salts thereofr in particular the sodium salt, and the Cl-& alkyl esters thereof, in particular the ethyl, isopropyl, tert-butyl and hexyl esters.
The compounds of the invention are prepared by cyclizing a com-pound of foxmula (II) ~ o~ J Q ~
wherein ~ , ~ and R3 are as defined above or a salt thereof and/or, if desired, converting a compound of general form~la (I) into another compound of s~
general formula (I) by known metho~s, and/or, if desired, converting a corn-pound of general formula (I) into a pharmaoe utically acceptable salt and/or, if desired, converting a salt into a free cor~ound.
The cyclization of the compound of formula (II) is preferably per-formed in presenoe of acid catalysts, such as, for example, hydrochloric acid, hydroiodic acid, sulphuric acid, formic acid, at a ter~erature ranging preferably between 20 and 120 & and in an inert solvent selected for in-stanoe from the group consisting of rnethanol, ethanol, dioxane, tetrahydro-furan, benzene, toluene, aoe tic acid and their r~xtures.
A campound of general formula (I) may be converted, as hereabove stated, into another compound of general formula (I) by known rrethods. For example, a compound of formula (I) wherein ~ is an esterified carboxy group, rnay be converted into a compound of formula (I) wherein ~ is carboxy by basic hydrolysis, using, e.g. sodium or potassium hydroxide in a solvent such as a water or a lower aliphatic alcohol and operating at a temperature ranging from the roon temperature to about 150C; the same reaction may be also carried out by treatr~nt with lithium bromide in dirnethylform~mide at a temperature higher than 50&.
A compound of general formula (I) wherein R is a carboxy group, may be canverted into a co~pound of general formula (I) wherein R is an esterified carboxy group, for example, by reaction of the alkaline salt of the acid with the suitable aIkyl or alkenvl halide, in an inert solvent such as acetone, dioxane, dimethylformamide, hexamethylphosphorotriamide at a temperature ranging from about o& to about loo&.
Also the optional salification of the compounds of formula (I) as well as the optional CQnversion of a salt into a free acid, may be perfonned according to conventional methods.
~ e compounds of formula (II) may be prepared by reacting a com-pound of formula (III) .~;'` , 7 ~ ~ ~
3 (III) OH
wherein is as defined above with a compound of formula (IV) R500C ~ (IV) ~ ~ R3 wherein ~ and R3 are as defined above and ~ is aryl, preferably phenyl, or alkyl, preferably methyl or ethyl.
The reaction between the oompound of formula (III) and the com-pound of formula (IV~ is preferably effected in an organic solvent such as e.g. methanol, ethanol, dioxane and pyridine, in presence of a strong base, such as, for instance, sodium methoxide, sodium ethoxide, sodium hydride and at a temperature ranging between the room temperature and the reflux tempera-ture.
~ n alternative methcd to prepare the compounds of form~la (II) consists in reacting a co~pound of formula (III) with a compound oE formula (V) XOC~ (V) _~_ 7~5~
wherein R2 and R3 are as defined above and X is halogen, preferably chlorine or bromine, by conventional methods, e~g. operating in an inert solvent such as benzene, toluene, dioxane at a temperature ranging from 0C to the reflux temperature, in the presence of a basic agent such as pyridine, triethyl-amine as acid acoeptor, so obtaining a compound of formula (VI) ~o0~ ~VI) wherein Rl, ~ and R3 are as defined above and then submitting the compound of formula (VI) to a rearrangement to give the compound of formula (II); the rearrangement is carried out in an inert solvent, for example, pyridine, toluene, methyl-ethyl-ketone, isopropyl alcohol, in the presence of a strong base, e.g. sodium, sodium amide, potassi~n or sodium hydroxide, potassiurn or sodiurn carbona~e, at a temperature ranging frcn the roan temperature to the reflux temperature.
~ e compounds of formula (III) may be obtained from 4-acetoxy--benzoic acid or frorn suitable 4-acetoxy-benzoic esters by means of a Fries rearrangement, using AlC13 in the absence of solvents or in the presen oe of an inert solvent such as, preferably, tetrachloroethane, tetrachlorcethylene, trichloroethylene, dichloroethane, at a teT~perature ranging from 20 & to 180&.
me compounds of formula (IV) and (V) are known compounds and may be prepared by conventional methods, starting from commercially available products, e.g. optionally substituted salicylic acid or salicylic esters.
The compounds of the invention own anti-allergic ac ivity, as is shown by the fact that they are active in the passive cutaneous anaphylaxis ,; ., 9~j7 (PC~) test in rats, according to Gcose JO and Blair A.M.J.N. (Immunology, 16, 749, 1969).
They can be therefore used in prevention and treatment of e.g.
broncllial asthma, allergic rhinitis, hay fever, urticaria and derma-tosis.
Furthermore, the campounds of the invention offer the important advantage of being highly active as anti-allergic agents also when orally administered, as is shcwn by the following Table, where the potency ratio of a compound of the invention is reported with respect to the compound 6--carboxy-2'-isopropoxy-flavone (K 10149), i.e. the most active flavone derivative an~ng those described in the British Patent Specification No.
1,479,518.
To the anti-allergic activity of the ccmpound ~ 10149 the conven-tional value 1 was given.
T A B L E
Compound Potency ratio Fiducial limits (K 10149cl) for P=0.95 . . ___ .__ 6-carboxy-2'--isopropoxy-5'- 4.65 (3.42 - 6.31) -ITs3thyl-flavone . ..... _ me anti-allergic activity was determined ~y the inhibition of the IgE-mediated PCA according to Goose J. and Blair A.M.J.N. (Loc.cit.) using homocytotropic antibodies raised in rats follcwing the method of Mota I., Imm~nology, ~ 681 (1964). The tested compounds were administered per os 15 minutes before the administration of the antigen at 3 or more dosage levels.
