Substituted flavonoid compounds, their salts, their manufacture and medicines containing these materials.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to substituted flavonoid compounds, and to these compounds used as medicaments.

Discussion of the Background

U.S. 4,602,034 discloses (oxo-4-4H-(1)-benzopyran-8-yl) alkanoic acids and their derivatives, represented by the formula: <chemistry id="chem0001" num="0001"><img file="EP0341104A2_D0001.tif" /></chemistry>wherein, in the above formula, AR is hydrogen, a phenyl radical which may or may not be substituted, thenyl, furyl, naphthyl, a lower alkyl, cycloalkyl, aralkyl radical, B is a lower alkyl radical, R₁ is hydrogen or a phenyl radical, X is hydrogen or a lower alkyl or alkoxy radical, and n is equal to 1, as well as some salts, esters, amino esters and amides of these compounds.

Fifty-seven specific examples of this class of compounds are reported in U.S. 4,602,034. These compounds are disclosed to be useful in the control of tumors, however their anticancer activity reported is limited to P388 lymphocytic leukemia and carcinoma 38 of the colon.

Rubin et al in "Lancet", 8567,11:1081-1082 (1987) disclose that flavone-8-acetic acid, one of the compounds disclosed by U.S. 4,602,034, inhibits ristocetin-induced platelet agglutination and prolongs bleeding time.

Wiltrout et al in "The Journal of Immunology", vol. 140, no. 9, pp. 1-5 (1988) disclose that flavone-8-acetic acid, the same compound discussed above, also augments systemic natural killer cell activity and synergizes with interleukin-2 (IL-2) for treatment of murine renal cancer.

In view of the wide variety of cancers found in animals, and in particular in humans, however there is a strongly felt need for other materials useful in the treatment of other types of cancers, e.g., pancreatic cancer, not to mention the fact that there is also a strongly felt need for new compounds possessing other desirable pharmaceutical properties, e.g., the property of inhibiting platelet agglutination. Such pharmaceutical properties would also include immunomodulatory properties.

SUMMARY OF THE INVENTION

Accordingly, it is an object of this invention to provide a novel class of compounds possessing anticancer activity.

It is another object of this invention to provide a novel class of compounds possessing antipancreatic cancer activity.

It is another object of this invention to provide a novel class of compounds possessing immunomodulatory properties.

It is another object of this invention to provide a novel class of compounds possessing immunomodulatory properties where these properties include the property of stimulating the production of interferon (IFN).

It is another object of this invention to provide a novel class of compounds possessing immunomodulatory properties where these properties include the property of stimulating the formation of killer cells.

It is another object of this invention to provide a novel class of compounds possessing the property of inhibiting platelet agglutination.

It is another object of this invention to provide compounds possessing very favorable threshold values in the exploitation of their properties (threshold value being defined as the difference between the lowest level of administration of the compound at which the activity is observed and the level of administration at which the compound becomes toxic to the patient).

It is another object of this invention to provide pharmaceutical compositions containing at least one of the compounds provided by this invention.

It is another object of this invention to provide a method for the treatment of a patient suffering from a condition which the compounds of the present invention are able to ameliorate or treat, by administering to this patient at least one of the compounds of the invention.

The inventors have now discovered a class of compounds which satisfy all of the above objects of the invention and other objects which will become apparent from the description of the invention given hereinbelow. These compounds have the formula (I): <chemistry id="chem0002" num="0002"><img file="EP0341104A2_D0002.tif" /></chemistry>wherein: <ul id="ul0001" list-style="none"><li>X is N, 0, Se, or S(O)_n, wherein n is 0, 1 or 2;</li><li>R₁ is H; C_1-7 alkyl; naphthyl; phenyl; phenyl substituted by at least one member selected from the group consisting of halogens, C₁-₁₂ alkyl, trifluoromethyl, hydroxyl, C₁-₆ alkoxy, (̵-C_1-6-alkylene)̵COOR₁₀, nitro, C_1-6(̵alkyl)̵carboylamino, benzoyl, C_1-6(̵alkyl)earboyl, CONR₁₀R₁₁, (where Rio and R₁₁ are each independently H or C₁-₆ alkyl), NR₁₀R₁₁, -N=N-NR₁₀R₁₁, phenyl substituted by at least one halogen atom, phenol, -O(̵C_1-6 alkyfene)̵NR₁₀R₁₁, thiazolyl, and thiazolyl substituted by C₁-₆ alkyl or amino; or R₁ is pyrridyl; pyrridyl substituted by at least one member selected from the group consisting of C_1-6 alkyls and halogens; trifluoromethyl; benzoyl or benzyl;</li><li>R₂ is H; phenyl; OH; C_1-3 alkyl; or C_1-3 alkoxy;</li><li>R₃ and R₄ are each, independently of each other, H; C₁-₆ alkyl; OH; C₁-₆ alkoxy; or halogen;</li><li>R₅ is H; C_1-3 alkyl; CN; or COOR₁₀</li><li>R₆ is H; Ci-6 alkyl; OH; (̵C_1-3 alkylene)̵CN; COORio; -O-CO(̵C_1-6 alkyl);</li></ul>or R₅ and R₆ together are a group =CR₁₀R₁₁, or a group =NOH, or a group = or a group =CHR₁₂ (where R₁₂ is phenyl, pyrridyl, phenyl substituted by at least one member selected from the group consisting of halogen atoms, trifluoromethyl and C_1-3 alkyls or pyrridyl substituted by at least one member selected from the group consisting of halogen atoms, trifluoromethyl and C_1-3 alkyls); <ul id="ul0002" list-style="none"><li>R₇ is H; CHO; COORio; -CH=CH-COORio; -P(O)(OR₁₀R₁₁)₂; NR₁₃R₁₄ (where R₁₃ and R₁₄ are independently H; phenyl; phenyl substituted by a halogen atom or a C_1-3 alkyl group or a group -COORio, -CO-0-CH(CH₃)-COORio, morpholinyl, -C(CH₂0H)₂(CH₃), imidazolinyl, (̵C_1-6 alkylene)̵OH, (̵C_1-6 al- kylene)̵COOR₁₀, or C_1-3 alkoxy, or wherein R₁₃ and R₁₄ together with the nitrogen atom to which they are both bound from an imidazole or a N(̵C_1-3 alkyl)̵piperazinyl); or</li><li>R₇ is -CO(̵C_1-6 alkyl); -S-(C_1-6 alkyl); -SH; -S-CO(̵C_1-3 alkyl); -S(̵CH₂)̵_<o>m</o> COORio (with 0 &lt; m ≦ 6); -CO-O(̵C_1-6 alkylene)-NR₁₀R₁₁; -O(̵C_1-6 alkylene)̵-NR₁₀R₁₁; -NR₁₀NR₁₀R₁₁; C₁-₆ alkyl; -CONR₁₀R₁₁; -CSNR₁₀R₁₁; thiazolyl; thiazolyl substituted by at least one member selected from the group consisting of -NH₂, C_1-3 alkyl, phenyl, and COOR₁₀; -NH-CO(̵C_1-3-alkyl); or (̵C_1-3-alkylene)̵CH(NH₂(COOH); or -CR₅R₆R₇ is a group of one of the formulae <chemistry id="chem0003" num="0003"><img file="EP0341104A2_D0003.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP0341104A2_D0004.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0341104A2_D0005.tif" /></chemistry>wherein Q is at least one member selected from the group consisting of H; COORio; phenyl; -O(̵C_1-3-alkylene)̵-COOR₁₀; C_1-3 alkyl; -O-CS-NR₁₀R₁₁; -O(̵C_1-3-alkylene)̵NR_{10R 11}; OH; C_1-3 alkoxy; and NR₁₀R₁₁; or</li><li>wherein any two of R₃, R₄, R₅, R₆ and R₇ together form a benzene ring; or a benzene ring substituted by (̵C_1-3-alkylene)̵COOR₁₀; (̵C_1-3 alkyl)̵OH, COOR₁₀, or (̵C_1-3-alkylene)̵O-CO(̵C_1-3-alkyl); or a naphthalene system; or a naphthalene system substituted by (̵C_1-3-alkylene(̵-COOR₁₀, (̵C_1-3 alky)̵OH, COORio, or (̵C_1-3-alkylene(̵O-CO(̵C_1-3 alkyl); and</li><li>physiologically acceptable salts thereof,</li><li>with the proviso that when -CR₅R₆R₇ is situated at the 8-position of formula (I) and X is 0, <ul id="ul0003" list-style="none"><li>(i) when R₂, R₃, R₄, Rs and R₆ are all H and R₇ is CN, R₁ is other than phenyl, 2-thenyl, 3,4-dimethoxy phenyl, 3-methoxy phenyl, para-tolyl, 2-furyl, 2-naphthyl, 4-methoxy phenyl, benzyl, methyl, or cyclohexyl;</li><li>(ii) when R₂, R₃, R₄, Rs and R₅ are all H and R₇ is COOH, R₁ is other than phenyl, 2-thenyl, 3-methoxy phenyl, 3,4-dimethoxy phenyl, 2-furyl, para-tolyl, 2-naphthyl, 4-methoxy phenyl, cyclohexyl, benzyl, or methyl;</li><li>(iii) when R₂, R₃, R₄, Rs and R₆ are all H and R₇ is -CO-O-CH₂CH₂ N(C₂H₅)₂, R₁ is other than phenyl, 2-thenyl, para-tolyl, or 4-methoxy phenyl;</li><li>(iv) when R₂, R₃, R₄, Rs and R₆ are all H and R₇ is <chemistry id="chem0006" num="0006"><img file="EP0341104A2_D0006.tif" /></chemistry></li></ul></li><li>R₁ is other than phenyl; <ul id="ul0004" list-style="none"><li>(v) when R₂, R₃, R₄, R₅ and R₆ are all Hand R₇ is -CO-O(̵CH₂)̵₃N(CH₃)₂; R₇ is other than phenyl;</li><li>(vi) when R₂, Rs, R₄, R₅ and R₆ are all H and R₇ is -CO-O-C₂Hs, R₁ is other than phenyl;</li><li>(vii) when R₂, R₃, R₄, Rs and R₆ are all H and R₇ is -CO-O-CH₃, Ri is other than phenyl or 2-thenyl;</li><li>(viii) when R₂, R₃, R₄, Rs and R₆ are all H and R₇ is -CO-O-Na, R₁ is other than phenyl;</li><li>(ix) when R₂, R₃, R₄, R₅ and R₆ are all H and R₇ is -CO-0-CH₂CH₂0H, R₁ is other than phenyl;</li><li>(x) when R₂, R₃, R₄, R₅ and R₆ are all H and R₇ is -CO-NH-CH₂CH₂N(C₂H₅)₂, R₁ is other than phenyl;</li><li>(xi) when R₂, R₄, Rs and R₆ are all H, R₃ is methyl at the 6-position of formula (I) (6-CH₃) and R₇ is COOH, R₁ is other than phenyl;</li><li>(xii) when R₂, R₄, Rs and R₆ are all H, R₃ is 6-CHs and R₇ is COOHs, R₁ is other than phenyl;</li><li>(xiii) when R₂, R₄, R₅ and R₆ are all H, R₃ is 6-CH₃ or 6-OCH₃ and R₇ is -CO-O-CH₂CH₂-N(CH₂H₅)₂, R₁ is other than phenyl;</li><li>(xiv) when R₂ and R₃ are H, R₄ is H or 6-CH₃, R₅ is methyl, R₆ is -COOC₂Hs, and R₇ is -COOC₂H₅, R₁ is other than phenyl;</li><li>(xv) when R₂ and R₃ are H, R₄is H or 6-CH₃, R₅ is H, R₆ is CH₃ and R₇ is COOH, R_i is other than phenyl;</li><li>(xvi) when R₂, R₃, R₄ and Rs are all H, R₆ is CH₃ and R₇ is -CO-O-CH₂CH₂N(C₂H₅)₂, R₁ is other than phenyl;</li><li>(xvii) when R₂, R₃, R₄ and R₇ are all H, R₅ and R₆ are =O, R₁ is other than phenyl;</li><li>(xviii) when R₂, R₃, R₄, and R_s are all H and -CR₅R₆R₇ is -CH=CH-COOH, -CH=_CH-COOCH₂CH₂N(C₂Hs)2, <chemistry id="chem0007" num="0007"><img file="EP0341104A2_D0007.tif" /></chemistry>-CH₂CH(COOC₂Hs)₂, or-CH₂CH₂COOH, R₁ is other than phenyl;</li><li>(xix) when R₂ and R₃ are both H, R₄ is 6-CH₃ or 6-OCH₃, R₆ and R₇ are H and Rs is CN, R₁ is other than phenyl;</li><li>(xx) when R₂ and R₃ are H, R₄ is 6-OCHs or 6-OH, and R₅ and R₆ are H and R₇ is COOH, R₁ is other than phenyl;</li><li>(xxi) when R₂ is phenyl, R₃ and R₄ are H, R₅ and R₆ are =0, or R₆ is CN or COOH, R₁ is other than phenyl.</li></ul></li></ul>

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds of the present invention have been surprisingly discovered to possess anticancer activity, in particular antipancreatic cancer activity, and better threshold characteristics as compared to available compounds, namely those disclosed in U.S. 4,602,034. These compounds have further surprisingly been discovered to also possess immunomodulatory activity, in particular they stimulate the formation of interferon and of killer cells. And, it is believed that the compounds of the present invention inhibit platelet agglutination and prolong bleeding times. These compounds are therefore useful in the treatment of cancers, e.g.., pancreatic cancers, and are believed to be useful in the suppression of clot formation.

In conjunction with Messrs. Robert H. Wiltrout and Ronald L. Hornung of the National Cancer Institute at Frederick, Maryland, U.S.A., the inventors have also found that the compounds of the present invention surprisingly potentiate the activity of interleukin-2 (IL-2).

The terms "alkyl", "alkylene", and "alkoxy" used in this document refer to linear or branched or cyclic, saturated or unsaturated alkyl, alkylene, or alkoxy groups unless otherwise specified.

The term "halogen" in this document refers to fluoro, chloro, bromo and iodo, preferably fluoro and chloro, and most preferably fluoro, unless otherwise specified.

The term "salt" is used in this document in accordance with its accepted definition to include all possibilites in which the compound of the invention is either the cationic or the anionic component of the salt. The compounds of the invention have acidic and/or basic functionalities which can of course be both present in the same molecule.

With acidic functionalities, the salts of the compounds are obtainable through reaction with either an organic or an inorganic base. Such bases include all bases known to be useful to make physiologically acceptable salts, for example, Na₂CO₃, NaHCO₃, KOH, NaOH, NH₃ and bases of the formula NR₂₇R₂₈R₂₉ where R₂₇, R₂₈ and R₂₉ are H, C₁-₆ alkyl, C₁-₆ hydroxyalkyl, etc.

With basic functionalities, the salts of the compounds are obtained by reaction with inorganic or organic acids. The acids which can be used are all the acids known to be useful to make physiologically acceptable salts, for example, HCI, HBr, HI, phosphoric acid, phosphonic acid, para-toluene sulfonic acid, formic acid, oxalic acid, fumaric acid, etc. These salt forms of the compounds are generally readily soluble in water, and permit administration of the compounds in solution to a patient.

The present invention also provides pharmaceutical compositions containing at least one of the present compounds. These pharmaceutical compositions are prepared in accordance with the general knowledge in the pharmaceutical art. They can be pharmaceutical compositions suitable for intravenous injection, oral administration, nasal administration (e.g. a nasal sprav) or eye drops. The pH of these compositions is preferably at a value compatible with human administration, e.g. the pH is at a value of between 7 and 8. These compounds can be administered following any protocol known in this art. For example, they can be administered intravenously at a dosage of 1 to 10 g m-² for a period of time of 1 to 24 hours or longer. The compounds of the present invention, when not in solution in a pharmaceutically suitable carrier, are preferably lyopholized before storage. In lypholized form they are more easily dissolved in a pharmaceutical medium.

In a preferred embodiment, when R₁ is C_1-7 alkyl, the preferred alkyl groups are Ci-3 alkyl, e.g., methyl, ethyl, n-propyl or iso-propyl. When R₁ is a substituted phenyl group, the substituents are C_1-3 alkyl, halogen, trifluoromethyl, hydroxy, Ci-3 alkoxy or nitro. Phenyl substituted by one halogen atom is particularly preferred. When R₁ is a substituted pyrridyl, the same preferred substituents for phenyl as given above, are also preferred.