At least 8 rats were used per each dose.
me potency ratios were calculated according to the methcd of Finney, D.J. (1952) Statistical Method in Biological Assay, C. Griffin London, page 118.
me campounds of the inv~ntion own also spasmolytic activity, for example the comFound 6-carboxy-2'-isopropoxy-5'-methyl-flav~ne has a '7~
spasrnolytic activity on the guinea plg trachea (stimulated with acetyl-choline~ which is three tirnes higher than that of K 10149.
The cornpounds of -the invention may be administered in a conven-tional manner, ~or instance, orally and parenterally at a daily dosage pre-ferably of 0.25 to 15 rrg/kg, or by inhalation, preferably at a daily dosage of 0.25 to 100 rng, preferably 0.5 to 25 rng, or by topical application.
The nature of the pharmaceutical campositions containing the com~
pounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired rnode of administration.
The campositions rnay be formulated in the conventional rnanner with the usual ingredients. For example, the compounds of the invention may be administered in the for~n of aqueous or oily solutions or suspensions, aerosols, as well as powders, tablets, pills, gelatine capsules, syrups, or creams, or lotions for topical use.
Thus, for oral administration, the pharmaceutical cornpositions con-taining the compounds of this invention, are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as, for example, lactose, dextrose, sucrose, rnannitol, sorbitol, oe llu-lose; lubricants, for instance, silica, talc, stearic acid, rnagnesium orcalcium stearate, and/or polyethylene glycols; or they mav also contain binders, such as, for example, starches, gelatine, methylcellulose, carboxy~
methylcellulose, gum~arabic, tragacanth, polyvinylpyrrolidone, disintegrat-ing agents, such as, for instance, starches, alginic acid, alginates, sodium s~rch glyoolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as, for instanoe, lecithin, polisorbates, laurylsulphabes; and, in general, non-taxic and pharmacologically inactive substances used in pharmaoe utical formulations. Said pharmaceutical preparations may be m~nu- `
factured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
7~7 For the treatment of allergic asthma, the compounds of the inven-tion are also administered by inhalation. For such use, suitable composi-tions may oQmprise a suspension or solution of the active ingredient, prefer-ably in the form of a salt, such as the sodium salt, in water, for administra-tion by means of a conventional nebulizer. Alternatively, the c~ositions may comprise a suspension or a solution of the active ingredient in a conven-tional liquified propellant, such as, dichlorodifluoromethane or dichloro-tetrafluorcethane to be administered from a pressurized container, i.e., an aerosol dispenser. ~hen the medicament is not soluble in the propellant, it may be necessary to add a co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate, and/or a surface-active agent to the composition, in orde~ to suspend the medicament in he propellant medium and such surface-active agents may be any of those cQ~monly used for this purpose, such as non-ionic surface-active agents, e.g., lecithin.
The campounds of the invention may also be administered in the form of pcwders by means of a suitable insufflator device and in this case the fine particle sized powders of the active ingredient may be mixed with a diluent material such a lactose.
Furthermore, the compounds of this invention may also be admin-istered by intradermal or intravenous injection in the conventional manner.
In additian to the internal administration, the cQmpounds of thisinventiQn may find use in compositions for topical application, e.g. as creams, lotiQns or pastes for use in dermatological treatm~ents. For these compositions the active ingredient may be mixed with conventiQnal oleaginous or emulsifying excipients.
The following examples illustrate but do not limit the present inventiQn.
Example 1 Methyl 3-acetyl-4-hydroxy-benzoate (6 g) in dioxane (100 ml) was reacted with 2-isopropoxy-5-methyl-benzoyl chloride (10 g) in the presence of ~7~57 pyridine (10 ml) at rocn~ temperature for 16 hours. After dilution with water, the precipitate was extracted with ethyl acetate and the organic solution was washed with 5~ NaHCO3 and water and then evaporated to dryness to give methyl 3-aoetyl-4-(2'-isopropoxy-5'-methyl-benzoyloxy)-benzoate (13 g, oil, which was dissolved in methyl-ethyl-ketone (200 ml) and treated with anhydrous potassium carbonate (22 g) under stirring at the reflux temperature for 4 hours.
After cooling the reaction mixture was diluted in i oe-water and ex~racted with ethyl-aoetate: the organic solution was washed with water and evaporated to dryness. The residue (12.7 g) was crystallized from methanol, so obtaining 8.1 g of (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-5--methyl-benzoyl)-methane, m.p. = 85-86 &, which were refluxed for 15 mLnutes with 30 ml of 99~ formic acid. After oooling and dilution with water the precipitate was extracted with chloroform and the organic solution was washed with water until neutral and then evaporated to dryness. The residue was crystallized from methanol to give 6.3 g of 6-carbQmethoxy-2'-isopropoxy-5'--methyl-flavone, m.p. = 149-151&, which were hydrolyzed with 1% solution of KQH in 95% ethanol (95 ml) at reflux temperature for 30 mLnutes. After cool-ing the reaction mixture was acidified with 23% ~ICl to pH=3 and the precipi-tate was filtered off and washed with ethanol and wa~er so obtaining 5.9 gof 6-carboxy-2'-isopropoxy-5'-methyl-flavone, m.p. = 209-210C.
By proceeding analogously, the following co~lpounds were prepared:
6-carboxy-2'-isopropoxy-3' methyl-flavone, m.p. = 198-200&;
6-carboxy-2' isopropoxy-4'-methyl-flavone, m.p. = 296-298&;
6-carboxy-2'-isopropoxy-3'-propyl-flavone;
6-carboxy-2'-isopropoxy-5'-ethyl-flavone, m.p. = 203-205 &;
6-carboxy-2'-isopropoxy-5'-propyl-flavone, m.p. = 236-237&;
6-carboxy-2'-isopropoxy-5'-isopropyl-flavone;
6-carbo~y-2'-(2"-ethoxy-ethoxy)-3'-m~ethyl-flavon~, 6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone;
6-carboxy-2'-allyloxy-5'-methyl-flavone.
~L'7~57 Example 2 A solution of ~ethyl 3-acetyl-4-hydroxy-benzoate (6 g) and methyl
- The compounds of the invention have the following formula ~I) O
5' wherein ` 1 a) carboxy or b) -COOR4, wherein R4 is Cl C12 alkyl or C3-C4 alkenyl;
R2 is a') Cl-C6 alkyl, which may be unsubstituted or substituted by Cl-C2 alkoxy, or b') C3-C4 alkenyl;
. R3 is Cl-C4 alkyl-! The present invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I) with bases.
In the compounds of the invention, the alkyl, alkenyl and alkoxy groups may be branched or straight chain.
Preferably, the compounds of the present invention are those compounds wherein Rl is carboxy or carbalkoxy of 1 to 6 carbon atoms ~O in the alkoxy groupJ and R2 is a Cl-C6 alkyl. More preferably, R2 is a Cl-C4 alkyl, most preferably methyl or isopropyl, or 2-ethoxy-ethyl.
R4 is most preferably Cl-C6 alkyl, in particular ethyl, isopropyl, t-butyl or hexyl, and R3 is preferably methyl or propyl. Preferably R
is carboxy. Preferably R3 is in the 3', 4' or 5' position on the phenyl ring, most preferably in the 5'-position.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides or with organic bases, such as lysine, triethyl-amine, triethanolamine, dibenzylamine~ `
- 1- ~ ''` ' methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethyl-piperidine, N,N-diethylaminoethylamine, N-ethyl~orpholine, ~-phenethylamine, N-benzyl-~--phenethylamine, N-benzyl-N,N-dimethylam~le and the other acceptable organic amines.
Examples of particularly preferred compounds of the invention are:
6-carboxy-2'-isopropoxy-3'-methyl-flavone;
6-carboxy-2'-isopropoxy-4'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-ethyl-flavone;
10 6- OE boxy-2'-isopropoxy-3'-propyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl-flavone;
6-carboxy-2'-isopropoxy-5'-isopropyl-flavone;
6-carboxy-2'-methoxy-3'-methyl-flavone;
6-carboxy-2'-methoxy-5'-methyl-flavone;
6-carboxy-2'-methoxy-3'-propyl-flavone;
6-car~oxy-2'-(2"-ethoxy-ethoxy)-3'-methyl-flavone;
6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone;
as well as the pharmaceutically ac oeptable salts thereofr in particular the sodium salt, and the Cl-& alkyl esters thereof, in particular the ethyl, isopropyl, tert-butyl and hexyl esters.
The compounds of the invention are prepared by cyclizing a com-pound of foxmula (II) ~ o~ J Q ~
wherein ~ , ~ and R3 are as defined above or a salt thereof and/or, if desired, converting a compound of general form~la (I) into another compound of s~
general formula (I) by known metho~s, and/or, if desired, converting a corn-pound of general formula (I) into a pharmaoe utically acceptable salt and/or, if desired, converting a salt into a free cor~ound.
The cyclization of the compound of formula (II) is preferably per-formed in presenoe of acid catalysts, such as, for example, hydrochloric acid, hydroiodic acid, sulphuric acid, formic acid, at a ter~erature ranging preferably between 20 and 120 & and in an inert solvent selected for in-stanoe from the group consisting of rnethanol, ethanol, dioxane, tetrahydro-furan, benzene, toluene, aoe tic acid and their r~xtures.
A campound of general formula (I) may be converted, as hereabove stated, into another compound of general formula (I) by known rrethods. For example, a compound of formula (I) wherein ~ is an esterified carboxy group, rnay be converted into a compound of formula (I) wherein ~ is carboxy by basic hydrolysis, using, e.g. sodium or potassium hydroxide in a solvent such as a water or a lower aliphatic alcohol and operating at a temperature ranging from the roon temperature to about 150C; the same reaction may be also carried out by treatr~nt with lithium bromide in dirnethylform~mide at a temperature higher than 50&.
A compound of general formula (I) wherein R is a carboxy group, may be canverted into a co~pound of general formula (I) wherein R is an esterified carboxy group, for example, by reaction of the alkaline salt of the acid with the suitable aIkyl or alkenvl halide, in an inert solvent such as acetone, dioxane, dimethylformamide, hexamethylphosphorotriamide at a temperature ranging from about o& to about loo&.
Also the optional salification of the compounds of formula (I) as well as the optional CQnversion of a salt into a free acid, may be perfonned according to conventional methods.
~ e compounds of formula (II) may be prepared by reacting a com-pound of formula (III) .~;'` , 7 ~ ~ ~
3 (III) OH
wherein is as defined above with a compound of formula (IV) R500C ~ (IV) ~ ~ R3 wherein ~ and R3 are as defined above and ~ is aryl, preferably phenyl, or alkyl, preferably methyl or ethyl.
The reaction between the oompound of formula (III) and the com-pound of formula (IV~ is preferably effected in an organic solvent such as e.g. methanol, ethanol, dioxane and pyridine, in presence of a strong base, such as, for instance, sodium methoxide, sodium ethoxide, sodium hydride and at a temperature ranging between the room temperature and the reflux tempera-ture.
~ n alternative methcd to prepare the compounds of form~la (II) consists in reacting a co~pound of formula (III) with a compound oE formula (V) XOC~ (V) _~_ 7~5~
wherein R2 and R3 are as defined above and X is halogen, preferably chlorine or bromine, by conventional methods, e~g. operating in an inert solvent such as benzene, toluene, dioxane at a temperature ranging from 0C to the reflux temperature, in the presence of a basic agent such as pyridine, triethyl-amine as acid acoeptor, so obtaining a compound of formula (VI) ~o0~ ~VI) wherein Rl, ~ and R3 are as defined above and then submitting the compound of formula (VI) to a rearrangement to give the compound of formula (II); the rearrangement is carried out in an inert solvent, for example, pyridine, toluene, methyl-ethyl-ketone, isopropyl alcohol, in the presence of a strong base, e.g. sodium, sodium amide, potassi~n or sodium hydroxide, potassiurn or sodiurn carbona~e, at a temperature ranging frcn the roan temperature to the reflux temperature.