The groups R₂, R₃ and R₄ are preferrably H.

Groups Rs and R₆ are preferably =CR₁₀R₁₁ with Rio=R₁₁=H.

Preferably R₇ is a group which is metabolized in vivo to leave an acidic function on the flavonoid nucleus for R₇. Accordingly, -CHO, -COORio, P(O)(OR₁₀R₁₁), -CH₂CH-COOR₁₀, and -CONR₁₀R₁₁ are preferred for R₇. In another of its preferred embodiments, the present invention provides compounds of the following formula (II) <chemistry id="chem0008" num="0008"><img file="EP0341104A2_D0008.tif" /></chemistry>wherein: <ul id="ul0005" list-style="none"><li>X is N, 0, Se, or S(O)_n where n is 0, 1 or 2;</li><li>R₁ is methyl, phenyl, substituted phenyl, biphenyl, or trifluoromethyl;</li><li>R₂ is hydrogen or OH, or</li><li>R₁ and R₂, together, form a naphthalene system fused to the hetero-ring of the flavonoid nucleus;</li><li>R₃ and R₄ are hydrogen, alkyl, C₁-₆ alkoxy hydroxy, halogen, or R₃ and R₄ together form a benzene system fused to the benzene ring of the flavonoid nucleus;</li><li>R₁₅ is hydrogen when R₁₆ is a carboxylic radical, a carbamyl radical, a mercapto radical, a carboxymethylthio radical, an aminoether radical, a phosphonic group, a substituted hydrazino, an amino group, a substituted amino group, a lower alkyl group, CONH-R₁₇, -CS-NH-R₁₈ (where R₁₇ and R₁₈ are C_1-6 alkyl), oximino, or a substituted thiazolyl, NR₁₉R₂₀, (wherein R₁₉ and R₂o are hydrogen, an aromatic group, a substituted aromatic group, an hydroxyalkyl group, a carboxymethylene group, or R₁₉ and R₂₀ together form an imidazole ring or N-methyl-piperazinyl;,</li><li>when R₁₅ is R-CH=, R₁ is hydrogen, phenyl, 3-pyrridyl, 4-pyrridyl, and R₁₆ is COOH. R₁₅ and R₁₆ can also be a tetronic moiety or a substituted tetronic moiety.</li><li>When R₁₆ is =0, R₁s is preferably -COOH, -CH=CH-COOH, -CH₃, -CH₂-Br, -CH=CH-AR, with AR being H, phenyl, 3-pyrridyl or 4-pyrridyl ; or</li><li>R₁₅ and R₁₆ can together form a tetronic moiety, a substituted thiazolyl moiety, indolizinyl, imidazo [2,1-b] thiazolyl, imidazo [1,2-a] pyridino, a tetrahydropyran which is substituted or a cyclic lactonic moiety.</li></ul>

When R₄ and R₁₅ together form a benzene system, R₁₆ is preferably COOH, or CH₂COOH.

When R₁ and R₂ together form a naphthylene system, preferably R₁₅ is hydrogen and R₁₆is COOH.

When R₃ and R₄ form a benzene system, preferably R₁₅ is hydrogen and R₁₆ is COOH.

When R₁₅ is hydroxyl, R₁₆ is preferably COOH or -CH₂CH₂COOH.

When R₁₅ is =0, R₁₆ is preferably COOH, or CH₂CH₂COOH, -CH=CH-COOH.

These compounds and their derivatives are particularily useful as antitumor agents, notably as antipancreatic cancer agents.

The compounds of formula (II) can be prepared in accordance with one of the methods of preparation generally outlined below which provides these compounds in good yields.

In a first process, a compound of (III) <chemistry id="chem0009" num="0009"><img file="EP0341104A2_D0009.tif" /></chemistry>is reacted either with (1) alkaline nitrile component followed by hydrolysis, or (2) with an amine (NR₁₉R₂₀), or (3) with triethylphosphite followed by hydrolysis, or (4) with a compound of formula R₃₂-SH, or R₃₂-OH, wherein R₃₂ can be -CH₂COOEt or -CH₂CH₂-N(C₂Hs)₂.

In another process to obtain the compounds of formula (II), the compound of formula (III) is reacted either with (1) potassium acetate followed by hydrolysis, oxidation, bromination and condensation with thiourea, thioacetamide. thiobenzamide, 2-aminothiazole, 2-methylpyridine, 2-aminothiazole, or ethoxycarbonyl acetamide.

Compounds of formula (II) can also be obtained by reacting appropriate compounds of formula (II) wherein R₁₅ is hydrogen and R₁₆ is COOH with an alpha halogenated ester followed by cyclization. Compounds of formula (II) can also be obtained by reacting appropriate compounds of formula (III) with hexamethylene tetramine and condensation of the carbonylated compound obtained with thiosemicarbazide, hydrazinoimidazole, hydroxylamine, or malonic acid.

Compounds of formula (II) can also be obtained by reacting appropriate compounds of formula (II) wherein R₁₅ is hydrogen and R₁₆ is COOH with bromine followed by potassium acetate with subsequent hydrolysis and then oxidation.

Compounds offormula (11) can also be obtained from appropriate compounds of formula (II) wherein R₁₅ is methyl and R₁₆ is COO(C₂Hs) by reaction with methyl iodide followed by hydrolysis.

Compounds of formula (II) can also be obtained by reacting compounds of formula (II) wherein R₁₅ is hydrogen and R₁₆ is CN or COOH with H₂S or ammonia in the presence of carbonyldiimidazole.

The compounds of formula (II) have been found to-surprisingly possess antitumor activity. In particular, the compounds of the invention have been discovered to possess in vitro activity against a variety of tumors in accordance with the following method.

The compounds being tested are placed on a paper disk which is set in the middle of an agar-agar base in which a culture of the selected tumor has been placed. The activity is measured by examining the inhibition of growth of the tumor being cultured. The growth is measured as a function of units (1 unit = 25 microns) which are inhibited. These units represent the surface of the growth of the tumor culture. A product is considered to represent a notable level of activity if the number of zones which are inhibited is superior to 250. The tumors used in these tests were adinocarcinomic pancreatic PO3 and. colon C08.

In the tests run by the inventors, in the inhibition of tumor P03 the compounds of formula 19, 58 and 70 at an application of 1000 micrograms per disk an inhibition value of from 900, 350 and 400, respectively. In the case of tumor C08, the compounds of formula 31,19 and 70 administered at 1000 micrograms per disk displayed an inhibition value of 500, 450 and 500, respectively.

Additionally, the compounds of the present invention demonstrated in animal studies, a surprising threshold level, i.e. a relationship between activity and toxicity which provides a therapeutic margin superior to a reference compound, in particular flavone-8-acetic acid. For example, flavone-8-acetic administered at 400 mg/kg, to a group of 10 mice, provided a mortality rate of 10 mire out of the 10 mice tested after 20 days. The compound of the present invention provided by formula 31 provided only 6 deaths out of 10 at an administration level of 400 mg/kg after 20 days. The compound of formula 29 provided 1 death out of 10 at an administration rate of 400 mg/kg after 20 days. And the compound of formula 58 resulted in no deaths of the group of 10 mice at an administration level of 400 mg/kg after 20 days.

In another of its embodiments, the present invention provides compounds of the formula (IV) <chemistry id="chem0010" num="0010"><img file="EP0341104A2_D0010.tif" /></chemistry>wherein: <ul id="ul0006" list-style="none"><li>AR₂₆ is phenyl, substituted phenyl, biphenylyl, pyridyl, or trifluoromethyl;</li><li>R₂ is hydrogen, hydroxyl, or C_1-3 alkoxy;</li><li>R₂₂ is hydrogen, hydroxyl, or C₁-₆ alkoxy;</li><li>R₂₃ is hydrogen, or fluoro;</li><li>R₂₄ is hydrogen, or hydroxy;</li><li>R₂s is hydrogen, 2-methylpyridyl, benzylidene, 4-methylenepyrridyl, or methylene; or</li><li>R₂₂ and R₂₃ together form a benzene ring fused to the flavonoid nucleus;</li><li>R₂₃ and R₂₄ form a benzene ring fused to the flavonoid nucleus; or</li><li>R₂₅ and R₂₄ form a benzene ring fused to the flavonoid nucleus.</li></ul>

These compounds possess an immunomodulating activity and in particular they stimulate the formation of interferon and of killer cells.

The compounds of (IV) can be obtained by the hydrolysis of the nitriles of formula (V): <chemistry id="chem0011" num="0011"><img file="EP0341104A2_D0011.tif" /></chemistry>wherein AR₂₆, R₂, R₂₂, R₂₃, R₂₄ and R₂₅are as defined above. The nitriles of formula (V) are obtained by the reaction of an alkali cyano compound with a compound of formula (Vl): <chemistry id="chem0012" num="0012"><img file="EP0341104A2_D0012.tif" /></chemistry>wherein AR ₂₆, R₂, R₂₂, R₂₃, R₂₄ and R₂₅ are as defined above.

With compounds of formula (IV) when R₂₅ is methylene or arylidene, the compounds are obtained by the reaction of compounds of formula (IV) wherein R₂₅ is hydrogen, with N,N,N,N-tetramethyldiaminomethane or with an aromatic aldehyde or an heteroaromatic aldehyde.

The compounds of formula (IV) have been discovered to surprisingly possess immunomodulating properties. The inventors have now discovered that the compounds of formula (IV) possessed a surprisingly high activity with the immune system and that in particular they stimulated the activity of killer cells and induce the formation of interferon (INF).

Stimulation of the activity of killer cells:

The determination of the activity of killer cells was made in accordance with the following. Mice BALB/C were treated intraveneously, either with 0.25 ml of HBSS or with 200 mg/kg of a compound of formula (IV). Twenty four hours after administration of the compound, the spleens of the animals were reduced to a state of suspension. Debris and cellular wastes are eliminated by sedimentation and the red corpuscles are lysed with distilled water. The cellular suspension obtained was then filtered over sterile gauze and washed twice with HBSS.

Different quantities of splenic cells are incubated with 1 x 10⁴ tumored cells of the type YAC-1 stained with chromium 51. The length of incubation was 4 hours at 37°C in a RPMI 1640-type medium supplemented with 50/0 of FBS, pencillin (100 U/ml) streptomycin (100 µg/ml), L-glutamine (20 mM), sodium pyruvate (1 mM), and nonessential amino acids (0.1 mM) in a buffered medium. The floating bodies are removed and a count effectuated.

The results are expressed in lytic units (ULi_o): where UL₁₀ is the quantity necessary to effectuate lysis of 1 x 10⁴ target cells. For example, it was discovered that the compound of formula 19, provided 80 UL. The compound of formula 25 provided 60 UL. The compound of formula 42 provided 110 UL. And the control animais treated with HBSS demonstrated no activity measureable in terms of lytic units (UL).

Interferon induction:

Mice BALB/C received intravenously, either 0.25 ml of HBSS or 200 mg/kg of one compound of formula (IV). Interferon activity was determined by utilizing the method of viral vesicular stomatitis. A unit of IFN is the quantity of IFN in 1 ml of sample need to reduce the viral lysis by 50%. For example, it was discovered that with the compound of formulae 19, 25 and 67, an activity of 1000 units of IFN was obtained, whereas the control animals treated with HBSS demonstrated no induction in the production of IFN.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Example 1

a) OXO-1 PHENYL-3-1H-NAPHTO (2,1-b) PYRAN-5-ACETONITRILE

C₂₁H₁₃NO₂ MW=311,344

A mixture of 8.2 g (0.0224 mole) of bromomethyl-5-phenyl-3-[1H]-naphto(2.1-b)pyranol-1, of 4.9 g (0.031 mole) of tetraethylammonium cyanide in 250 ml of dichloroethane is stirred for 18 hours at room temperature. Evaporation is then carried out in a vacuum, the mixture is solidified using water, and the solid thus formed is filtered and dried. Weight obtained: 6.9 g (Yield: 98%); PF_k=260°_C; IR: Vc=o=7039 cm-¹, Vc= N; 2160 and 2220 cm-1.

b) OXO-1-PHENYL-3-(1H)-NAPHTO (2.1-b) PYRAN-5-ACETIC ACID

C₂₄H₁₄O₄ MW=330.34 [Formula 1]

<chemistry id="chem0013" num="0013"><img file="EP0341104A2_D0013.tif" /></chemistry>

A mixture of 6.9 g (0.022 mole) of oxo-1-phenyl-3-[1H]-naphto(2.1-b)pyran-5-aceto-nitrile, 50 ml of acetic acid, 50 ml of water and 50 ml of H₂S0₄ in concentrated form is heated by reflux. The medium is then poured into water and frozen; the solid thus formed is centrifuged, dried, recrystallized in acetic acid. Weight obtained: 2.1 g (Yield: 28%); PF_G=291-293°C; IR: Vc=o (acid)=1700 cm-¹, Ve=o (pyrone)=1638 cm-^1; NMR (DMSO)δ in ppm in relation to TMS: 2H at 4.03 (s), 1H at 7.1 (s), 9H at 7.3 to 8.3 (n), 1H at 12.5 (exchangeable).

Elemental analysis

<tables id="tabl0001" num="0001"><img file="EP0341104A2_D0014.tif" /></tables>

Using the same technique the following compounds are prepared:

OXO-4-PHENYL-2-4H-NAPHTO (2.3-b) PYRAN-1-ACETIC ACID

C₂₄H₁₄O₄ MW= 330.34 [Formula 2]

<chemistry id="chem0014" num="0014"><img file="EP0341104A2_D0015.tif" /></chemistry>

PF_G = 276-288°C; IR: Vc=o (acid) = 1720 cm^-1, VC=o (pyrone)=7610 cm-¹; NMR (DMSO)8 in ppm in relation to TMS: 2H at 4.4 (s), 1H at 6.97 (s), 9H at 7.2 to 8.5 (m), 1H at 8.62 (s), 1H at 12,5 (exchangeable).

Elemental analysis

<tables id="tabl0002" num="0002"><img file="EP0341104A2_D0016.tif" /></tables>

OXO-4-PHENYL-2-4H-NAPHTO (1.2-b) PYRAN-10-ACETIC ACID

C₂₁H₁₄O₄ MW 330.34 [Formula 3] <chemistry id="chem0015" num="0015"><img file="EP0341104A2_D0017.tif" /></chemistry>

PF_G=259-261°C; IR: Vc=0 (acid)=1710 cm-¹, Vc=o (pyrone)=7630 cm-¹; NMR (DMSO)8 in ppm in relation to TMS: 2H at 4.45(s), 1 H at 6.9 (s), 10H at 7.3 to 8.3 (m), 1H at 12.2 (exchangeable).

Elemental analysis

<tables id="tabl0003" num="0003"><img file="EP0341104A2_D0018.tif" /></tables>

METHOXY-3-OXO-4-PHENYL-2H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₄O₅ MW=310.292 (Formula 4] <chemistry id="chem0016" num="0016"><img file="EP0341104A2_D0019.tif" /></chemistry>

PF_G=187-192°C; IR Vc=o (acid)=1720 cm^-1, Vc=o (pyrone)=1610 cm-¹; NMR (DMSO)δ in ppm in relation to TMS: 3H at 3.8 (s), 2H at 4 (s), 8H at 7.4 to 8.3 (m), 1H 11.9 (exchangeable).

Elemental analysis

<tables id="tabl0004" num="0004"><img file="EP0341104A2_D0020.tif" /></tables>

METHOXY-5-OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₄O₅ MM=310.292 [Formula 5] <chemistry id="chem0017" num="0017"><img file="EP0341104A2_D0021.tif" /></chemistry>

PFG=245-248°C; IR vc=o (acid)=1720 cm^-1, Vc = o (pyrone) 1640 cm-¹; NMR (DMSO)δ in ppm in relation to TMS: 5H at 4 (s), 1H at 7.2 (s), 7H at 7.7 to 8.7 (m), 1H at 12.2 (exchangeable).