~ e compounds of formula (III) may be obtained from 4-acetoxy--benzoic acid or frorn suitable 4-acetoxy-benzoic esters by means of a Fries rearrangement, using AlC13 in the absence of solvents or in the presen oe of an inert solvent such as, preferably, tetrachloroethane, tetrachlorcethylene, trichloroethylene, dichloroethane, at a teT~perature ranging from 20 & to 180&.
me compounds of formula (IV) and (V) are known compounds and may be prepared by conventional methods, starting from commercially available products, e.g. optionally substituted salicylic acid or salicylic esters.
The compounds of the invention own anti-allergic ac ivity, as is shown by the fact that they are active in the passive cutaneous anaphylaxis ,; ., 9~j7 (PC~) test in rats, according to Gcose JO and Blair A.M.J.N. (Immunology, 16, 749, 1969).
They can be therefore used in prevention and treatment of e.g.
broncllial asthma, allergic rhinitis, hay fever, urticaria and derma-tosis.
Furthermore, the campounds of the invention offer the important advantage of being highly active as anti-allergic agents also when orally administered, as is shcwn by the following Table, where the potency ratio of a compound of the invention is reported with respect to the compound 6--carboxy-2'-isopropoxy-flavone (K 10149), i.e. the most active flavone derivative an~ng those described in the British Patent Specification No.
1,479,518.
To the anti-allergic activity of the ccmpound ~ 10149 the conven-tional value 1 was given.
T A B L E
Compound Potency ratio Fiducial limits (K 10149cl) for P=0.95 . . ___ .__ 6-carboxy-2'--isopropoxy-5'- 4.65 (3.42 - 6.31) -ITs3thyl-flavone . ..... _ me anti-allergic activity was determined ~y the inhibition of the IgE-mediated PCA according to Goose J. and Blair A.M.J.N. (Loc.cit.) using homocytotropic antibodies raised in rats follcwing the method of Mota I., Imm~nology, ~ 681 (1964). The tested compounds were administered per os 15 minutes before the administration of the antigen at 3 or more dosage levels.
At least 8 rats were used per each dose.
me potency ratios were calculated according to the methcd of Finney, D.J. (1952) Statistical Method in Biological Assay, C. Griffin London, page 118.
me campounds of the inv~ntion own also spasmolytic activity, for example the comFound 6-carboxy-2'-isopropoxy-5'-methyl-flav~ne has a '7~
spasrnolytic activity on the guinea plg trachea (stimulated with acetyl-choline~ which is three tirnes higher than that of K 10149.
The cornpounds of -the invention may be administered in a conven-tional manner, ~or instance, orally and parenterally at a daily dosage pre-ferably of 0.25 to 15 rrg/kg, or by inhalation, preferably at a daily dosage of 0.25 to 100 rng, preferably 0.5 to 25 rng, or by topical application.
The nature of the pharmaceutical campositions containing the com~
pounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired rnode of administration.
The campositions rnay be formulated in the conventional rnanner with the usual ingredients. For example, the compounds of the invention may be administered in the for~n of aqueous or oily solutions or suspensions, aerosols, as well as powders, tablets, pills, gelatine capsules, syrups, or creams, or lotions for topical use.
Thus, for oral administration, the pharmaceutical cornpositions con-taining the compounds of this invention, are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as, for example, lactose, dextrose, sucrose, rnannitol, sorbitol, oe llu-lose; lubricants, for instance, silica, talc, stearic acid, rnagnesium orcalcium stearate, and/or polyethylene glycols; or they mav also contain binders, such as, for example, starches, gelatine, methylcellulose, carboxy~
methylcellulose, gum~arabic, tragacanth, polyvinylpyrrolidone, disintegrat-ing agents, such as, for instance, starches, alginic acid, alginates, sodium s~rch glyoolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as, for instanoe, lecithin, polisorbates, laurylsulphabes; and, in general, non-taxic and pharmacologically inactive substances used in pharmaoe utical formulations. Said pharmaceutical preparations may be m~nu- `
factured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
7~7 For the treatment of allergic asthma, the compounds of the inven-tion are also administered by inhalation. For such use, suitable composi-tions may oQmprise a suspension or solution of the active ingredient, prefer-ably in the form of a salt, such as the sodium salt, in water, for administra-tion by means of a conventional nebulizer. Alternatively, the c~ositions may comprise a suspension or a solution of the active ingredient in a conven-tional liquified propellant, such as, dichlorodifluoromethane or dichloro-tetrafluorcethane to be administered from a pressurized container, i.e., an aerosol dispenser. ~hen the medicament is not soluble in the propellant, it may be necessary to add a co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate, and/or a surface-active agent to the composition, in orde~ to suspend the medicament in he propellant medium and such surface-active agents may be any of those cQ~monly used for this purpose, such as non-ionic surface-active agents, e.g., lecithin.
The campounds of the invention may also be administered in the form of pcwders by means of a suitable insufflator device and in this case the fine particle sized powders of the active ingredient may be mixed with a diluent material such a lactose.
Furthermore, the compounds of this invention may also be admin-istered by intradermal or intravenous injection in the conventional manner.
In additian to the internal administration, the cQmpounds of thisinventiQn may find use in compositions for topical application, e.g. as creams, lotiQns or pastes for use in dermatological treatm~ents. For these compositions the active ingredient may be mixed with conventiQnal oleaginous or emulsifying excipients.
The following examples illustrate but do not limit the present inventiQn.