Elemental analysis

<tables id="tabl0005" num="0005"><img file="EP0341104A2_D0022.tif" /></tables>

(METNOXY-2-F'WENYL)-2-OXO-4-4H-(1) BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₄O₅ MW=310.292 [Formula 6]

<chemistry id="chem0018" num="0018"><img file="EP0341104A2_D0023.tif" /></chemistry>

PF_G=203-205°C; IR vc=o (acid)=1730 cm-¹; Vc=o (pyrone)=1610 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 5H at 4 (s), 1H at 7 (s), 7H at 7.1 to 8.1 (m), 1H at 12.8 (exchangeable).

Elemental analysis

<tables id="tabl0006" num="0006"><img file="EP0341104A2_D0024.tif" /></tables>

HYDROXY-3-OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-AGETIG ACID

C₁₇H₁₂O₃ MW=296.266 [Formula 7] <chemistry id="chem0019" num="0019"><img file="EP0341104A2_D0025.tif" /></chemistry>

PF_G=221-223°C; IR Vc=o (acid)=1700 cm^-1, Vc=0 (pyrone)=1610 cm-¹; NMR (DMSO)8 in ppm in relation to the TMS; 2H at 4 (s), 8H) at 7.3-8.4 (m), 1H at 9.6 (exchangeable), 1H at 12.3 (exchangeable).

Elemental analysis

<tables id="tabl0007" num="0007"><img file="EP0341104A2_D0026.tif" /></tables>

HYDROXY-5-OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₅ MW=296.266 [Formula 8]

<chemistry id="chem0020" num="0020"><img file="EP0341104A2_D0027.tif" /></chemistry>

PF_G=233-238°C; IR Vc=o (acid)=1700 cm^-1, Vc=0 (pyrone)=1680 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 3.8 (s), 1H at 6.8 (d), 1H at 7.1 (s), 6H at 7.4 to 8.2 (m), 1H at 42.4 (exchangeable).

Elemental analysis

<tables id="tabl0008" num="0008"><img file="EP0341104A2_D0028.tif" /></tables>

HYDROXY-7-OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₅ MW=296.266 [Formula 9] <chemistry id="chem0021" num="0021"><img file="EP0341104A2_D0029.tif" /></chemistry>

PF_G=227-238°C; IR Vc=o (acid)=1700 cm-¹, Vo=0 (pyrone)=1630 cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 2H at 3.8 (s), 8H at 6.8 to 8.2 (m), 2H at 10.8 to 11.1 (exchangeable).

Elemental analysis

<tables id="tabl0009" num="0009"><img file="EP0341104A2_D0030.tif" /></tables>

(HYDROXY-2-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₃ MW=296.266 [Formula 10]

<chemistry id="chem0022" num="0022"><img file="EP0341104A2_D0031.tif" /></chemistry>

PF_G=288-292°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1640 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 1H at 7 (S), 1H at 7 (s), 7H at 7.2 to 8.2 (m), 2H at 10.8 to 12.9 (exchangeable).

Elemental analysis

<tables id="tabl0010" num="0010"><img file="EP0341104A2_D0032.tif" /></tables>

(HYDRQXY-3-PHENYL)-2-OXO-4-4H-(1)-BENZORYRAN-8-ACETIC ACID

C₁₇H₁₂O₅^MW=296.266 [Formula _11]<chemistry id="chem0023" num="0023"><img file="EP0341104A2_D0033.tif" /></chemistry>

PF_G=259-288°C; IR Vc=o (acid)=1720 cm-¹, Vc=0 (pyrone)=1630 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4.1 (s), 1H at 7 (s), 7H at 7.1 to 8.2 (m), 1H at 10 at 10 (exchangeable), 1H at 12.8 (exchangeable).

Elemental analysis

<tables id="tabl0011" num="0011"><img file="EP0341104A2_D0034.tif" /></tables>

(HYDROXY-4-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₅ MW=296.266 [Formula 12]

<chemistry id="chem0024" num="0024"><img file="EP0341104A2_D0035.tif" /></chemistry>

PF_G=261-268°C; IR Vc=o (acid)=1690 cm-¹, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 3.8 (s), 8H at 6.7 to 8 (m), 1H at 10.3 (exchangeable), 1H at 12.2 (exchangeable).

Elemental analysis

<tables id="tabl0012" num="0012"><img file="EP0341104A2_D0036.tif" /></tables>

CHLOROHYDRATE OF (DIETHYLAMINOETHOXY-3-PHENYL)-2-OXO-4-4H-BENZOPYRAN-8-ACETIC ACID

C₂₃H₂₆CINO₃ MW=431.903 [Formula 13] <chemistry id="chem0025" num="0025"><img file="EP0341104A2_D0037.tif" /></chemistry>

PF_G=17₆-179°C; IR Vc=o (acid)=1₇₂₀ cm-¹, Vc=0 (pyrone)=1₆₄₀ cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 3H at 1..4 (t), 11 H at 3 to 4.6 (m, of which 1H is interchangeable), 1 H at 7.1 (s), 6H at 7.2 to 8.1 (m), 1H at 1.3.2 (interchangeable).

Elemental analysis

<tables id="tabl0013" num="0013"><img file="EP0341104A2_D0038.tif" /></tables>

(PHENOXY-2-PHENYL-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIG ACID

C₂₃H₁₆O₃ MW=372.38 (Formula 14]

<chemistry id="chem0026" num="0026"><img file="EP0341104A2_D0039.tif" /></chemistry>

PF_G=218-220°C; IR Vc=o (acid)=1680 cm^-1, Vc=0 (pyrone)=1640 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 2H at 3.8 (s), 13H at 6.8 to 8 (m), 1H at 12.6 (interchangeable)

Elemental analysis

<tables id="tabl0014" num="0014"><img file="EP0341104A2_D0040.tif" /></tables>

FLUORO-6-OXO-4-PHENYL,-2-4H-(1)-EENZOPYRAN-8-AGERTIG ACID

C₁₇H₁₁FO₄ MW=298.26 [Formula 15] <chemistry id="chem0027" num="0027"><img file="EP0341104A2_D0041.tif" /></chemistry>

PF_G=225-239°C: IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=164₀ cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 3H at 3 to 4 (m, of which 1 H is interchangeable), 1 H at 7 (s), 7H at 7,1H at 8.4 (m).

Elemental analysis

<tables id="tabl0015" num="0015"><img file="EP0341104A2_D0042.tif" /></tables>

(FLUORO-2-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁FO₄ MW=298.26 [Formula 16]

<chemistry id="chem0028" num="0028"><img file="EP0341104A2_D0043.tif" /></chemistry>

PF_G=193-199°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1610 cm-¹ NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 6.7 (s), 7H at 7.2 to 8.4 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0016" num="0016"><img file="EP0341104A2_D0044.tif" /></tables>

(FLUORO-PHENYL)-2-OXO-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁FO₄ MW=298.26 [Formula 17] <chemistry id="chem0029" num="0029"><img file="EP0341104A2_D0045.tif" /></chemistry>

PF_G=215-217°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1640 cm-¹; NMR (CF₃COOD)δ in ppm in relation to TMS; 2H at 4 (s), 8H at 7 to 9 (m).

Elemental analysis

<tables id="tabl0017" num="0017"><img file="EP0341104A2_D0046.tif" /></tables>

(FLUORO-3-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁FO_{4 MW}=₂₉₇.₂₆ [Formula 181

<chemistry id="chem0030" num="0030"><img file="EP0341104A2_D0047.tif" /></chemistry>

PF_G=201-203°_C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1₆₄₀ cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 7.1 (s), 7H at 7.2 to 8 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0018" num="0018"><img file="EP0341104A2_D0048.tif" /></tables>

PHENYL-4-PHENYL)2-OXO-4-4H-(1),BENZOPYRAN-8-ACETIC ACID

C₂₃H₁₁6O₄ MW⁼356.36 [Formula _19]<chemistry id="chem0031" num="0031"><img file="EP0341104A2_D0049.tif" /></chemistry>

PF_G=₂₂₉-₂₃₁°_C; IR Vc=_o (acid)=₁₇₁₀ cm^-1, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 1H at 7 (s), 12H at 7.2 to 8.4 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0019" num="0019"><img file="EP0341104A2_D0050.tif" /></tables>

(CHLORO-4-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁CIO₄ MW=314.71 [Formula 20]

<chemistry id="chem0032" num="0032"><img file="EP0341104A2_D0051.tif" /></chemistry>

PF_G=238-242°C; IR Vc=o (acid)=1720 cm-¹, Vc=0 (pyrone)=1620 cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 7 (s), 7H at 7.2 to 8.2 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0020" num="0020"><img file="EP0341104A2_D0052.tif" /></tables>

(CARBOXY-4-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₂O₆ MW=324.27 [Formula 21] <chemistry id="chem0033" num="0033"><img file="EP0341104A2_D0053.tif" /></chemistry>

PF_G=312-314°C; IR Vc=o (acid)=1700-1120; cm^-1, Vc=0 (pyroner=1640 cm-¹.

Elemental analysis

<tables id="tabl0021" num="0021"><img file="EP0341104A2_D0054.tif" /></tables>

(FLUORO-2-PHENYL)-4-PHENYL)-2-OXO-4-4H-(1): BENZOPYRAN-8-ACETIC ACID

C₂₃H₁₅FO₄ MW=374.35 [Formula 22]

<chemistry id="chem0034" num="0034"><img file="EP0341104A2_D0055.tif" /></chemistry>

PF_G=226-228°_C; IR Vc=o (acid)=1720 cm-¹, Vc=0 (pyrorre)=1630 cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (S), 12H at 7 to 8.4 (m), 1H to 12.8 (interchangeable).

Elemental analysis

<tables id="tabl0022" num="0022"><img file="EP0341104A2_D0056.tif" /></tables>

(NITRQ-2-PHENI!L)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁NO₄ MW⁼325.28 [Formula 23] <chemistry id="chem0035" num="0035"><img file="EP0341104A2_D0057.tif" /></chemistry>

PF_G=180-₁82°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1640 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 6.8 (s), 7H at 7.3 to 8.3 (m), 1H at 12.8 (interchangeable).

Elemental analysis

<tables id="tabl0023" num="0023"><img file="EP0341104A2_D0058.tif" /></tables>

(NITRO-3-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁NO₆ MW=325.28 [Formula 24]

<chemistry id="chem0036" num="0036"><img file="EP0341104A2_D0059.tif" /></chemistry>

PF_G=203-208°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1630 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 7.3 (s), 7H at 7.4 to 9 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0024" num="0024"><img file="EP0341104A2_D0060.tif" /></tables>

(NlTRO-4-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁NO₆ MW=325.28 [Formula 25] <chemistry id="chem0037" num="0037"><img file="EP0341104A2_D0061.tif" /></chemistry>

PF_G=242-244°C; IR Vc=o (acid)=1720 cm-¹, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 7 (s), 7H at 7.2 to 8.3 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0025" num="0025"><img file="EP0341104A2_D0062.tif" /></tables>

(AMINO-3-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₃NO₄ MW=295.28 [Formula 26]

<chemistry id="chem0038" num="0038"><img file="EP0341104A2_D0063.tif" /></chemistry>

PF_G=227-139°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1630 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 9H at 6.8 to 8 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0026" num="0026"><img file="EP0341104A2_D0064.tif" /></tables>

(AMINO-2-4-PHENYL)-2-OXO-4-4H-(1)-BENZOPYRAN-8-AGETIC ACID

C₁₇H₁₃NO₄ MW⁼295.28 [Formula _27]<chemistry id="chem0039" num="0039"><img file="EP0341104A2_D0065.tif" /></chemistry>

PFG=189°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1620 cm^-1.

Elemental analysis

<tables id="tabl0027" num="0027"><img file="EP0341104A2_D0066.tif" /></tables>

OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₄ MW=280.28 [Formula 28]

<chemistry id="chem0040" num="0040"><img file="EP0341104A2_D0067.tif" /></chemistry>

PF_G=240-242°C; IR Vc=o (acid)=1740 cm-¹, Vc=0 (pyrone)=1640 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 1H at 7 (s), 8H at 7.2 to 8.4 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0028" num="0028"><img file="EP0341104A2_D0068.tif" /></tables>

OXO-4-PHENYL-2-4H-(1) BENZOPYRAN-7-ACETIC ACID

C₁₇R₁₂O₄ MW=280.28 [Formula 29] <chemistry id="chem0041" num="0041"><img file="EP0341104A2_D0069.tif" /></chemistry>

PF_G=237-239°C; IR Vc=o (acid)=1740 cm^-1, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)δ in ppm relation to TMS; 2H at 3.7 (s), 1H at 6.8 (s), 7H at 7.2 to 8 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0029" num="0029"><img file="EP0341104A2_D0070.tif" /></tables>

TRIFLUOROMETHYL-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC AGID

C₁₂H₇F₃O₄ MW=272.17 [Formula 30]

<chemistry id="chem0042" num="0042"><img file="EP0341104A2_D0071.tif" /></chemistry>

PF_G=141-143°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1650 cm^-1.

Elemental analysis

<tables id="tabl0030" num="0030"><img file="EP0341104A2_D0072.tif" /></tables>

OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₃S MW⁼296.34 [Formula 31] <chemistry id="chem0043" num="0043"><img file="EP0341104A2_D0073.tif" /></chemistry>

PF_G=198-200°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1610 cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 1H at 7.3 (s), 7H at 7.3 to 8.4 (m), 1H at 12.5 (s), 1H at 7.3 (s), 7H at 7.3 to 8.4 (m), 1 H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0031" num="0031"><img file="EP0341104A2_D0074.tif" /></tables>

OXO-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₅S MW=328.34 [Formula 32]

<chemistry id="chem0044" num="0044"><img file="EP0341104A2_D0075.tif" /></chemistry>

PF_G=184-187°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1660 cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 1H at 7 (s), 7H at 7.2 to 8.2 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0032" num="0032"><img file="EP0341104A2_D0076.tif" /></tables>

OXO-4-PHENYL-2-DIHYDRO-1-4-QUINOLINE-8-ACETIC ACID

C₁₇H₁₃NO₃ MW=279.2.9 [Formula 33] <chemistry id="chem0045" num="0045"><img file="EP0341104A2_D0077.tif" /></chemistry>

PF_G=236-238°C; IR Vc=o (acid)=1680 cm^-1, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 8H at 7 to 8.3 (m), 1H at 8.5 (interchangeable).

Elemental analysis

<tables id="tabl0033" num="0033"><img file="EP0341104A2_D0078.tif" /></tables>

OXO-4-PHENYL-2-4H-(1)-BENZOSELENOPYRAN-8-ACETIC ACID

C₁₇H₁₂O₃Se MW=343.24 [Formula 34]

<chemistry id="chem0046" num="0046"><img file="EP0341104A2_D0079.tif" /></chemistry>

PF_G=182-184°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrone)=1600 cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 8H at 7.4 to 8.6 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0034" num="0034"><img file="EP0341104A2_D0080.tif" /></tables>

OXO-7-7H-BENZO(c)XANTHENYL-11-ACETIC ACID

C₁₉H₁₂O₄ MW=304.31 [Formula 35] <chemistry id="chem0047" num="0047"><img file="EP0341104A2_D0081.tif" /></chemistry>

PF_G=270-272°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1620 cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4 (s), 9H at 7.4 to 9.2 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0035" num="0035"><img file="EP0341104A2_D0082.tif" /></tables>

OXO-4-7-7H-DIBENZO(c,h)XANTHENYL-1-ACETIC ACID

C₂₃H₁₄O₄ MW=354.37 [Formula 36]

<chemistry id="chem0048" num="0048"><img file="EP0341104A2_D0083.tif" /></chemistry>

PF_G=276-278°C; IR Vc=o (acid)=1700 cm^-1, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 2H at 4 (s), 11H at 7.4 to 8.8 (m), 1H at 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0036" num="0036"><img file="EP0341104A2_D0084.tif" /></tables>

CARBOXYMETHYL-4-PHENYL)-2-4H-(1) BENZOPYRANONE-4

C₁₇H₁₂O₄ MW₌280.17 [Formula 3_7]<chemistry id="chem0049" num="0049"><img file="EP0341104A2_D0085.tif" /></chemistry>

PF_G=204°C; IR Vc=o (acid)=1720 cm^-1, Vc=0 (pyrone)=1640 cm-¹.