Example 1 Methyl 3-acetyl-4-hydroxy-benzoate (6 g) in dioxane (100 ml) was reacted with 2-isopropoxy-5-methyl-benzoyl chloride (10 g) in the presence of ~7~57 pyridine (10 ml) at rocn~ temperature for 16 hours. After dilution with water, the precipitate was extracted with ethyl acetate and the organic solution was washed with 5~ NaHCO3 and water and then evaporated to dryness to give methyl 3-aoetyl-4-(2'-isopropoxy-5'-methyl-benzoyloxy)-benzoate (13 g, oil, which was dissolved in methyl-ethyl-ketone (200 ml) and treated with anhydrous potassium carbonate (22 g) under stirring at the reflux temperature for 4 hours.
After cooling the reaction mixture was diluted in i oe-water and ex~racted with ethyl-aoetate: the organic solution was washed with water and evaporated to dryness. The residue (12.7 g) was crystallized from methanol, so obtaining 8.1 g of (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-5--methyl-benzoyl)-methane, m.p. = 85-86 &, which were refluxed for 15 mLnutes with 30 ml of 99~ formic acid. After oooling and dilution with water the precipitate was extracted with chloroform and the organic solution was washed with water until neutral and then evaporated to dryness. The residue was crystallized from methanol to give 6.3 g of 6-carbQmethoxy-2'-isopropoxy-5'--methyl-flavone, m.p. = 149-151&, which were hydrolyzed with 1% solution of KQH in 95% ethanol (95 ml) at reflux temperature for 30 mLnutes. After cool-ing the reaction mixture was acidified with 23% ~ICl to pH=3 and the precipi-tate was filtered off and washed with ethanol and wa~er so obtaining 5.9 gof 6-carboxy-2'-isopropoxy-5'-methyl-flavone, m.p. = 209-210C.
By proceeding analogously, the following co~lpounds were prepared:
6-carboxy-2'-isopropoxy-3' methyl-flavone, m.p. = 198-200&;
6-carboxy-2' isopropoxy-4'-methyl-flavone, m.p. = 296-298&;
6-carboxy-2'-isopropoxy-3'-propyl-flavone;
6-carboxy-2'-isopropoxy-5'-ethyl-flavone, m.p. = 203-205 &;
6-carboxy-2'-isopropoxy-5'-propyl-flavone, m.p. = 236-237&;
6-carboxy-2'-isopropoxy-5'-isopropyl-flavone;
6-carbo~y-2'-(2"-ethoxy-ethoxy)-3'-m~ethyl-flavon~, 6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone;
6-carboxy-2'-allyloxy-5'-methyl-flavone.
~L'7~57 Example 2 A solution of ~ethyl 3-acetyl-4-hydroxy-benzoate (6 g) and methyl
2-methoxy-5-methyl-benzoate (12 g) in dioxane (40 ml) was 510wly added under stirring at room temperature to a suspension of sodium hydride 50% (4.5 g) in dioxane (40 ml). The mixture was kept under stirring for 3 hours at 80 C, cooled, then diluted with petroleum ether (100 ml), and filtered. m e collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl-acetate.
m e organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbc~iethoxy-benzoyl)-(2-nethoxy-5-methyl-benzoyl)-methane (7.9 g; m.p. =
145-147 &), which was then refluxed for 15 minutes with 99% formic acid (28 ml). After cooling and dilution in water and filtration, the collected precipitate was crystallized from acetone to obtain 6-carbomethoxy-2'--methoxy-5'-1nethyl-flavone (6 g), m.p. = 154-156 &, which was hydrolyzed with a 1% solution of potassiuml hydroxide (100 ml) in 95~ ethanol at reflux te~perature for 30 minutes. The mixture was cooled, acidified with 23% HCl to p~3, and the precipitate was filtered, washed with ethanol 95% and water so obtaining, after crystallization from ethanol, 6-carboxy-2'-~ethoxy-5'--methyl-flavone (5.3 g), m.p. = 246-247C.
By proceeding analogously, the following compounds were obtained:
6- OE boxy-2'-methoxy-3'-methyl-flavone;
6-carboxy-2'-methoxy-3'-propyl-flavone.
Example 3 6-car~oxy-2'-isopropoxy-5'-me-thyl-flavone (4.8 g~ in dioxane (30 ml) was treated with thionyl chloride (4 ml) at the reflux temperature for 2 hours. After cooling, the reaction mixture was evaporated to dryness and reacted with an excess of anhydrous ethanol at 50 & for 1 hour. m e mixture was concentrated to a small volume and diluted with water so obtaining, by filtration, 6-carbethoxy-2'-isopropoxy-5'-methyl-flavone (4.7 g).
.~
35~
By proceeding analo~ously, the following compounds were prepared:
6-carbethoxy-2'-isopropoxy-3'-methyl-flavone;
6-carbetho~y-2'-isopropoxy-3'-propyl-flavone;
6-carbethoxy-2'-isopropoxy-4'-methyl-flavone;
6-carbethoxy-2'-isopropoxy-5'-propyl-flavone;
6-carbethoxy-2'-methoxy-5'-methyl-flavone;
6-carbethoxy-2'-(2"-ethoxy-ethoxy)-3'-methyl-flav~ne;
6-carbethoxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Example 4 sy proceeding according to Example 3 and using the suitable aliphatic alcohols, the isopropyl ester, tert-butyl ester, hexyl ester and allyl ester of the following acids were prepared:
6-carboxy-2'-isopropoxy-3'-methyl-flavone;
6-carboxy-2'-isopropoxy-4'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl-flavone;
6-carboxy-2'-methoxy-5'-methyl-flavone;
6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Example S
6-carboxy-2'-isopropoxy-5'-methyl-flavone (3~35 g) ~as treated with a hot aqueous solution containing NaHQ03 (800 mg). m e small undissolved portion of acid was filtered off and the clear solution was concentrated under vacu~n nearly to dryness.
By treatment with acetone (250 ml) crystallization of the sodium salt of 6-carboxy-2'-isopropoxy-5l-methyl-flavone (3.15 g; m.p. > 300C) was obtained.