Elemental analysis

<tables id="tabl0037" num="0037"><img file="EP0341104A2_D0086.tif" /></tables>

(CARBOXYMETHYL-3-PHENYL)-2-4H-(1) BENZOPYRANONE-4

C₁₇H₁₂O₄ MW=280.27 [Formula 38]

<chemistry id="chem0050" num="0050"><img file="EP0341104A2_D0087.tif" /></chemistry>

PF_G=181-183°C; IR Vc=o (acid)=1720 cm-¹, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 3.8 (s), 1H at 7 (s), 8H at 7.4 to 8.2 (m), 1H at 12.4 (interchangeable).

Elemental analysis

<tables id="tabl0038" num="0038"><img file="EP0341104A2_D0088.tif" /></tables>

(CARBOXYMETHYL-2-PHENYL)-2-4H-(1) BENZOPYRANONE-4

<chemistry id="chem0051" num="0051"><img file="EP0341104A2_D0089.tif" /></chemistry>

PF_G = 179-181°C; IR Vc=o (acid) = 1730 cm-¹, Vc=0 (pyrone)=1630 cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 2H at 3.9 (s), 1H at 6.6 (s), 8H at 7.2 to 8.2 (m), 1H at 12.4 (interchangeable).

Elemental analysis

<tables id="tabl0039" num="0039"><img file="EP0341104A2_D0090.tif" /></tables>

((OXO-4-PHENYL-2-4H-(1) BENZOPYRAN-8-YL) METHYL) PHOSPHONATE OF DIETHYL

<chemistry id="chem0052" num="0052"><img file="EP0341104A2_D0091.tif" /></chemistry>

PF_G = 107-109°C; IR Vc=0 (pyrone) = 1640 cm^-1; NMR (CDCl₃)δ in ppm in relation to TMS; 6H at 1.2 (d), 2H at 3.57 (d), 4H at 3.7 to 4.4 (m), 1H at 6.85 (s), 8H at 7.2 to 8.4 (m).

Elemental analysis

<tables id="tabl0040" num="0040"><img file="EP0341104A2_D0092.tif" /></tables>

((OXO-4-PHENYL-2-4H-(1) BENZOPYRAN-8-YL) METHYL) PHOSPHONIC ACID

C₁₆H₁₃O₅ MW=316.24 [Formula _41]<chemistry id="chem0053" num="0053"><img file="EP0341104A2_D0093.tif" /></chemistry>

PF_G=₃₃1-₃₃₄°_C; IR V OH = 3400 to 2200 cm-¹, Vc=0 (pyrone)=1620 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 3.45 (d), 1H at 7.03 (s), 8H at 7.2 to 8.4 (m), 2H at 9.7 (interchangeable).

Elemental analysis

<tables id="tabl0041" num="0041"><img file="EP0341104A2_D0094.tif" /></tables>

Example 2

(PHENYL-2-OXO-4-4H-(1) BENZOPYRAN-8-YL)-2-ACRYLIC ACID

C₁₈H₁₂O₄ MW=292.27 [Formula 42]

<chemistry id="chem0054" num="0054"><img file="EP0341104A2_D0095.tif" /></chemistry>

8.4 g (0.03 mole) of oxo-4-phenyl-2-4M-{4}-benzopyran-8-acetic and 81 ml of N,N,N',N' tetramethyldiamino- methane are mixed. 81 ml acetic acid are then added to the reaction mixture cooled in an ice bath. The temperature rises to 65°C, then falls to 20°C. Stirring continues for one (1) hour, then the mixture is poured into water. The solid formed is centrifuged, dried, and recrystallized in acetic acid. Weight obtained: 3.4 g (yield: 38.6%); PF_G = 240-247°C; IR Vc=o (acid) = 1689 cm^-1, Vc = 0 (pyrone) =₁₆₂0 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 2H at 6.3 (d), 1H at 7 (s), 8H at 7.3 to 8.2 (m), 1H at 13 (interchangeable).

Elemental analysis

<tables id="tabl0042" num="0042"><img file="EP0341104A2_D0096.tif" /></tables>

Example 3

PHENYL-3-(PHENYL-2-OXO-4-4H-[1] BENZOPYRAN-8-YL)-2-ACRYLIC ACID

C₂₄H₁₆O₄^MW⁼368.36 [Formula 43]

<chemistry id="chem0055" num="0055"><img file="EP0341104A2_D0097.tif" /></chemistry>

A mixture of 9.2 g (0.087 mole) of benzaldehyde, 16.8 g (0.06 mole) of oxo-4-phenyl-2-4H-[1]-benzopy- ranacetic acid, 30.9 ml of acetic anhydride, and 8.32 ml of triethylamine is refluxed for ten (10) minutes. The mixture is then poured into 30 ml of water. The precipitate formed is centrifuged, dried and recrystallized in acetic acid. Weight obtained: 9.8 g (yield: 44.3%); PF_G=2₁₅-220°C; IR Vc=o (acid)=1680 cm^-1, Vc=0 (pyrone) = 1630 cm^-1 NMR (DMSO)8 in ppm in relation to TMS; 15H at 6.8 (m), 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0043" num="0043"><img file="EP0341104A2_D0098.tif" /></tables>

Using the same technique, the following compounds were prepared:

(BROMO-2-PHENYL)-3-(PHENYL-2-OXO-4-4H-[1] BENZOPYRAN-8-YL]-3-ACRYLIC ACID

C₂₄H₁₅BrO₄ MW=447.27 [Formula 44] <chemistry id="chem0056" num="0056"><img file="EP0341104A2_D0099.tif" /></chemistry>

PF_G=2₁₇-₂₁₉°C; IR Vc=o (acid)=1680 cm-¹, Vc = 0 (pyrone)=1640 cm-¹; NMR (DMSO)8 in ppm in relation to TMS; 14H at 6.8 to 8.1 (m), 1H at 12.8 (interchangeable).

Elemental analysis

<tables id="tabl0044" num="0044"><img file="EP0341104A2_D0100.tif" /></tables>

(PYRIDINYL-4)-3-(PHENYL-2-OXO-4-4H-[1] BENZOPYRAN-8-YL)-3-ACRYLIC ACID

C₂₃H₁₅NO₄ MW=369.36 [Formula 45]

<chemistry id="chem0057" num="0057"><img file="EP0341104A2_D0101.tif" /></chemistry>

PF_G=272-283°C; IR Vc=o (acid)=1700 cm-¹, Vc=0 (pyrane) = 1640 cm-¹; NMR (DMSO)δ in ppm in relation to TMS; 14H at 6.8 to 8.4 (m), 1H at 12.8 (interchangeable).

Elemental analysis

<tables id="tabl0045" num="0045"><img file="EP0341104A2_D0102.tif" /></tables>

(PYRIDINYL-3)-3-(PHENYL-2-OXO-4-4H-[1] BENZOPYRAN-3-ACRYLIG ACID

C₂₃H₁₅NO₄ MW=369.36 [Formula ₄6]

<chemistry id="chem0058" num="0058"><img file="EP0341104A2_D0103.tif" /></chemistry>

PF_G = 118-124°C; IR Vc=o (acid) = 1720 cm^-1, Vc = 0 (pyrone) = 1630 cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 14H at 7 to 8.5 (m), 12.5 (interchangeable).

Elemental analysis

<tables id="tabl0046" num="0046"><img file="EP0341104A2_D0104.tif" /></tables>

Example 4

CHLOROHYDRATE OF [(METHYL-4-PIPERAZINYL) METHYL]-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₂₁H₂₃ClN₂O₂ MW⁼370.87 [Formula 47]

<chemistry id="chem0059" num="0059"><img file="EP0341104A2_D0105.tif" /></chemistry>

18.9 g (0.06 mole) of Bromomethyl-8-oxo-4-phenyl-2-4H-[1] Benzopyranone, 6.57 g (0.066 mole) of N-methyl piperazine, and 8.3 g (0.06 mole) of potassium carbonate in 200 ml of toluene are refluxed for 8 hours. Insolubles are filtered, and the solvent is evaporated in a vacuum. The solid obtained is recrystallized in hexane. Weight obtained: 9.69 g. PF_G = 139°C; IR Vc=0 (pyrone) = 1640 cm^-1. Using an HCI treatment in CHCl₃, the chlorohydrate is obtained: PF_G=244-246°C.

Elemental analysis

<tables id="tabl0047" num="0047"><img file="EP0341104A2_D0106.tif" /></tables>

Using the same technique, the following compounds were prepared:

BROMOHYDRATE OF N[IMIDAZOLINYL-2], N [(OXO-4-PHENYL-2-4H-[1] BENZOPYRAN-8-YL) METHYL]-DICHLORO-2-6-ANILINE

C₂₅H₂₀BrCl₂N₃O₂ MW = 545.26 [Formula 48]

<chemistry id="chem0060" num="0060"><img file="EP0341104A2_D0107.tif" /></chemistry>

PF_G = 289-290°C; IR Vc=o (pyrons) = 1640 cm^-1; V NH = 3000-3200 cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 4H at 3.4 (s), 2H at 5.5 (s), 1H at 7 (s), 11H at 7.2 to 8.3 (m), 2H at 8.5 to 9.5 (interchangeable).

Elemental analysis

<tables id="tabl0048" num="0048"><img file="EP0341104A2_D0108.tif" /></tables>

[(OXO-4-PHENYL-2-4H-(1) BENZOPYRAN-8-YLO METHYL AMINO]-4-BENZOIC ACID

C₂₃H₁₇NO₄ MW=371.396 [Formula 49]

<chemistry id="chem0061" num="0061"><img file="EP0341104A2_D0109.tif" /></chemistry>

PF_G = 269-271°C; IR Vc=o (acid)=1710 cm^-1, Vc=0 (pyrone)=16₄₀ cm^-1; NMR (DMSO)8 in ppm in relation to TMS; 2H at 4.8 (m), 13H at 6.9 to 8.27 (m), 1H at 12.6 interchangeable).

Elemental analysis

<tables id="tabl0049" num="0049"><img file="EP0341104A2_D0110.tif" /></tables>

N-[(OXO-4-PHENYL-2-4H-(1) BENZOPYRAN-8-YL)METHYL] N-METHYL, AMINO-4-BENZOIC ACID

C₂₄H₁₉NO₄ MW=385.424 [Formula 50]

<chemistry id="chem0062" num="0062"><img file="EP0341104A2_D0111.tif" /></chemistry>

PF_G = 260-262°C; IR Vc=o (acid)=1710 cm^-1, Vc = 0 (pyrone) = 1640 cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 3H at 3.2 (s), 2H at 5 (s), 13H at 6.8 to 8.4 (m), 1H at 12.6 (interchangeable).

Elemental analysis

<tables id="tabl0050" num="0050"><img file="EP0341104A2_D0112.tif" /></tables>

[(OXO-4-PHENYL-2-4H-[1] BENZOPYRAN-8-YLO METHYLAMINO]-3, METHYL-3, PROPANEDIOL-1-3

C₂₀H₂₄NO₄ MW = 339.398 [Formula 51]

<chemistry id="chem0063" num="0063"><img file="EP0341104A2_D0113.tif" /></chemistry>

PF_G = 150-152°C; IR Vc=o (pyrone) = 1630 cm-¹, V OH=3380 cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 3H at 1 (s), 4H at 3.2 (d), 2H at 4 (s), 2H at 4.5 (t, interchangeable), 1H at 7 (s), 8H at 7.2 to 8.2 (m).

Elemental analysis

<tables id="tabl0051" num="0051"><img file="EP0341104A2_D0114.tif" /></tables>

CHLOROHYDRATE OF (AMINOMETHYL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₁₆H₁₄ClNO_{4 MW}=₂₈₇.₁₉ [Formula 52]

<chemistry id="chem0064" num="0064"><img file="EP0341104A2_D0115.tif" /></chemistry>

PF_G = 275-279°C; IR V NH₃⁺ = 3100 to 2600 cm^-1; Vc -(pyrone)=₁₆₂₀ cm^-1; NMR (DMSO)δ in ppm in relation to TMS; 8H at 7.3 to 8.4 (m), 3H at 8.8 (interchangeable).

Elemental analysis

<tables id="tabl0052" num="0052"><img file="EP0341104A2_D0116.tif" /></tables>

PHENYL-2-(TRIMETHOXY-3,4,5-PHENYLAMINOMETHYL)-8-4H-[1] BENZOPYRANONE-4

C₂₄H₂₃NO₅ MW = 417.47 [Formula 53]

<chemistry id="chem0065" num="0065"><img file="EP0341104A2_D0117.tif" /></chemistry>

PF_G=219-2221C; IR V NH = 3350 cm^-1, Vc=o (pyrone) = 1620 cm-¹; NMR (CF₃COOD)δ in ppm in relation to TMS; 6H at 3.15 (s), 3H at 3.35 (s), 2H at 4.93 (s), 1H at 6.1 (s), 11H at 7 to 8.3 (m).

Elemental analysis

<tables id="tabl0053" num="0053"><img file="EP0341104A2_D0118.tif" /></tables>

Example 5

(ACETYLOXY-1-ETHYL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₁₉H₁₆O₄ MW⁼308.32 [Formula 54]

<chemistry id="chem0066" num="0066"><img file="EP0341104A2_D0119.tif" /></chemistry>

61.2 g (0.186 mole) of (bromo-1-ethyl)-8-phenyl-2-4H-[1] benzopyranone-4 and 20.1 g (0.204 mole) of potassium acetate in 290 ml of DMF are mixed and heated, with stirring to 45° C. Heating is stopped and the reaction mixture is returned to room temperature for 3 hours, with stirring. After one night at rest, the mixture is poured into ice water. The precipitate formed is filtered and recrystallized in alcohol. Weight obtained: 51 g (yield: 88.9%);

PF_G = 137°C; IR Vc = o (ester) = 1740 cm-¹, Vc=o (pyrone) = 1640 cm-¹; NMR (CDCl₃)δ in ppm in relation to TMS; 3H at 1.7 (d), 3H at 2.1 (s), 1H at 6.6 (g), 1H at 6.8, 8H at 7.2 to 8.4 (m).

Example 6

(HYDROXY-1-ETHYL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₁₇H₁₄O₃ MW=266.3 [Formula 55]

<chemistry id="chem0067" num="0067"><img file="EP0341104A2_D0120.tif" /></chemistry>

194.3 g (0.63 mole) of (acetoloxy-1-ethyl)-8-phenyl-2-4H-[1] benzopyranone-4 68.8 g (0.818 mole) of sodium bocarbonate are mixed in 239 ml of ethanol and 1628 ml of water. The mixture is kept under reflux for 5 hours. The mixture is heat-filtered, the filtrate is evaporated in a vacuum, the residue is taken up in water and recrystallized in toluene. Weight obtained: 152.9 g (yield: 91%);

PF_G = 154-157°C; IR V OH=3350 cm-¹, Vc = 0 (pyrone)=1620 cm-¹; NMR (CDCl₃)δ in ppm in relation to TMS; 3H at 1.62 (d), 1H at 2.8 (interchangeable).

Elemental analysis

<tables id="tabl0054" num="0054"><img file="EP0341104A2_D0121.tif" /></tables>

Example 7

ACETYL-8-PHENYL-2-4H-1 BENZOPYRANONE-4

C₁₇H₁₂O₃ MW=₂₆₄.₂₈ [Formula 56]

<chemistry id="chem0068" num="0068"><img file="EP0341104A2_D0122.tif" /></chemistry>

59.5 g (0.223 mole) of (hydroxy-1-ethyl)-8-phenyl-2-4H-[1] benzopyranone-4 are placed in 670 ml of dioxane. The medium is heated until a solution is obtained. This is then cooled to 20° C, and a reagent solution, prepared using 19.7 g (0.19 mole) of CrOs, 50 ml of water, 13.6 ml of concentrated H₂S0₄ is added in a dropwise manner. This mixture is kept for three hours at room temperature while being stirred, the insoluble is filtered, the filtrate is evaporated in a vacuum and the residue obtained is recrystallized in methyl isobutylcetone. Weight obtained: 43.3 g (yield: 73.4%);

PF_G=125-126°C; IR Vc=o (cetone) = 1675 cm-¹, Vc = 0 (pyrone) = 1690 cm-¹; NMR (CDCl₃)δ in ppm in relation to TMS; 3H at 2.8 (s), 1H at 6.8 (s), 8H at 7.3 to 8.6 (m).

Elemental analysis

<tables id="tabl0055" num="0055"><img file="EP0341104A2_D0123.tif" /></tables>

Example 8

(BROMOACETYL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₁₇H₁₁BrO₃ MW = 343.18 [Formula 57]

<chemistry id="chem0069" num="0069"><img file="EP0341104A2_D0124.tif" /></chemistry>

To a solution of 40 g (0.19 mole) of acetyl-8-phenyl-2-4H-[1] benzopyranone-4 in 750 ml of dioxane, 56.9 g (0.151 mole) of phenyltriethylammoniumtribromide are added. The mixture is stirred for 48 hours at room temperature, filtered, and the precipitate obtained is washed in water and recrystallized in acetone. Weight obtained: 42.9 g (yield: 82%);

PF_G = 142°C; IR Vc=o -1630 cm-¹, NMR (CDCl₃)δ in ppm in relation to TMS; 2H at 4.64 (s), 1 H at 6.8 (s), 8H at 7.2 to 8.6 (m).

Example 9

(AMINO-2-THIAZOL-4-YL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₁₈H₁₂N₂O₂S MW=320.37 [Formula 58]

<chemistry id="chem0070" num="0070"><img file="EP0341104A2_D0125.tif" /></chemistry>

A mixture of 5 g (0.0146 mole) of (bromoacetyl)-8-phenyl-2-4H-[1] benzopyranone-4 and 2.22 g g (0.029 mole) thiourea in 100 ml of ethanol is heated for three hours under reflux, then poured into 200 ml of ice water. The precipitate formed is filtered, washed in water and recrystallized in a mixture of water and DMF. Weight obtained: 2.8 g (yield: 59%); IR V NH₂=3300 to 3350 cm-¹ Vc=o=1630 cm-¹; NMR (CDCl₃)δ in ppm in relation to TMS; 2H at 3.34 (interchangeable).

Elemental analysis

<tables id="tabl0056" num="0056"><img file="EP0341104A2_D0126.tif" /></tables>

Using this same technique, the following compounds were prepared:

[METHYL-2-THIAZOL-4YL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₁₉H₁₃NO₂S MW=319.37 [Formula 59]

<chemistry id="chem0071" num="0071"><img file="EP0341104A2_D0127.tif" /></chemistry>

PF_G=148-153°C; IR Vc=o (acid) =1639 cm-¹, NMR (CDCl₃)δ in ppm in relation to TMS; 3H at 2.8 (s), 1H at 6.8 (s), 9H at 7.2 to 8.5 (m).

Elemental analysis

<tables id="tabl0057" num="0057"><img file="EP0341104A2_D0128.tif" /></tables>

IMIDAZO [2,1-B] THIAZOL-6-YL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₂₀H₁₂N₂O₂^S MW⁼344.39 [Formula 60]

<chemistry id="chem0072" num="0072"><img file="EP0341104A2_D0129.tif" /></chemistry>

PF_G = 229-233°C; IR Vc = o = 1630 cm^-1, NMR (DMSO + CF₃COOD)δ in ppm in relation to TMS; 1H at 7 (s), 11H at 7.4 to 8.8 (m).

Elemental analysis

<tables id="tabl0058" num="0058"><img file="EP0341104A2_D0130.tif" /></tables>

[IMIDAZO [1,2-A] PYRIDIN-2-YL]-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₂₂H₁₄N₂O₂ MW = 338,35 [Formula 61]

<chemistry id="chem0073" num="0073"><img file="EP0341104A2_D0131.tif" /></chemistry>

PF_G=203-₂0₅°C; IR Vc = o = 1635 cm-¹, NMR (CDCl₃)δ in ppm in relation to TMS; 1H at 6.8 (s), 13H at 7 to 8.7 (m).

Elemental analysis

<tables id="tabl0059" num="0059"><img file="EP0341104A2_D0132.tif" /></tables>

(INDOLIZIN-2-YL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₂₃H₁₅NO₂ MW⁼337.36 [Formula _62]

<chemistry id="chem0074" num="0074"><img file="EP0341104A2_D0133.tif" /></chemistry>

PF_G=204-207°C; IR Vc=o 1639 cm-¹, NMR (CDCl₃)δ in ppm in relation to TMS; 1H at 6.8 (s), 1H at 7.3 to 8.3 (m).

Elemental analysis

<tables id="tabl0060" num="0060"><img file="EP0341104A2_D0134.tif" /></tables>

PHENYL-2-(PHENYL-2-THIAZOL-4-YL)-8-4H-[1] BENZOPYRANONE-4

C₂₄H₁₅O₂S MW⁼381.46 [Formula 6_3]

<chemistry id="chem0075" num="0075"><img file="EP0341104A2_D0135.tif" /></chemistry>

PF_G = 199-202°C; IR Vc=o = 1650 cm^-1, NMR (CF₃COOD)8 in ppm in relation to TMS; 15H at 7.4 to 8.8.

Elemental analysis

<tables id="tabl0061" num="0061"><img file="EP0341104A2_D0136.tif" /></tables>

(DIHYDRO-2-3-IMIDAZO [2,1-B] THIAZOL-6-YL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4

C₂₀H₁₄N₂O₂ S MW=346.40 [Formula 64]

<chemistry id="chem0076" num="0076"><img file="EP0341104A2_D0137.tif" /></chemistry>

PF_G = 226-230°C; IR Vc=o = 1635 cm^-1, NMR (DMSO)δ in ppm in relation to TMS; 4H at 4 to 5 (m), 1H at 7 (s). 9H at 7.4 to 8.3 (m).

Elemental analysis

<tables id="tabl0062" num="0062"><img file="EP0341104A2_D0138.tif" /></tables>

EXAMPLE 10

ACETOXYMETHYL-10-PHENYL-2-4H-NAPHTO [1,2-b] PYRANONE-4

C₂₂H₁₆O₄ MW = 334.37 [FORMULA 65]

<chemistry id="chem0077" num="0077"><img file="EP0341104A2_D0139.tif" /></chemistry>

A mixture of 19.8 g (0.054 mole) of bromomethyl-10-phenyl-2-4H-naphtho[1,2-b]pyranone-4, 5.3 g (0.054 mole) of potassium acetate, and 110 ml of DMF is heated to 45° with stirring. This mixture is allowed to return to room temperature while still being stirred for one hour. It is poured into a mixture of water and ice, and the solid obtained is then filtered and used in the following step, without further purification. Weight obtained: 18.5 g (quantitative yield); PF_G = 170°C; IR Vc = o (ester) = 1740 cm-¹, Vc = o (pyrone) = 1635 cm-¹; NMR (CDCl₃) 8 in ppm in relation to TMS: 3H at 2.1 (s), 2H at 5.9 (s), 1H at 6.9 (s), 10H at 7.2 to 8.6 (m).

HYDROXYMETHYL-10-PHENYL-2-4H-NAPHTO[1,2-b]PYRANONE-4

^C₂₀^H₁₄⁰₃ MW ⁼ 302.33 [FORMULA 66]

<chemistry id="chem0078" num="0078"><img file="EP0341104A2_D0140.tif" /></chemistry>

A mixture of 18.9 G (0.054 mole) of acetoxymethyl-10-phenyl-2-4H-naphto [1,2-b pyranone-4, 100 ml of ethanol and 39 g (0.07 mole) of potassium in tablet form is heated in a reflux for two hours. It is then poured into a water-ice mixture and acidified using 6N HCI. The precipitate obtained is filtered, dried, and used in the following step without further purification. Weight obtained: 16.2 g (yield = 99%): I_R V OH = 3400 cm-¹; V_c = o = 1630 cm-¹; NMR (DMSO) 8 in ppm in relation to TMS: 1 H at 3.5 (s, large), 2H at 5.4 (s), 1 H at 7 (s), 10H at 7.2 to 8.4.

OXO-4-PHENYL-2-4H-NAPHTO[1,2-b]PYRANONE-4

C₂₀H₁₂O₄ MW = 316.31 [FORMULA 67]

<chemistry id="chem0079" num="0079"><img file="EP0341104A2_D0141.tif" /></chemistry>

A mixture of 16.2 g (0.0536 mole) of hydroxymethyl-10-phenyl-2-4H-naphto [1,2-b] pyranone 4, 430 ml of pyridine, and 100 ml of water is heated to 60°C. 31.7 g (0.2 mole) of potassium permanganate is added over two hours in portions, then the mixture is heated for 4 hours in a reflux. It is then cooled, and treated with a watery solution of sodium metasulfite, until discoloration is obtained. It is poured into 1 liter of water, the insoluble is filtered, and the organic phase is poured off. After evaporation in a vacuum, the residue is taken up again by the water, acidified using 6N HCI. The precipitate obtained is filtered and recrystallized in acetic acid. Weight obtained: 1.1g (yield 6.5%); mp = 278-280°C; IR Vc = o (acid) = 1700 cm^-1, Vc = o (pyrone) = 1620 cm-¹; NMR (DMSO) 8 in ppm in relation to TMS: 1H at 7.15 (s), 10H at 7.4 to 8.4 (m), 1H at 13.5 (interchangeable). <tables id="tabl0063" num="0063"><img file="EP0341104A2_D0142.tif" /></tables>

EXAMPLE 11

OXO-4-PHENYL-1-4H-[1]-BENZOPYRAN-8-ACETATE OF (ETHOXYCARBONYL)-1-ETHYL

C₂₀H₂₀O₆ MW ⁼ 380.38 [FORMULA 68]

<chemistry id="chem0080" num="0080"><img file="EP0341104A2_D0143.tif" /></chemistry>

To a suspension of 30.6 g (0.109 mole) of oxo-4-phenyl-2-4H-1-benzopyran-8-acetic acid in 1.9 I of boiling ethanol is added dropwise a solution of 7.2 g (0.109 mole) of potassium in 100 ml of ethanol. The solution obtained is stirred for 30 minutes, allowed to return to room temperature, and evaporated in a vacuum. The residum is taken up using 300 ml of ethanol and evaporated in a vacuum, then taken up agin using 30 ml of benzene and evaporated in a vacuum. 546 ml of methyl isobutylketone (MIBK) is added to the residuum, followed by a solution of 21.7 g (0.12 mole) of ethyl a-bromopropionate in 55 ml of MIBK. This mixture is heated in a reflux for 3 hours; next, 12 g (0.066 mole) of ethyl a-bromopropionate is added before continuing heating for 5 hours in a reflux. Heat-filtratioin is carried out, and the filtrate is evaporated in a vacuum. The residuum is triturated in hexane in order to obtain a precipitate which is filtered, washed with hexane and recrystallized in isopropanol. Weight obtained: 36.2 g (yield: 87%); mp = 104-106°C; IR Vc = o (pyrone) = 1730 cm^-1, Vc = o (pyrone) = 1640 cm^-1; NMR (CDCl₃) 8 in ppm in relation to TMS: 3H at 1.2 (t), 3H at 1.46 (d), 2H at 4.1 (s), 2H at 4.18 (q), 1H at 5.18 (q), 1H at 6.8 (s), 8H at 7.2 to 8.4 (m). (interchangeable).

HYDROXY-4-METHYL-5-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-3-5H-FURANONE-2

C₂₀H₁₄O₅ MW = 334.31 [FORMULA 69]

<chemistry id="chem0081" num="0081"><img file="EP0341104A2_D0144.tif" /></chemistry>

To a suspension of 2.62 g (0.109 mole) of sodium hydride in 226 ml of HMPT, is added dropwise to a solution of 41.7 g (0.109 mole) of oxo-4-phenyl-2-4H-[1]-benzopyran-8-acetate of (ethylcarbonyl)-1-ethyl in 260 ml of HMPT. This mixture is stirred overnight in an atmosphere of argon at room temperature, and is then carefully hydrolized using 2 I of 6N HCI. The precipitate obtained is filtered and recrystallized. Weight obtained: 28.3 g (yield 770/o); mp = 265-268°C; IR V OH = 3400 to 2200 cm^-1, Vc = o (lactone) = 1740 cm-¹; Vc = o (pyrone) = 1600 cm-¹; NMR (DMSO) 8 in ppm in relation to TMS: 3Hat 1.6 (d), 1H at 5.2 (q), 1 H at 7.1 (s), 9H at 7.2 to 8.6. <tables id="tabl0064" num="0064"><img file="EP0341104A2_D0145.tif" /></tables>

Using the same technique, the following compounds were obtained: (CHLORO-4-PHENYL)-5-HYDROXY-4-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-3-5H-FURANONE-2

C₂₅H₁₅C10₅ MW ₌ 430.83 [FORMULA 70] <chemistry id="chem0082" num="0082"><img file="EP0341104A2_D0146.tif" /></chemistry>

mp = 265-273°C; IR Vc = o (lactone) = 1750 cm^-1, Vc = o (pyrone) = 1660 cm^-1 NMR (DMSO) δ in ppm in relation to TMS: 1H at 6.16 (s), 1H at 7(s), 13H at 7.1 to 8.4. <tables id="tabl0065" num="0065"><img file="EP0341104A2_D0147.tif" /></tables>

METHYL-3-HYDROXY-4-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-5-5H-FURANONE-2

C₂₀H₁₄O₅ MW = 334.31 [FORMULA 71]

<chemistry id="chem0083" num="0083"><img file="EP0341104A2_D0148.tif" /></chemistry>

mp = 160" C: IR v c = o (lactone) = 1760 cm^-1, Vc = o (pyrone) = 1640 cm^-1; NMR (DMSO) δ in ppm in relation to TMS: 3H at 1.8 (s), 1H at 6.55 (s), 1H at 7.75 (s), 8H at 7.5 to 8.3 (m). <tables id="tabl0066" num="0066"><img file="EP0341104A2_D0149.tif" /></tables>

EXAMPLE 12

CHLORHYDRATE OF [(N,N-DIETHYLAMINO)-2-ETHOXY]-4-METHYL-5-[OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL]-3-5H-FU-RANONE-2

C₂₆H₂₈ClNO₅ MW = 469.95 [FORMULA 72] <chemistry id="chem0084" num="0084"><img file="EP0341104A2_D0150.tif" /></chemistry>

A mixture of 20 g (0.06 mole) of hydroxy-4-methyl-5-(oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)-3-5H-fu- ranone-2, 9.93 g (0.72 mole) of potassium carbonate, and 0.36 g (0.002 mole) of potassium iodide in 490 ml of MIBK is heated for 1 hour at reflux. Next, a solution of 10.6 g (0.078 mole) of 2-(diethylamino)ethyl chloride in 90 ml of MIBK is added, and heating is continued for 7 hours. The minerals are heat filtered and the filtrate is evaporated in a vacuum. The residum is washed twice in hexane then solubilized in the minimum amount of acetone and diluted using hexane. A light insoluble is filtered, the filtrate is evaporated in a vacuum and the residuum is dissolved in 200 ml of ethanol. This product is cooled in an ice bath and HCI is bubbled through until a pH of 2 is achieved. By adding ether, a precipitate is obtained, which is filtered and recrystallized in an ethanol-ether mixture. Weight obtained: 16.9 g (yield 60%); mp = 168-169°C; IR Vc = o (lactone) = 1740 cm-¹, Vc = o (pyrone) = 1640 cm-¹; NMR (DMSO-CDCl₃) 8 in ppm in relation to TMS: 6H at 0.9 (t), 3H at 1.5 (d), 6H at 2.6 to 3.3 (m), 2H at 4.2 (t), 1H at 5.2 (q), 1H at 6.75 (s), 8H at 7.3 to 8.2. <tables id="tabl0067" num="0067"><img file="EP0341104A2_D0151.tif" /></tables>

Using the same technique, the following compounds were obtained:

[DIHYDRO-2-5-METHY-5-OXO-2-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-3-FURAN-4-YL] ETHYL OXYACETATE

^C₂₄^H₂₀⁰₇ MW ⁼ 420.4 [FORMULA 73]

<chemistry id="chem0085" num="0085"><img file="EP0341104A2_D0152.tif" /></chemistry>

mp = 153°C; IR Vc = o NMR (ester and lactone) = 1755 cm-¹, Vc = o (pyrone) = 1640 cm-¹ NMR (CDCl₃) 8 in ppm in relation to TMS: 3H at 1 (t), 3H at 1.7 (d), 2H at 3.9 (q), 2H at 4.5 (s), 1 H at 5.18 (q), 1 H at 6.9 (s), 8H at 7.2 to 8.5.