By proceeding analogously, the sodium salts of the following c~n-pounds were prepared:
6-carboxy-2'-isopropoxy-3'-methyl-flavone;
6-carboxy-2'-isopropoxy-4'-~ethyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl--flavone;
!; ~
t~ ~
~ 115 6- boxy-2'-methoxy-5'-methyl-flavone;
6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Example 6 A mixture of 6-carkoxy-2'-isopropoxy-5'-methyl-flavone (3.5 g) and l~-methyl-N-benzyl-an m e (1.6 g) was stirred at 120C for 30 minutes. After cooling, ethyl aoetate ~50 n~) was added and the mixture was left to crystal-lize under stirring.
After filtration and washing with ethyl aoetate 4.35 g of N-methyl--N-kenzylammonium salt of 6-ca~boxy-2'-isopropoxy-5'-m~thyl-flavone were ob-tained.
By proceeding analogously the N-methyl-N-benzylammonium salts of the follcwing acids were prepared:
6-carboxy-2'-isopr~poxy-3'-methyl-flavone;
6- boxy-2'-isopropoxy-4'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl-flavone;
6-carboxy-2'-methoxy-5'-methyl-flavane;
6-carkoxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Tablets, each weigning 150 ~g and containing 50 mg of the active substance were manufactured as follows:
CGmpositiQn (for 10,000 tablets) 6- boxy-2'-isopropoxy-5'-methyl-flavone 500 g lactose 710 g corn starch 237.5 g talc pcwder 37.5 g magnesium stearate 15 g 6-carboxy-2'-isopropoxy-5'-methyl-flavone, lactose and a half of the corn starch were mixed; the mixture was then forced through a sleve of 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml)O
Tl~e resulting paste was used to granulate the powder. The granules were --1~--:t ~
dried, comminuted on a sieve of sieve size 1.4 nm, then the remaining quantity of starch, talc and magnesium stearate were added, carefully mixed, and processed into tablets using punches of 8 mm diameter.
Example 8 Aerosol formulation:
_ _ 6-carboxy-2'-isopropoxy-5'-methyl-flav~ne 2 %
ethanol lO %
lecithin 0.2 %
mixture of dichlorodifluoromethane and dichlorotetrafluoroethane (70:30 mixture) ad lOO %
~ .' - . . ,
m e organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbc~iethoxy-benzoyl)-(2-nethoxy-5-methyl-benzoyl)-methane (7.9 g; m.p. =
145-147 &), which was then refluxed for 15 minutes with 99% formic acid (28 ml). After cooling and dilution in water and filtration, the collected precipitate was crystallized from acetone to obtain 6-carbomethoxy-2'--methoxy-5'-1nethyl-flavone (6 g), m.p. = 154-156 &, which was hydrolyzed with a 1% solution of potassiuml hydroxide (100 ml) in 95~ ethanol at reflux te~perature for 30 minutes. The mixture was cooled, acidified with 23% HCl to p~3, and the precipitate was filtered, washed with ethanol 95% and water so obtaining, after crystallization from ethanol, 6-carboxy-2'-~ethoxy-5'--methyl-flavone (5.3 g), m.p. = 246-247C.
By proceeding analogously, the following compounds were obtained:
6- OE boxy-2'-methoxy-3'-methyl-flavone;
6-carboxy-2'-methoxy-3'-propyl-flavone.
Example 3 6-car~oxy-2'-isopropoxy-5'-me-thyl-flavone (4.8 g~ in dioxane (30 ml) was treated with thionyl chloride (4 ml) at the reflux temperature for 2 hours. After cooling, the reaction mixture was evaporated to dryness and reacted with an excess of anhydrous ethanol at 50 & for 1 hour. m e mixture was concentrated to a small volume and diluted with water so obtaining, by filtration, 6-carbethoxy-2'-isopropoxy-5'-methyl-flavone (4.7 g).
.~
35~
By proceeding analo~ously, the following compounds were prepared:
6-carbethoxy-2'-isopropoxy-3'-methyl-flavone;
6-carbetho~y-2'-isopropoxy-3'-propyl-flavone;
6-carbethoxy-2'-isopropoxy-4'-methyl-flavone;
6-carbethoxy-2'-isopropoxy-5'-propyl-flavone;
6-carbethoxy-2'-methoxy-5'-methyl-flavone;
6-carbethoxy-2'-(2"-ethoxy-ethoxy)-3'-methyl-flav~ne;
6-carbethoxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Example 4 sy proceeding according to Example 3 and using the suitable aliphatic alcohols, the isopropyl ester, tert-butyl ester, hexyl ester and allyl ester of the following acids were prepared:
6-carboxy-2'-isopropoxy-3'-methyl-flavone;
6-carboxy-2'-isopropoxy-4'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl-flavone;
6-carboxy-2'-methoxy-5'-methyl-flavone;
6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Example S
6-carboxy-2'-isopropoxy-5'-methyl-flavone (3~35 g) ~as treated with a hot aqueous solution containing NaHQ03 (800 mg). m e small undissolved portion of acid was filtered off and the clear solution was concentrated under vacu~n nearly to dryness.
By treatment with acetone (250 ml) crystallization of the sodium salt of 6-carboxy-2'-isopropoxy-5l-methyl-flavone (3.15 g; m.p. > 300C) was obtained.
By proceeding analogously, the sodium salts of the following c~n-pounds were prepared:
6-carboxy-2'-isopropoxy-3'-methyl-flavone;
6-carboxy-2'-isopropoxy-4'-~ethyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl--flavone;
!; ~
t~ ~
~ 115 6- boxy-2'-methoxy-5'-methyl-flavone;
6-carboxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Example 6 A mixture of 6-carkoxy-2'-isopropoxy-5'-methyl-flavone (3.5 g) and l~-methyl-N-benzyl-an m e (1.6 g) was stirred at 120C for 30 minutes. After cooling, ethyl aoetate ~50 n~) was added and the mixture was left to crystal-lize under stirring.
After filtration and washing with ethyl aoetate 4.35 g of N-methyl--N-kenzylammonium salt of 6-ca~boxy-2'-isopropoxy-5'-m~thyl-flavone were ob-tained.