[DIHYDRO-2-5-METHYL-5-OXO-2-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-3-FURAN-4-YL] OXYACETIC ACID

C₂₂H₁₆O₇ MW ⁼ 392.39 [FORMULA _74]<chemistry id="chem0086" num="0086"><img file="EP0341104A2_D0153.tif" /></chemistry>

mp = 257-259°C; IR V OH = 2400 cm^-1, Vc = o (lactone) = 1740 cm-¹, Vc = o (acid) = 1710 cm-¹, Vc = o (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm in relation to TMS: 3H at 1.6 (d), 1H at 4 (interchangeable), 2H at 4.66 (s), 1H at 5.4 (q), 1H at 7.08 (s), 8H at 7.2 to 8.4 (m).

<tables id="tabl0068" num="0068"><img file="EP0341104A2_D0154.tif" /></tables>

DIMETHYL CARBAMOTHIOATE OF

O-[DIHYDRO-2,5-METHYL-5-OXO-2-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-3-FURN-4-YL]

C₂₃H₁₉NO₅S MW = 421.46 [FORMULA 75]

<chemistry id="chem0087" num="0087"><img file="EP0341104A2_D0155.tif" /></chemistry>

mp = 173-175°C; IR Vc = o (lactone) = 1740 cm-¹, Vc = o (pyrone) = 1630 cm^-1; NMR (CDCl₃) δ in ppm in relation to TMS: 3H at 1.66 (d), 6H at 2.8 (s), 1H at 6.16 (q), 1H at 6.8 (s), 8H at 7.2 to 8.4 (m).

<tables id="tabl0069" num="0069"><img file="EP0341104A2_D0156.tif" /></tables>

EXAMPLE 13

ACETYLTHIMETHYL-8-OXO-4-PHENYL-2-4H-[1]-BENZOPYRANE

C₁₈H₁₄O₃S MW = 310.38 [FORMULA 76]

<chemistry id="chem0088" num="0088"><img file="EP0341104A2_D0157.tif" /></chemistry>

To a mixture of 17.4 g (0.152 mole) of potassium thioacetate in 120 ml of DMF is added 48 g (0.152 mole) of bromomethyl-8-phenyl-2-4H-[1]-benzopyranone-4, by portions while being stirred. This is stirred for 1 hour at room temperature and then poured into a water-ice mixture. The precipitate obtained is filtered and recrystallized in ethyl acetate. Weight obtained: 38 g (yield: 80%); mp = 160°C; IR Vc = o (ester) = 1690 cm^-1, Vc = o (pyrone) = 1655 cm^-1; NMR (CDCl₃) δ in ppm in relation to TMS: 3H at 2.4 (s), 2H at 4.5 (s), 1 H at 6.9 (s), 8H at 7.2 to 8.4 (m).

EXAMPLE 14

MERCAPTOMETHYL-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4

C₁₆H₁₂O₂S MW ⁼268.34 [FORMULA 77]

<chemistry id="chem0089" num="0089"><img file="EP0341104A2_D0158.tif" /></chemistry>

To a mixture of 38 g (0.122 mole) of thioacetylmethyl-8-phenyl-2-4H-[1]-benzopyranone-4 and 230 ml of ethanol are added at one time 150 ml of saturated ethanol in anhydrous HCI. This is heated for 18 hours in a reflux. This mixture is cooled and the precipitate obtained is heated and recrystallized in ethanol. Weight obtained: 39.7 g (yield: 97%); mp = 162°CJ; IR Vc = o = 1640 cm-¹ NMR (CDCl₃) 8 in ppm in relation to TMS: 1H at 2 (t), 2H at 4.1 (d), 1H at 6.8 (s), 8H at 7.2 to 8.4 (m) (interchangeable). <tables id="tabl0070" num="0070"><img file="EP0341104A2_D0159.tif" /></tables>

Using the same technique, the following compounds were prepared:

(OXO-4-PHENYL-2-4H-[1 ]-BENZOPYRAN-8-YL)-METHYL] METHYL THIOACETATE

C₁₉H₁₆O₄S MW ⁼ 340.4 [FORMULA 78] <chemistry id="chem0090" num="0090"><img file="EP0341104A2_D0160.tif" /></chemistry>

mp = 110°C; IR Vc = o (ester) = 1720 cm-¹, Vc = o (pyrone) = 1650 cm^-1 NMR (CDCl₃) δ in ppm in relation to TMS: 2H at 3.2 (s), 3H at 3.7 (s), 2H at 4.2 (s), 1H at 6.8 (s), 8 H at 7.2 to 8.4 (m).

(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL) METHLTHIOACETIC ACID

C₁₈H₁₄O₄S MW ⁼ 326.37 [FORMULA 79]

<chemistry id="chem0091" num="0091"><img file="EP0341104A2_D0161.tif" /></chemistry>

mp = 202-204°C; IR V OH = 3100-2400 cm-¹ o (acid) = 1720 cm^-1, Vc = o (pyrone) = 1640 cm^-1, NMR (DMSO) δ in ppm in relation to TMS: 2H at 3.2 (s), 2H at 4.25 (s), 1H at 6.8 (s), 9H at 7.2 to 8.4 (m).

<tables id="tabl0071" num="0071"><img file="EP0341104A2_D0162.tif" /></tables>

OXALATE OF DIETHYLAMINO-2-ETHOXYMETHYL)-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4

C₂₄H₂₇NO₇ MW = 441.48 [FORMULA 80]

<chemistry id="chem0092" num="0092"><img file="EP0341104A2_D0163.tif" /></chemistry>

mp = 162-164°C; IR Vc = o = 1660 cm-¹; NMR (DMSO) δ in ppm in relation to TMS: 3H at 1.2 (t), 6H at 2.95 to 3.5 (m), 1 H at 3.8 to 4.2 (m), 2H at 5.05 (s), 2H at 5.4 (interchangeable), 1H at 7.1 (s), 8H 7.5 to 8.5 (m). <tables id="tabl0072" num="0072"><img file="EP0341104A2_D0164.tif" /></tables>

[[HYDROXY-2-(HYDROXYMETHYL)-1-ETHOXY] METHYL]-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4

C₁₉H₁₈O₅ MW ⁼ 326.33 [FORMULA 81]

<chemistry id="chem0093" num="0093"><img file="EP0341104A2_D0165.tif" /></chemistry>

mp = 162°C; IR V OH = 3300 cm^-1; IR Vc = o 1620 cm-¹, NMR (DMSO) δ in ppm in relation to TMS: 5H at 3.3 to 3.7 (m), 2H at 4.5 (interchangeable), 2H at 5 (s), 1H at 6.93 (s), 8H at 7.2 to 8.2 (m).

<tables id="tabl0073" num="0073"><img file="EP0341104A2_D0166.tif" /></tables>

EXAMPLE 15

OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-ACETAMIDE

C₁₇H₁₃NO₃ MW = 279.28 [FORMULA 82]

<chemistry id="chem0094" num="0094"><img file="EP0341104A2_D0167.tif" /></chemistry>

A suspension of 5 G (0.0178 mole) of oxo-4-phenyl-2-4H-[1]-benzopyran-8-acetic acid in 180 ml of dioxane is heated until it dissolves. A solution of 3.5 g (0.0124 mole) of N,N'-carboxyldiamidazol in 30 ml of dioxane is added and the mixture is heated for 1 hour to 80°C. It is then cooled to 20°C and approximately 10 ml (0.4 mole) liquified anhydrous ammonia at -33° C is slowly added. The mixture is stirred for 10 minutes at 20° C, then for 3 hours at 80° C. This is left overnight, filtered, washed with hexane, then with hot 5% sodium bicarbonate solution, then with water; it is next recrystallized in ethanol. Weight obtained: 3.3 g (yield 66%); mp = 232-258°C; IR V NH = 3370 to 3200 cm-¹; IR vc = o (acid) = 1660 cm-¹, Vc = o (pyrone) = 1630 cm-¹; NMR (CDCl₃ + CF₃COOD) δ in ppm in relation to TMS: 2H at 4.33 (s), 9H at 7.5 to 8.7 (m), 2H at 11.5. <tables id="tabl0074" num="0074"><img file="EP0341104A2_D0168.tif" /></tables>

EXAMPLE 16

OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-THIOACETIMIDE

C₁₇H₁₃NO₂S MW = 295.35 [FORMULA 83]

<chemistry id="chem0095" num="0095"><img file="EP0341104A2_D0169.tif" /></chemistry>

In a mixture of 60 g (0.229 mole) of oxo-4-phenyl-2-4H-[1]-benzopyran-8-acetonitrile, 16.2 ml (0.116 mole) of triethylamine and 900 ml of pyridine, a stream of H₂S is bubbled through for 3 hours. A nitrogen stream is then passed through this mixture and it is poured into 5 I of ice water, acidified to a pH 5-6 with HCI, filtered, washed in ether, dried, and crystallized in 6N DMF. Weight obtained: 24.7 g (yield: 36%); mp = 223-224°C; IR V NH = 3250 and 3080 cm^-1; IR Vc = o = 1620 cm-¹; NMR (DMSO) δ in ppm in relation to TMS: 2H at 4.15 (s), 1H at 6.9 (s), 8H at 7.2 to 8.4 (m), 2H at 9.4 (s). <tables id="tabl0075" num="0075"><img file="EP0341104A2_D0170.tif" /></tables>

EXAMPLE 17

PHENYL-2-[(PHENYL-4-THIAZOL-2-YL)METHYL]-8-4H-[1]-BENZOPYRANONE-4

C₂₅H₁₇NO₂ MW = 395.46 [FORMULA 84]

<chemistry id="chem0096" num="0096"><img file="EP0341104A2_D0171.tif" /></chemistry>

A mixture of 5 g (0.0169 mole) of oxo-4-phenyl-2-4H-[1]-benzopyran-8-thioacetamide, 4g (0.0203 mole) of d-bromoacetophenone and 120 ml of methoxyethanol is heated for five hours of reflux, then cooled and left overnight at -20° C. The solid obtained is filtered and recrystallized in MIBK then in acetone. Weight obtained: 3.3 g (yield: 49%); IR Vc = o 1620 cm-¹; NMR (CDCl₃) 8 in ppm in relation to TMS: 2H at 4.7 (s), 1H at 6.75 (s), 14 H at 7.1 to 8.3 (m). <tables id="tabl0076" num="0076"><img file="EP0341104A2_D0172.tif" /></tables>

Using this same technique, the following compounds were prepared:

[(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL) METHYL]-2-THIAZOL-4-ETHYL CARBOXYLATE

C₂₂H₁₇NO₄S MW = 391.43 [FORMULA 85]

<chemistry id="chem0097" num="0097"><img file="EP0341104A2_D0173.tif" /></chemistry>

mp = 152-153°C; IR Vc = o (ester) = 1710 cm^-1, Vc = o (pyrone) = 1640 cm^-1; NMR (CDCl₃) δ in ppm in relation to TMS: 3H at 1.3 (t) 2H at 4.4 (q), 2H at 4.73 (s), 1H at 6.7 (s), 9H at 7.1 to 8.3 (m).

[(OXO-4-PHENYL-2-4H-{12}-BENZOPYRAN-8-YL) METHYL-2-THIAZOL-4-CARBOXYLIC ACID

C₂₀H₁₅NO₄S MW ₌ 362.38 [FORMULA 86] <chemistry id="chem0098" num="0098"><img file="EP0341104A2_D0174.tif" /></chemistry>

mp = 237-240°C; IR V OH = 3100 to 2400 cm-¹; IR Vc = o (acid) = 1720 cm-¹, Vc = o (pyrone) = 1620 cm^-1 NMR (DMSO) 8 in ppm in relation to TMS: 1H at 4.7 (s), 1H at 6.9 (s), 8H at 7.2 to 8.15 (m), 1H at 8.2 (s).

<tables id="tabl0077" num="0077"><img file="EP0341104A2_D0175.tif" /></tables>

EXAMPLE 18

[OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)METHYLENE]-2-HYDRAZINE CARBOTHIOAMIDE

C₁₇H₁₃N₃O₂S MW = 323.36 [FORMULA 87]

<chemistry id="chem0099" num="0099"><img file="EP0341104A2_D0176.tif" /></chemistry>

A suspension of 5 g (0.02 mole) of (oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl) carboxaldehyde in 120 ml of dioxane was heated until dissolution. This was cooled to 25°C, a solution of 2 g (0.022 mole) of thiosemicarbazide in 40 ml of dioxane was added and this was heated for 5 minutes at 90° C, then left to return to 25°C while stirring. The precipitate was filtered and recrystallized in methoxyethanol. Weight obtained: 48 g (yield: 41%); mp = 258-262°C; IR V NH = 3400 to 3100 cm-¹, V C = O: 7640 cm^-1. <tables id="tabl0078" num="0078"><img file="EP0341104A2_D0177.tif" /></tables>

Using the same method, the following compound was prepared:

DIHYDRO-4,5-[1H]-IMIDAZ09LE-2-YL-HYDRAZONE BROMHYDRATE (OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL) CARBOXALDEHYDE

C₁₉H₁₇BrN₄O₄ MW = 413.28 [FORMULA 88]

<chemistry id="chem0100" num="0100"><img file="EP0341104A2_D0178.tif" /></chemistry>

mp = 301-303°C; IR: V NH = 3300 cm-¹; V C = N - C = 0 = 1660 and 1640 cm-¹; NMR (DMSO) 8 in ppm in relation to TMS: 2H to 3.4 (s), 4H to 3.8 (s), 1H to 7.1 (s), 10H from 7.3 to 9 (m of which 1H is exchangeable). <tables id="tabl0079" num="0079"><img file="EP0341104A2_D0179.tif" /></tables>

Example 19

(OXO-4-TETRAHYDRO-2,3,5,6-4H-PYRAN-2-YL)-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4

C₂₀H₁₆O₄ MW = 320.33 [FORMULA 89]

<chemistry id="chem0101" num="0101"><img file="EP0341104A2_D0180.tif" /></chemistry>

20 g (0.08 mole) of oxo-4-phenyl-2-4H-[1]-benzopyran-8-carboxaldehyde were added in parts to a mixture of 22.8 g (0.16 mole) of trimethylsilyloxy-2-butadiene-1-3 and 12 g (0.088 mole) of anhydrous ZnCl₂ in 500 ml of anhydrous dioxane. This was brought to reflux for 8 hours under nitrogen and then left under stirring for 48 hours at room temperature. A slight insoluble product was filtered and 1 liter of a solution of 5% NaHCO₃ was added to the filtrate. The insoluble product formed was filtered and the filtrate was extracted using ethyl acetate, then dried and evaporated under a vacuum. The residue was dissolved in 300 ml of methanol and brought to reflux for 3 hours. After having been cooled to 25° C, 3.6 ml of acetic acid were added and this was left under stirring for one night. This was evaporated under a vacuum and the residue was recrystallized in MIBK. Weight obtained: 9.2 g (yield: 30%); mp = 220-221°C; IR V C = 0 (pyranone) = 7695 cm-¹, V C = 0 (pyrone) = 1640 cm-¹; NMR (CDCl₃) 8 in ppm in relation to TMS: 4H from 2.3 to 3.2 (m), 2H from 3.7 to 4.7 (m), 1H to 5.3 (dd), 1H to 6.8 (s), 8H from 7.1 to 8.3 (m). <tables id="tabl0080" num="0080"><img file="EP0341104A2_D0181.tif" /></tables>

EXAMPLE 20

(HYDROXY-4-TETRAHYDRO-3,4,5,6-2H-PYRAN-2-YL)-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4

C₂₀H₁₈O₄ MW = 322.34 [FORMULA 90]

<chemistry id="chem0102" num="0102"><img file="EP0341104A2_D0182.tif" /></chemistry>

A mixture of 6.8 g (0.021 mole) of the compound of Example 18,116 ml of dioxane and 58 ml of methanol was heated until dissolution. It was cooled to 35°C and 0.9 g (0.023 mole) of NABH₄ were added in parts. This was then brought to reflux for 3 hours. After having been cooled, water was added and the precipitate obtained was filtered and recrystallized in isopropanol. Weight obtained: 3 g (yield: 43%); mp = 187-190°C; IR VOH 3400-3200 cm^-1; Vc = o = 1610 cm-¹ NMR CDCP₃) δ in ppm in relation to TMS: 4H at 1 to 2.76 m; 4H from 3.2 to 4.4 (m, of which 1H is exchangeable), 1H to 4.9 (dd) 1H to 6.8 (s), 8H from 7.2 to 8.2 (m). <tables id="tabl0081" num="0081"><img file="EP0341104A2_D0183.tif" /></tables>

EXAMPLE 21

OXO-4-(OXO-PNENYL-2-4H-[1]-BENZOPYRAN-8-YL)-4-BUTEN-2-OIC ACID

C₁₉H₁₂O₅ MW ₌ 320.29 [FORMULA 91]

<chemistry id="chem0103" num="0103"><img file="EP0341104A2_D0184.tif" /></chemistry>

A mixture of 2 g (0.0076 mole) of acetyl-8-phenyl-2-4H-[1]-benzopyranone-4, 1.4 g (0.019 mole) of glyoxylic acid and 25 ml of acetic acid was brought to reflux for 2 hours. This was then poured into water and the precipitate formed was filtered. This was heat dissolved with a solution of 5% NaHCOs and acidified using acetic acid. The precipitate was filtered, washed with water and recrystallized in the dioxane-hexane mixture. Weight obtained: 0.5 g (yield: 20.6%); mp = 217-218°C; IR V C = O (acid) 1710 cm-¹, V C = 0 (ketone) = 1760 cm-¹, V C = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm in relation to TMS 1H to 3.8 (exchangeable), 11H from 6.5 to 8.5 (m). <tables id="tabl0082" num="0082"><img file="EP0341104A2_D0185.tif" /></tables>

EXAMPLE 22

(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-2-HYDROXY-2-ACETIC ACID

C₁₇H₁₂O₅ MW = 296.28 [FORMULA 92]

<chemistry id="chem0104" num="0104"><img file="EP0341104A2_D0186.tif" /></chemistry>

A mixture of 8.75 g (0.134 mole) of potassium cyanide, 125 ml of water, 1.25 I of dioxane, 53 g (0.5 mole) of Na₂CO₃ and 15.32 g (0.061 mole) of oxo-4-phenyl-2-4H-benzopyran-8-carboxaldehyde was stirred at room temperature for 1 hour. 75 ml of acetic acid were then added and this was stirred for 6 hours at room temperature. It was poured into 4 liters of water. The precipitate obtained was washed with water and recrystallized in an acetic acid-water mixture. Weight obtained: 2.5 g (Yield: 14%); IR V OH-3450 cm-¹, V C = O (acid) = 1720 cm-¹, V C = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm in relation to TMS: 1 H at 3.4 (interchangeable), 1H at 5.6 (s), 1H at 7(s), 9H at 7.3 to 8.3 (m, of which 1H is interchangeable). <tables id="tabl0083" num="0083"><img file="EP0341104A2_D0187.tif" /></tables>

Example 23

(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-2-HYDROXY-2-ETHYL ACETATE

C₁₉H₁₆O₅ MW=₃₂₄.₃₂ [Formula 93] <chemistry id="chem0105" num="0105"><img file="EP0341104A2_D0188.tif" /></chemistry>

A mixture of 29 g (0.098 mole) of (oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)-2-hydroxy-2 acetic acid and 35 ml of concentrated H₂S0₄ in 585 ml of ethanol are brought to reflux for 5 hours. The mixture was then poured into water, extracted using ethyl acetate, dried, evaporated and the white solid obtained was recrystallized in MIBK-hexane. Weight obtained: 20.3 g (Yield: 64%); MP_K=135°C; IR: V OH=3420 cm-¹, V C=O (ester) = 1730 cm-¹, V C = O (pyrone) = 1640 cm-¹.

Example 24

(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-2-OXO-2-ETHYL ACETATE

C₁₉H₁₄O₅ MW=322.3 [Formula 94]

<chemistry id="chem0106" num="0106"><img file="EP0341104A2_D0189.tif" /></chemistry>

0.79 g (0.0077 mole) of CrOs and 0.84 g (0.0077 mole) of chlorotrimethylsilane were dissolved in 10 ml of methylene chloride. A solution of 2.5 g (0.0077 mole) of (oxo-4-phenyl-2-4H-[1]benzopyran-8-yl)-2-hydroxy-2-ethyl acetate in 20 ml of methylene chloride was added while cooling the red solution obtained. This was stirred at room temperature for 3 hours 50 minutes. The medium was then passed on a silica column and eluted with CHCl₃. This was evaporated and the residue was recrystallized in hexane. Weight obtained: 0.9 g (Yield: 36.3%); MP_K=85-90°C; IR V C=O (ester)=1730 cm-¹, V C=O (ketone)=1690 cm-¹ 1, V C=O (pyrone) = 1640 cm-¹, NMR (CDCl₃), δ in ppm in relation to TMS: 3H to 1.3 (t), 2H to 4.3 (q), 1H to 6.8 (s), 8H to 7.25 to 8.7 (m).

Example 25

(OXO-4-PHENYL-2-4H[1]BENZOPYRAN-8-YL]-2-OXO-2-ACETATE ACID

C₁₇H₁₀O₅ MW=294.25 [Formula 95] <chemistry id="chem0107" num="0107"><img file="EP0341104A2_D0190.tif" /></chemistry>

The mixture of 9.3 g (0.0288 mole) of (oxo-4-phenyl-2-4H-[1]benzopyran-8-yl)-2-oxo-2-ethyl acetate, 4.85 g (0.057 mole) of sodium bicarbonate, 150 ml of ethanol and 115 ml of water was refluxed for 4 hours 30 minutes. The ethanol was then evaporated, 150 ml of water were added, the mixture was acidified with 1/2 HCI and the precipitate obtained was filtered and recrystallized in dioxane. Weight obtained: 2.3 g (Yield 27%), MP_G = 232-235°C, IR V C = O (acid) = 1740 cm^-1, V C = O (ketone) = 1690 cm-¹, V C = O (pyrone) = 1660 cm-¹. NMR (DMSO) δ in ppm in relation to TMS: 1H to 7.3 (s), 9H to 7.4 to 8.5 (m, 1H of which is exchangeable).

Elemental analysis

<tables id="tabl0084" num="0084"><img file="EP0341104A2_D0191.tif" /></tables>

Example 26

METHYL-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-Y)-2-METHYL PROPANOATE

C₂₀H₁₈O₄ MW⁼322.34 [Formula 96]

<chemistry id="chem0108" num="0108"><img file="EP0341104A2_D0192.tif" /></chemistry>

A solution of 6.7 g (0.023 mole) of oxo-4-phenyl-2-4H-[1]benzopyran-8-methyl acetate in 120 ml of DMF was added slowly to a suspension of 2.33 g (0,0485 mole of sodium hydride in 10 ml of DMF. This was stirred for one hour at room temperature, then 6.6 cm (0.1 mole) of methyl iodide in 5 ml of DMF was added dropwise. This was stirred for 6 hours at room temperature and then 6.6 ml of CIHs in 5 ml ofDMF was added. This was stirred for one night, 15 ml of acetic acid were added, it was concentrated to 50 ml, water was added and the ethyl acetate was extracted. This was dried, evaporated under a vacuum and recrystallized in methanol. Weight obtained: 3.5 g (Yield 42%); MP_K = 157°C; IR V C = O (ester) = 1720 cm-¹, V C=O (pyrone) = 1650 cm-¹; NMR (CDCl₃) 8 in ppm in relation to TMS: 6H to 1.75 (s), 3H to 3.6 (s), 1H to 6.87 (s), 8H to 7.2 to 8.4 (m).

Example 27

METHYL-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-2-PROPIONIC ACID

C₁₉H₁₆O₄ MW=308.318 [Formula 97]

<chemistry id="chem0109" num="0109"><img file="EP0341104A2_D0193.tif" /></chemistry>

A mixture of 5.7 g (0.0177 mole) of methyl-2-(oxo-4-phenyl-2-4H-[1]benzopyran-8-yl)-2-methyl propanoate, 95 ml of acetic acid, 95 ml of concentrated sulfuric acid and 95 ml of concentrated hydrochloric acid were refluxed for 2 hours. This was then stirred for 12 hours at room temperature and brought again to reflux for 3 hours. It was cooled and the precipitate formed was filtered and stabilized in 250 ml of a 5% bicarbonate solution. It was acidified with 1/2 HCI and the precipitate was dried, washed with water and recrystallized in acetic acid.

Weight obtained: 3.1 g (Yield: 56.8%); MP_G = 255-260; IR V C=O (acid) = 1720 cm^-1, V C = O (pyrone) = 1620 cm-1; NMR (CF₃COOD) δ in ppm in relation to TMS: 6H to 2 (s), 9H from 7.6 to 8.6 (m), 1H to 11.7 (exchangeable).

Elemental analysis

<tables id="tabl0085" num="0085"><img file="EP0341104A2_D0194.tif" /></tables>

Example 28

OXO-4-PHENYL-2-4H[1]-BENZOPYRAN-8-CARBOXALDEHYDE OXIME (8)

C₁₆H₁₁NO₃ MW=265.256 [Formula 98]

<chemistry id="chem0110" num="0110"><img file="EP0341104A2_D0195.tif" /></chemistry>

A mixture of 10 g (0.04 mole) of oxo-4-phenyl-2-4H-[1]benzopyran-8-carboxaldehyde, 3.7 g (0.054 mole) of hydroxylamine hydrochlorate, 7.1 g (0.10 mole) of sodium acetate, 20 ml of water and 40 ml of ethanol was brought to reflux for 1 hours. After cooling, the product formed was dried and recrystallized in dioxane. Weight obtained: 6.3 g (Yield: 59.4%); MP_G = 230-238°C; IR V OH=32₀₀ to 2800 cm-¹, V C=O; NMR (CF₃COOD), 8 in ppm in relation to TMS: 10 H from 7.8 to 9.5 (m).

Elemental analysis

<tables id="tabl0086" num="0086"><img file="EP0341104A2_D0196.tif" /></tables>

Using the same method, the following compound was prepared:

ACETYL-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4- OXIME (8)

C₁₇H₁₃NO₃ MW=279.282 [Formula 99]

<chemistry id="chem0111" num="0111"><img file="EP0341104A2_D0197.tif" /></chemistry>

Elemental analysis

<tables id="tabl0087" num="0087"><img file="EP0341104A2_D0198.tif" /></tables>

Example 29

(MORPHOLIN-4-YL)-3-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL]-2-GLIJTARONITRILE

C₂₄H₂₁N₃O₃ MW=₃₉₉.₄₃ [Formula 100]

<chemistry id="chem0112" num="0112"><img file="EP0341104A2_D0199.tif" /></chemistry>

A solution of 1.33 g (0.025 mole) of acrylonitrile in 10 ml of dioxane was added dropwise to a mixture of 7 g (0.02 mole) of (morpholin-4-yl)- -(oxo-4-phenyl-2-4H-[1]benzopyran-8-yl)-2 acetonitrile. After 18 hours at room temperature, a slightly insoluble material was filtered and evaporated under a vacuum. The residue was recrystallized in isopropanol. Weight obtained: 3.1 g (Yield: 38.8%); MP_K=110°C; IR V C=N=2250 cm-¹, V C = 1640 cm-¹; NMR (CDCIs) 8 in ppm in relation to TMS: 8H from 1.8 to 3.2 (m); 4H to 3.9 (t), 1H to 7 (s), 8H from 7.4 to 8.6 (m).

Example 30

OXO-4-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-4-BUTYRIC ACID

C₁₉H₁₄O₅ MW⁼322.3 [Formula 101]

<chemistry id="chem0113" num="0113"><img file="EP0341104A2_D0200.tif" /></chemistry>

A mixture of 3 g (0.0075 mole) of the compounf od Example 29, 30 ml of 6N hydrochloric acid and 30 ml of acetic acid was refluxed for 4 hours. This was then poured into water and ice, the product was dried, it was replaced in a solution of 5% NaHCOs and acidified. The precipitate formed was dried and recrystallized in the MIBK-dioxane mixture. Weight obtained: 1.1 g (Yield: 45.5%); MP_F=207-209°C; IR V C= ) (acid=1720 cm^-1, V C=O (ketone) = ₁₆₈₀ cm-¹, V C=O (pyrone) = 1620 cm-¹; NMR DMSO) 8 in ppm in relation to TMS: 4H from 2.4 to 3.6 (m), 1H to 7.1 (s), 8H from 7.4 to 8.4 (m), 1H to 12.1 (exchangeable).

Elemental analysis

<tables id="tabl0088" num="0088"><img file="EP0341104A2_D0201.tif" /></tables>

Example 31

HYDROXY-4-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-Y]-BUTYRIC ACID

C₁₉H₁₆O₅ MW⁼324.32 [Formula 102]

<chemistry id="chem0114" num="0114"><img file="EP0341104A2_D0202.tif" /></chemistry>

By treating 5 g (0.0155 mole) of the product of Example 30 with 9.5 g (0.0468 mole) of aluminum isopropylate in 100 ml of isopropanol and 40 ml of dioxane for 6 hours at reflux, 1.9 g of isopropyl hydroxy ester (MP_K = 145°C) was obtained after recrystallization in hexane. This was placed in 10 ml of water, 17 m with 0.45 g of sodium bicarbonate. The medium was brought to reflux for 4 hours 30 minutes, evaporated and the residue was replaced in water. The insoluble material was filtered, acidified with acetic acid, dried, and recrystallized in dioxane. Weight obtained: 0.7 g MP_G=198-202° C; IR V OH =3₃₅₀ cm^-1, V C= O (acid) =1700 cm^-1, VC=O (pyrone)=1620 cm^-1; NMR (DMSO) δ in ppm in relation to TMS: 4H from 1.7 to 2.9 (m), 2H from 5.3 to 5.8 (m, of which 1H is exchangeable), 1H to 7.1 (s), 8H from 7.4 to 8.4 (m), 1H to 11.8 (exchangeable). <tables id="tabl0089" num="0089"><img file="EP0341104A2_D0203.tif" /></tables>

Example 32

ACETAMIDO-2-ETHOXYCARBONYL-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-2 ETHYL PROPIONATE

C₂₅H₂₅NO₇ MW=451.46 [Formula 103]

<chemistry id="chem0115" num="0115"><img file="EP0341104A2_D0204.tif" /></chemistry>

17.5 g (0.08 mole) of diethyl acetamidomalonate was added at 20°C in 20 minutes to a suspension of 3 g (0.08 mole) of sodium hydride in 100 ml of toluene. This was left under stirring for 1 hour, then 25 g (0.08 mole) of bromomethyl-8-phenyl-2-4H-[1]benzppyranone-4 were added in one hour. This was brought to a reflux for 8 hours and then hot filtered. the filtrate was evaporated under a vacum, the residue was replaced in water, the solid was dried and recrystallized in ethanol. Weight obtained: 24.4 g (Yield: 67.6%); MP_K=200°C; IR V NH=3370 cm-¹ V C=O (ester) = 1720 cm-¹ and 1760 cm-¹, V C=O (amide) =7670 cm^-1, V C=O (pyrone)=1640 cm-¹.

Example 33

AMINO-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-3-PROPIONIC ACID HYDROCHLORATE

C₁₈H₁₆ClNO₄ MW=345.78 [Formula 104]

<chemistry id="chem0116" num="0116"><img file="EP0341104A2_D0205.tif" /></chemistry>

A mixture of 10 g (0.022 mole) of the compound of Example 32 and 400 ml of 1/2 HCI was brought to reflux for 4 hours. After a night of rest, the precipitate formed was dried and recrystallized in the ACOH-water mixture. Weight obtained: 4.4 g (Yield: 57.6%), MP_G=243°C; IR V OH, NH₃⁽⁺⁾=3500-2500 cm-¹, V C=O (acid) = 1740 cm-¹, V C=O (pyrone) = 1625 cm^-1; NMR (DMSO) δ in ppm in relation to TMS: 3H from 3.4 to 4.4 (m), 1H to 7.1 (s), 1H from 7.4 to 10 (m, of which 4H are exchangeable).

Elemental analysis

<tables id="tabl0090" num="0090"><img file="EP0341104A2_D0206.tif" /></tables>

Following the experimental protocol outlined in Example 1 supra, the following compounds were prepared.