By proceeding analogously the N-methyl-N-benzylammonium salts of the follcwing acids were prepared:
6-carboxy-2'-isopr~poxy-3'-methyl-flavone;
6- boxy-2'-isopropoxy-4'-methyl-flavone;
6-carboxy-2'-isopropoxy-5'-propyl-flavone;
6-carboxy-2'-methoxy-5'-methyl-flavane;
6-carkoxy-2'-(2"-ethoxy-ethoxy)-5'-methyl-flavone.
Tablets, each weigning 150 ~g and containing 50 mg of the active substance were manufactured as follows:
CGmpositiQn (for 10,000 tablets) 6- boxy-2'-isopropoxy-5'-methyl-flavone 500 g lactose 710 g corn starch 237.5 g talc pcwder 37.5 g magnesium stearate 15 g 6-carboxy-2'-isopropoxy-5'-methyl-flavone, lactose and a half of the corn starch were mixed; the mixture was then forced through a sleve of 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml)O
Tl~e resulting paste was used to granulate the powder. The granules were --1~--:t ~
dried, comminuted on a sieve of sieve size 1.4 nm, then the remaining quantity of starch, talc and magnesium stearate were added, carefully mixed, and processed into tablets using punches of 8 mm diameter.
Example 8 Aerosol formulation:
_ _ 6-carboxy-2'-isopropoxy-5'-methyl-flav~ne 2 %
ethanol lO %
lecithin 0.2 %
mixture of dichlorodifluoromethane and dichlorotetrafluoroethane (70:30 mixture) ad lOO %
~ .' - . . ,
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of formula I
(I) wherein R1 is a) carboxy or b) -COOR4, wherein R4 is C1-C12 alkyl or C3-C4 alkenyl; R2 is a') C1-C6 alkyl, which may be unsubstituted or substituted by C1-C2 alkoxy, or b') C3-C4 alkenyl; R3 is C1-C4 alkyl; and the pharma-ceutically acceptable salts thereof, which process comprises the cyclization of a compound of formula (II) (II) wherein R1, R2 and R3 are as defined above or a salt thereof and, if required, converting a compound of general formula (I) into a pharmaceutically accept-able salt or converting a salt into a free compound of formula I.
(I) wherein R1 is a) carboxy or b) -COOR4, wherein R4 is C1-C12 alkyl or C3-C4 alkenyl; R2 is a') C1-C6 alkyl, which may be unsubstituted or substituted by C1-C2 alkoxy, or b') C3-C4 alkenyl; R3 is C1-C4 alkyl; and the pharma-ceutically acceptable salts thereof, which process comprises the cyclization of a compound of formula (II) (II) wherein R1, R2 and R3 are as defined above or a salt thereof and, if required, converting a compound of general formula (I) into a pharmaceutically accept-able salt or converting a salt into a free compound of formula I.
2. A process according to claim 1 wherein the cyclization reaction is carried out in the presence of an acid catalyst at a temperature between 20 and 120°C and in an organic solvent.
3. A process according to claim 2 wherein the acid catalyst is hydrochloric, hydriodic, sulphuric or formic acid and the organic solvent is methanol, ethanol, dioxan, tetrahydrofuran, benzene, toluene or acetic acid.
4. A process according to claim 1, 2 or 3 wherein the compound of formula (II) is obtained by reacting a compound of formula (III) (III) wherein R1 is as defined in claim 1, with a compound of formula (IV) (IV) wherein R2 and R3 are as defined in claim 1 and R5 is phenyl or alkyl.
5. A process according to claim 1, 2 or 3 wherein the compound of formula (II) is obtained by reacting a compound of formula (III) wherein R1 is as defined in claim 1, with a compound of formula (V) (V) wherein R2 and R3 are as defined in claim 1 and X is halogen, to form a compound of formula (VI) (VI) wherein R1, R2 and R3 are as defined in claim 1, and rearranging this com-pound to the compound of formula (II).
6. A process according to claim 1 wherein R1 is carboxy, R2 is C1-C6 alkyl, optionally substituted by C1-C2 alkoxy and R3 is C1-C4 alkyl.
7. A process according to claim 1 wherein R1 is carboxy, R2 is methyl, isopropyl or 2-ethoxy-ethyl and R3 is methyl or propyl.
8. A process according to claim 1 wherein R1 is carboxy, R2 is isopropyl and R3 is methyl in the 3'-, 4'- or 5'- position, ethyl in the 5'-position, n-propyl in the 3'- or 5'-position or isopropyl in the 5'-position.
9. A process according to claim 1 wherein R1 is carboxy, R2 is methyl and R3 is methyl in the 3'- or 5'-position or n-propyl in the 3'-position.
10. A process according to claim 1 wherein R1 is carboxy, R2 is 2'-ethoxyethyl and R3 is methyl in the 3'- or 5'-position.
11. A process according to claim 1 in which a compound of formula (I) obtained in which R1 is -COOR4 as defined in claim 1 is hydrolysed to give the corresponding compound of formula (I) in which R1 is carboxy.
12. A process according to claim 1 in which a compound of formula (I) obtained in which R1 is carboxy is converted into a corresponding compound of formula (I) in which R1 is -COOR4 as defined in claim 1 by esterification either directly or after conversion to the corresponding acid halide.
13. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
14. A process for preparing 6-carboxy-2'-isopropoxy-3'-methyl flavone or its sodium or N-methyl-N-benzylammonium salt which comprises refluxing (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-3-methyl-benzoyl)-methane with formic acid and hydrolysing the obtained 6-carbomethoxy-2'-isopropoxy-3'-methyl flavone and, if the sodium or N-methyl-N-benzylammonium salt is required reacting the acid so obtained with sodium bicarbonate or N-methyl-benzylamine.