2-(2-AMINOPHENYL)-4-OXO-4H-[1]BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₃NO₄ MW = 295.28 [Formula 105]

<chemistry id="chem0117" num="0117"><img file="EP0341104A2_D0207.tif" /></chemistry>

PF_G = 189° vC; IR vC = 0 (acid) 1710 cm^-1, vC = 0 (pyrone) = 1610 cm-¹

<tables id="tabl0091" num="0091"><img file="EP0341104A2_D0208.tif" /></tables>

2-(2-CHLOROPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₇H₁₁ClO₄ MW ⁼ 314.715 [Formula 106]

<chemistry id="chem0118" num="0118"><img file="EP0341104A2_D0209.tif" /></chemistry>

PF_G = 169°C; IR νC = 0 (acid) = 1710 cm^-1; νC = 0 (pyrone) = 1620 cm^-1; NMR (DMSO) δ in ppm relative to TMS: 2 H at 4.3 (s), 8 H from 7.5 to 8.7 (m), 1 H at 11.7 (exchangeable). <tables id="tabl0092" num="0092"><img file="EP0341104A2_D0210.tif" /></tables>

2-(2-CHLOROPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-AGETIG ACID

C₁₇H₁₁ClO₄ MW = 314.715 [Formula 107]

<chemistry id="chem0119" num="0119"><img file="EP0341104A2_D0211.tif" /></chemistry>

PF_G = 220-222°C; IR vC = 0 (acid) = 1730 cm^-1; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) 8 in ppm relative to TMS: 2 H at 4 (s), 1 H from 7.5 (s), 7 H from 7.3 to 8.3 (m), 1 H at 13 (exchangeable).

<tables id="tabl0093" num="0093"><img file="EP0341104A2_D0212.tif" /></tables>

2-(2-ACETAMIDOPHENYL)-4-OXO-4M-[1]-BENZOPYERAN-8-AGETIC ACID

C₁₉H₁₅NO₅ MW = ₃₃₇.₃₁₈ [Formula 109]

<chemistry id="chem0120" num="0120"><img file="EP0341104A2_D0213.tif" /></chemistry>

PF_G = 196-201°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 amide) = 1660 cm-¹; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 3 H at 2 (s), 2 H at 3.8 (s), 1 H at 6.5 (s), 7 H from 7.3 to 8.2 (m), 1 H at 8.8 (exchangeable), 1 H at 11.5 (exchangeable). <tables id="tabl0094" num="0094"><img file="EP0341104A2_D0214.tif" /></tables>

2-(4-ACETYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₉H₁₄O₅ MW = 322.302 [Formula 110] <chemistry id="chem0121" num="0121"><img file="EP0341104A2_D0215.tif" /></chemistry>

PF_G = 253-255°C; IR vC = 0 (pyrone) = 1620 cm^-1; NMR (CF₃COOD) δ in ppm relative to TMS: 3 H at 2.8 (s). 2 H at 4.3 (m), 8 H from 7.7 to 8.5 (m). <tables id="tabl0095" num="0095"><img file="EP0341104A2_D0216.tif" /></tables>

2-(3-ACETAMIDOPHENYL)-4-OXO-4H-[i]-BENZOPYRAN-8-ACETIC ACID

C₁₉H₁₅NO_{5 MW = 337}._{318 [}Formula 1111 <chemistry id="chem0122" num="0122"><img file="EP0341104A2_D0217.tif" /></chemistry>

PF_G = 284-288°C IR vC = 0 (acid) = 1720 cm^-1 ; vC = 0 (amide + pyrone) = 1630 cm-¹; NMR (DMSO) 8 in ppm relative to TMS: 3 H at 2 (s), 2 H at 4 (s), 1 H at 6.8 (s), 7 H from 7.1 to 8.1 (m), 1 H at 9.8 (exchangeable), 1 H at 12 (exchangeable).

<tables id="tabl0096" num="0096"><img file="EP0341104A2_D0218.tif" /></tables>

2-(2-DIETHYLAMINOETHOXYPHENYL]-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₂₃H₂₅ClNO₅ MW = 431.903 [Formula 112] (chlorhydrate)

<chemistry id="chem0123" num="0123"><img file="EP0341104A2_D0219.tif" /></chemistry>

PF_G = 1780-182°C C₁(chlorhydrate); IR vC = 0 (acid) = 1720 cm^-1; vC = 0 (pyrone) = 1640 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 6 H at 1 (t), 6 H from 2.8 to 3.8 (m), 1 H from 3.9 to 4.2 (m), 8 H from 6.8 to 8 (m), 1 H at 11 (exchangeable).

<tables id="tabl0097" num="0097"><img file="EP0341104A2_D0220.tif" /></tables>

2-(3-NITRO-4-CHLOROPHENYL)-4-OXO-4H-[1]-BENZOPYRAN,-8-ACETIC ACID

C₁₇H₁₀ClNO₄ MW = 359.715 [Formula 113]

<chemistry id="chem0124" num="0124"><img file="EP0341104A2_D0221.tif" /></chemistry>

PF_G = 232 - 234°C; IR vC = 0 (acid) = 1720 cm^-1; vC = 0 (pyrone) = 1640 cm-1; NMR (DMSO) δ in ppm relative to TMS: 2 H at 4 (s), 7 H from 7 to 8.8 (m), 1 H at 12.1 (exchangeable).

<tables id="tabl0098" num="0098"><img file="EP0341104A2_D0222.tif" /></tables>

2-(2,4-DIMETHOXYPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIG ACID

C₁₉H₁₆O₆ MW = 340.185 [Formula 114] <chemistry id="chem0125" num="0125"><img file="EP0341104A2_D0223.tif" /></chemistry>

PF_G = 225-227°C; IR vC = 0 (acid) = 1710 cm-¹; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 2 H at 3.5 (s), 3 H at 3.9 (s), 3 H at 4 (s), 7 H from 6.8 to 8, 1 H at 12.2 (exchangeable).

<tables id="tabl0099" num="0099"><img file="EP0341104A2_D0224.tif" /></tables>

2-(4-DIMETHYLAMINOETHOXYPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₂₃H₂₆ClNO₂ MW = 431.92 [Formula 115] (chlorhydate)

<chemistry id="chem0126" num="0126"><img file="EP0341104A2_D0225.tif" /></chemistry>

hF_G = 194-199°C (chlorhydate); IR vC = 0 (acid) = 1720 cm-¹; vC = 0 (pyrone) = 1630 cm^-1; NMR (DMSO) δ in ppm relative to TMS: 8 H from 3 to 4.7 (m), 8 H from 6.8 to 8.3 (m), 1 H from 10.4 to 10.8 (exchangeable).

<tables id="tabl0100" num="0100"><img file="EP0341104A2_D0226.tif" /></tables>

2-(4-CARBAMOYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₃NO₅ MW ⁼ 323.292 [Formula 116] <chemistry id="chem0127" num="0127"><img file="EP0341104A2_D0227.tif" /></chemistry>

PF_G = 228-290°C; IR vC = 0 (acid) = 1710 cm-¹; vC = 0 (amide + pyrone) = 1640 cm^-1

<tables id="tabl0101" num="0101"><img file="EP0341104A2_D0228.tif" /></tables>

[[methyl-2-thiazolyl-4]-4-phenyl]-2-OXO-4-4H[1]BENZOPYRAN-8-ACETIC ACID

C₂₁H₁₅NO₄S MW ⁼ 377.398 [Formula 11_7]

<chemistry id="chem0128" num="0128"><img file="EP0341104A2_D0229.tif" /></chemistry>

PF_G = 246-248°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 3 H at 4 (s), 1 H at 7 (s), 8 H from 7.1 to 8.1 (m), 1 H at 12.6 (exchangeable).

<tables id="tabl0102" num="0102"><img file="EP0341104A2_D0230.tif" /></tables>

2-(2-CHLOROPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₉H₁₇N₃O₄ MW = 351.35 [Formula 118] <chemistry id="chem0129" num="0129"><img file="EP0341104A2_D0231.tif" /></chemistry>

PF_G= 173-175°C; IR vC = 0 (acid) = 1710 cm^-1; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 6 H at 3.25 (s), 2 H at 4 (s), 1 H at 7 (s), 7 H from 7.2 to 8 (m), 1 H at 12.3 (exchangeable). <tables id="tabl0103" num="0103"><img file="EP0341104A2_D0232.tif" /></tables>

2-(2-AMINO-4-THIAZOLYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₂₀H₁₄O₄S MW = 378.388 [Formula 119] <chemistry id="chem0130" num="0130"><img file="EP0341104A2_D0233.tif" /></chemistry>

PF_G = 263-265°C; IR vC = 0 (acid) = 1710 cm-¹; vC = 0 (pyrone) = 1620 cm^-1; NMR (DMSO) 8 in ppm relative to TMS: 2 H at 4 (s), 11 H from 7 to 8.2 (m, with 2 H exchangeable), 1 H at 12.9 (exchangeable). <tables id="tabl0104" num="0104"><img file="EP0341104A2_D0234.tif" /></tables>

2-(3,5 DIMETHOXYPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₉H₁₆O₆ MW = 340.318 [Formula 120] <chemistry id="chem0131" num="0131"><img file="EP0341104A2_D0235.tif" /></chemistry>

PF_G = 261-263°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 pyrone) = 1630 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 6 H at 3.9 (s), 2 H at 4 (s), 7 H from 6.5 to 8 (m), 1 H at 12.9 (exchangeable). <tables id="tabl0105" num="0105"><img file="EP0341104A2_D0236.tif" /></tables>

2-(4-PYRIDYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₆H₁₁NO₄ MW = 281.256 [Formula 121] <chemistry id="chem0132" num="0132"><img file="EP0341104A2_D0237.tif" /></chemistry>

PF_G = 275-277°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 (pyrone) = 1600 cm-¹; NMR (DMSO + CFsCOOD) 8 in ppm relative to TMS: 2 H at 4 (s), 8 H from 7.3 to 8.8 (m). <tables id="tabl0106" num="0106"><img file="EP0341104A2_D0238.tif" /></tables>

2-(2-PYRIDYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₆H₁₁NO₄ MW ⁼ 281.256 [Formula 122] <chemistry id="chem0133" num="0133"><img file="EP0341104A2_D0239.tif" /></chemistry>

PF_G = 221-223°C; IR vC = 0 (acid) = 1720-1740 cm^-1; vC = 0 (pyrone) = 1640 cm^-1; NMR (DMSO) 8 in ppm relative to TMS: 2 H at 4.1 (s), 1 H at 7.2 (s), 8 H from 7.25 to 9 (m), 1 H at 13 (exchangeable). <tables id="tabl0107" num="0107"><img file="EP0341104A2_D0240.tif" /></tables>

2-(4-HEXYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₂₃H₂₄O₄ MW = 364.422 [Formula 123]

<chemistry id="chem0134" num="0134"><img file="EP0341104A2_D0241.tif" /></chemistry>

PF_G = 154-156°C; IR vC = 0 (acid) = 1720 cm^-1; vC = 0 (pyrone) = 1620 cm^-1; NMR (DMSO) 8 in ppm relative to TMS: 13 H from 0.7 to 2.8 (m), 2 H at 4 (s), 1 H at 7 (s), 7 H from 7.2 to 8.1 (m), 1 H at 12.9 (exchangeable).

<tables id="tabl0108" num="0108"><img file="EP0341104A2_D0242.tif" /></tables>

2-(3-METHYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₄O₄ MW = 294.292 [Formula 124] <chemistry id="chem0135" num="0135"><img file="EP0341104A2_D0243.tif" /></chemistry>

PF_G = 252-254° C; IR νC = 0 (acid) = 1720 cm^-1; vC = 0 (pyrone) = 1620 cm^-1; NMR (CF₃COOD) 8 in ppm relative to TMS: 2 H at 2.55 (s), 2 H at 4.5 (m), 8 H from 7.5 to 8.6 (m).

<tables id="tabl0109" num="0109"><img file="EP0341104A2_D0244.tif" /></tables>

2-(4-BENZOYLPHENYL)-4-OXO-4H-(1]-BENZOPYRAN-8-ACETIC ACID

C₂₄H₁₆O₄ MW = 384.368 [Formula 125] <chemistry id="chem0136" num="0136"><img file="EP0341104A2_D0245.tif" /></chemistry>

PF_G = 257-259°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 (benzoyl) = 1650 cm-¹; vC = 0 (pyrone) = 1620 cm-¹; NMR (CF₃COOD) δ in ppm relative to TMS: 2 H at 4.5 (s), 13 H from 7.5 to 8.7 (m). <tables id="tabl0110" num="0110"><img file="EP0341104A2_D0246.tif" /></tables>

2-(4-UNDECYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₂₈H₃₄O₄ MW = 434.552 [Formula 126] <chemistry id="chem0137" num="0137"><img file="EP0341104A2_D0247.tif" /></chemistry>

PF_G = 150-152° C; IR νC = 0 (acid) = 1710 cm-¹; vC = 0 (pyrone) = 1620 cm^-1; NMR (CF₃COOD) 8 in ppm relative to TMS: 23 H from 0.6 to 1.7 (m), 2 H at 4.5 (s), 8 H from 7.5 to 8.4 (m). <tables id="tabl0111" num="0111"><img file="EP0341104A2_D0248.tif" /></tables>

NITRO-3, PHENYL-4-PHENYL)-2-OXO-4-4H-[1]BENZOPYRAN-8-ACETIC ACID

C₂₃H₁₅NO₆ MW = 401.358 [Formula 127] <chemistry id="chem0138" num="0138"><img file="EP0341104A2_D0249.tif" /></chemistry>

PF_G= 270-272°C; IR vC = 0 (acid) = 1720 cm^-1; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) 8 in ppm relative to TMS: 2 H at 4 (s), 12 H from 7.2 to 8.7 (m), 1 H at 12.9 (exchangeable). <tables id="tabl0112" num="0112"><img file="EP0341104A2_D0250.tif" /></tables>

2-(4-TRIFLUOROMETHYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₁F₃O₄ MW = 348.268 [Formula 128] <chemistry id="chem0139" num="0139"><img file="EP0341104A2_D0251.tif" /></chemistry>

PF_G = 216-218°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 pyrone) = 1640 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 2 H at 4 (s), 8 H from 7.1 to 8.4 (m), 1 H at 12.8 (exchangeable).

Elemental analysis C% H% F% O% calculated: 63.07 3.18 16.37 18.38 found: 63.02 3.32 16.37

2-(4-DIMETHYLTRIAZENYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₉H₁₇N₃O₄^MW = 351.35 [Formula 129] <chemistry id="chem0140" num="0140"><img file="EP0341104A2_D0252.tif" /></chemistry>

PF_G = 209-211°C; IR vV = 0 (acid) = 1720 cm-¹; vC = 0 (pyrone) = 1620 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 6 H at 3.3 (m), 2 H at 4 (s), 1 H at 7 (s), 8 H from 7.2 to 8.1 (m), 1 H at 12.8 (exchangeable). <tables id="tabl0113" num="0113"><img file="EP0341104A2_D0253.tif" /></tables>

2-(3-NITRO-4-METHOXYPHENYL)-4-OXO-4M-[1]-BENZOPYRAN-8-ACETIC ACID

C₁₈H₁₃NO₇ MW = 355.292 [Formula 130]

<chemistry id="chem0141" num="0141"><img file="EP0341104A2_D0254.tif" /></chemistry>

PF_G= 254-256°C; IR vC = 0 (acid) = 1720 cm-¹; vC = 0 (pyrone) = 1620 cm-¹; NMR (CFsCOOD): 3 H at 4.1 (s), 2 H at 4.3 (s), 7 H from 7.1 to 9 (m). <tables id="tabl0114" num="0114"><img file="EP0341104A2_D0255.tif" /></tables>

2-(4-TERBUTYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID

C₂₁H₂₀O₄ MW ⁼ 336.37 [Formula 131] <chemistry id="chem0142" num="0142"><img file="EP0341104A2_D0256.tif" /></chemistry>

PF_G = 240-242°C; IR vC = 0 (acid) = 1720 cm^-1; vC = 0 (pyrone) = 1610 cm-¹; NMR (DMSO) δ in ppm relative to TMS: 6 H at 1.2 (s), 2 H at 4.5 (s), 8 H from 7.1 to 8.3 (m), 1 H at 12.9 (exchangeable). <tables id="tabl0115" num="0115"><img file="EP0341104A2_D0257.tif" /></tables>

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.