15. 6-Carboxy-2'-isopropoxy-3'-methyl flavone or its sodium or N-methyl-N-benzylammonium salt whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
16. A process for preparing 6-carboxy-2'-isopropoxy-4'-methyl flavone or its sodium or N-methyl-N-benzylammonium salts which comprises refluxing (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-4-methyl-benzoyl)-methane with folmic acid and hydrolysing the obtained 6-carbomethoxy-2'-isopropoxy-4'-methyl flavone and, if the sodium or N-methyl-N-benzylammonium salt is required reacting the acid so obtained with sodium bicarbonate or N-methyl-benzylamine.
17. 6-Carboxy-2'-isopropoxy-4'-methyl flavone or its sodium or N-methyl-N-benzylammonium salt whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.
18. A process for preparing 6-carboxy-2'-isopropoxy-5'-methyl flavone or its sodium or N-methyl-N-benzylammonium salts which comprises refluxing (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-5-methyl-benzoyl)-methane with formic acid and hydrolysing the obtained 6-carbomethoxy-2'-isopropoxy-5'-methyl flavone and, if the sodium or N-methyl-N-benzylammonium salt is required reacting the acid so obtained with sodium bicarbonate or N-methyl-benzylamine.
19. 6-Carboxy-2'-isopropoxy-5'-methyl flavone or its sodium or N-methyl-N-benzylammonium salts whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.
20. A process for preparing 6-carboxy-2'-isopropoxy-5'-propyl flavone or its sodium or N-methyl-N-benzylammonium salts which comprises refluxing (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-5-propyl-benzoyl)-methane with formic acid and hydrolysing the obtained 6-carbomethoxy-2'-isopropoxy-5'-propyl flavone and, if the sodium or N-methyl-N-benzylammonium salt is required reacting the acid so obtained with sodium bicarbonate or N-methyl-benzylamine.
21. 6-Carboxy-2'-isopropoxy-5'-propyl flavone or its sodium or N-methyl-N-benzylammonium salts whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.
22. A process for preparing 6-carboxy-2'-methoxy-5'-methyl flavone or its sodium or N-methyl-N-benzylammonium salts which comprises refluxing (2-hydroxy-5-carbomethoxy-benzoyl)-(2-methoxy-5-methyl benzoyl)-methane with formic acid and hydrolysing the obtained 6-carbomethoxy-2'-methoxy-5'-methyl flavone and if the sodium or N-methyl-N-benzylammonium salt is required reacting the acid so obtained with sodium bicarbonate or N-methyl-benzylamine.
23. 6-Carboxy-2'-methoxy-5'-methyl flavone or its sodium or N-methyl-N-benzylammonium salts whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.
24. A process for preparing 6-carboxy-2'-isopropoxy-5'-ethyl flavone which comprises refluxing (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-5-ethyl-benzoyl)-methane with formic acid and hydrolysing the obtained 6-carbomethoxy-2'-isopropoxy-5'-ethyl flavone.
25. 6-Carboxy-2'-isopropoxy-5'-ethyl flavone whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT28527/76A IT1069041B (en) | 1976-10-21 | 1976-10-21 | REPLACED FALVON-6-CARBOXYLIC ACIDS |
| IT28527A/76 | 1976-10-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1117957A true CA1117957A (en) | 1982-02-09 |
Family
ID=11223738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000289123A Expired CA1117957A (en) | 1976-10-21 | 1977-10-20 | 6-carboxy-flavone derivatives and process for their preparation |
Country Status (13)
| Country | Link |
|---|---|
| AT (1) | AT356104B (en) |
| AU (1) | AU508555B2 (en) |
| BE (1) | BE859940R (en) |
| CA (1) | CA1117957A (en) |
| DE (1) | DE2746166A1 (en) |
| FR (1) | FR2368484A2 (en) |
| GB (1) | GB1542986A (en) |
| IT (1) | IT1069041B (en) |
| NL (1) | NL7711215A (en) |
| NZ (1) | NZ185454A (en) |
| SU (1) | SU795474A3 (en) |
| YU (1) | YU242577A (en) |
| ZA (1) | ZA776161B (en) |
-
1976
- 1976-10-21 IT IT28527/76A patent/IT1069041B/en active
-
1977
- 1977-10-10 YU YU02425/77A patent/YU242577A/en unknown
- 1977-10-12 GB GB42541/77A patent/GB1542986A/en not_active Expired
- 1977-10-12 AT AT729877A patent/AT356104B/en not_active IP Right Cessation
- 1977-10-12 NL NL7711215A patent/NL7711215A/en not_active Application Discontinuation
- 1977-10-13 AU AU29675/77A patent/AU508555B2/en not_active Expired
- 1977-10-14 ZA ZA00776161A patent/ZA776161B/en unknown
- 1977-10-14 DE DE19772746166 patent/DE2746166A1/en not_active Withdrawn
- 1977-10-18 NZ NZ185454A patent/NZ185454A/en unknown
- 1977-10-20 BE BE181918A patent/BE859940R/en active
- 1977-10-20 CA CA000289123A patent/CA1117957A/en not_active Expired
- 1977-10-20 SU SU772531357A patent/SU795474A3/en active
- 1977-10-21 FR FR7731797A patent/FR2368484A2/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| AU2967577A (en) | 1979-04-26 |
| IT1069041B (en) | 1985-03-21 |
| ZA776161B (en) | 1978-06-28 |
| NZ185454A (en) | 1980-08-26 |
| YU242577A (en) | 1982-08-31 |
| SU795474A3 (en) | 1981-01-07 |
| AU508555B2 (en) | 1980-03-27 |
| NL7711215A (en) | 1978-04-25 |
| DE2746166A1 (en) | 1978-04-27 |
| ATA729877A (en) | 1979-09-15 |
| FR2368484A2 (en) | 1978-05-19 |
| GB1542986A (en) | 1979-03-28 |
| AT356104B (en) | 1980-04-10 |
| BE859940R (en) | 1978-02-15 |
| FR2368484B2 (en) | 1980-06-20 |
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