Substituted flavonoid compounds and salts thereof their preparation and pharmaceutical composition containing them

Substituted flavonoid compounds and salts thereof, their preparation and pharmaceutical compositions containing them

LIPHA, LYONNAISE INDUSTRIELLE PHARMACEUTIQUE

C. 77271

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 and Israel Patent 67291 disclose (0X0-4-4H(l)-benzopyran-8-yl) alkanoic acids and their derivatives, represented by the formula:

AR (B)״-COOH wherein, in the above formula, AR is hydrogen, a phenyl radical which may or may not be substituted, thenyl, furyl, naphthyl, a lower alkyl, cycloalkyi, aralkyl radical, B is a lower alkyl radical, R^ 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, t,

J. Med. Chem. — Chim. Then. 20:(5), 393-402 (1985), describes benzopyrane derivatives as interesting tools for controlling adenocarcinoma 38, which actually bear a resemblance to the presently claimed compounds. Said prior art is however silent concerning immunomodulatory properties and more particularly with respect to the ability to stimulate the formation of interferons and killer cells, which properties characterize the compounds of the invention.

a 89840/1

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.

/2

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.

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 aoparent from the description, of the invention given hereinbelow. These compounds have the formula (I):

<img file="IL89840A_D0001.tif" />

(1) wherein:

X is NH, 0, Se or S(0)_n, wherein n is 0, 1 or 2;

R₁ is phenyl; phenyl substituted by at least one member selected from halogens, alkyl, trifluoromethyl, hydroxyl, 0₆_ן- alkoxy, (C!,₆alkylene)COOR_I0, nitro, C^alkyljcarbonylamino, benzoyl, C^falkyl)carbonyl, CONR₁₀R_״, (where R_1o and R_״ are each independently H or alkyl), NR₁₀R_״, -N=N-NR_1OR_U, phenyl, -0(0^$ alkylene)NR₁₀R_u, thiazolyl, and thiazolyl substituted by Cj_₆ alkyl or amino; or R! is pyridyl; pyridyl substituted by at least one member selected from C^₆ alkyls and halogens; trifluoromethyl; benzoyl or benzyl;

R₂ is H; phenyl; OH; C!_₃ alkyl; or C!_₃ alkoxy; or

19.xii. 1991 R, and R-, together form a naphthalene ring fused to the flavonoid nucleus;

R₃ is H, OH or halogen;

R₄ is H;

R₅ is H or Cj_₃ alkyl;

R₆ is H; -OH or -0-C0(C_P6 alkyl);

or R₅ and R₆ together are a group =CR₁₀R_״ or a group =N0H, or a group =0 or a group -CHR₁₂ (where R₁₂ is phenyl, pyridyl, phenyl substituted by at least one member selected from halogen atoms, trifluoromethyl and Cj_₃ alkyls or pyridyl substituted by at least one member selected from halogen atoms, tri fluoromethyl and C!_₃ alkyls);

R₇ is H; COOR₁₀; “?(OXORjoRu)^ NR₁₃R₁₄ (where R₁₃ and R₁₄ are independently H; phenyl; phenyl substituted by one or two halogen atom(s) or a Cj_₃alkyl group or a group -COOR₁₀, -CO-O-CH(CH₃)-COOR₁₀, morpholinyl, -C(CH₂OH)₂(CH₃), imidazolinyl, (Q_₆ alkylene)OH, (Cj_₆alkylene)COOR_I0, or Cj_₃ alkoxy, or wherein R₁₃ and R₁₄ together with the nitrogen atom to which they are both bound form an imidazole or a N(C!_₃ a!kyl)piperazinyl);

or

R₇ is -CO(C!_₆ alkyl); -S-.((^ alkyl); -SH; -S-CO(C_H3- alkyl); StCH^COOR״. (with 0 &lt; m 5 6); -O(C^ alky!cne)NR₁₀R₁₁; -NR_]ONR_WR_״; C!_₆ alkyl; thiazolyl; thiazolyl substituted by at least one member selected from the group consisting of -NH₂, Cj.j alkyl, phenyl, and COOR₁₀; -NH-CCKC^-alkyl); or (C_I_₃alkylene)CH(NH₂)(COOH); or

-CR₅R₆R₇ is a group of the formula wherein Q 13 at least one member selected from the group consisting of H; COOR^q; phenyl;

alkylene-yCOOR^g; C^_j alkyl; ; *θ^^Ιי”3.י־ alkylenetNR_{10R11; 0H; C1}_₃ alkoxy; and NR_1O^R11^; °^r

89840/ 4 wherein any two of R₃, R₄, R₅, Rg and R_? together form a benzene ring; or a benzene ring substituted by fC₁_₃-alkyleneKOOR₁₀; tq^-alkyljOH, COOR_1Q/ or fC₁־₃״ alkylene-fO-COfC^-alkyl); or a naphthalene system; or a naphthalene system substituted by fC^-alkylenetCOOR^,

COOR_I0, or fC^-alkylene jO-COfC^.-jalkyl); and physiologically acceptable salts thereof,

With the proviso that (1) When R₇ is COOR_to, R₆ is H, R₂ is selected from hydrogen and phenyl and R, is selected from hydrogen and hydroxyl then R! does not represent phenyl, it being understood that when both R₂ and R₃ represent hydrogen then R₁ does not further represent 3-methoxyphenyl, 4methoxyphenyl, 3,4-dimethoxyphenyl, paratolyl, 4-chlorophenyl or benzyl.

(2) When R₇ is-O-fCj-Cj-alkylene)-NR_1oR_11׳ and r₃, R₅and R₆ are all hydrogen then R! does not represent phenyl.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds 0¢ 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 interleukin2־ (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, Ι^ΟΟβ, NaHCOp KOH, NaOH, NH3 and bases of the formula NR27^R28^R29 ״here ^R27' ^r28 ^an&lt;* ^R29 ^{are Hr c}l-6 ^alJ&lt;yl/ C^.g 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, HC1, 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 spray) 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 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 is C_1-7 alkyl, the preferred alkyl groups are alkyl, e.g., methyl, ethyl, n-propyl or iso-propyl. When R| is a ־־־13substituted phenyl group, the substituents are C!-3 alkyl, halogen, trifluoromethyl, hydroxy, alkoxy or nitro. Phenyl substituted by one halogen atom is particularly preferred. When is a substituted pyrridyl, the same preferred substituents for phenyl as given above, are also preferred.

The groups Ry, R3 and R₄ are preferrably H. Groups R5 and Rg are preferably =CR|qR^]_ with ^R10^=R11^=H.

Preferably Ry is a group which is metabolized in vivo to leave an acidic function on the flavonoid nucleus for Ry. Accordingly, -COOR^q, P(O) (OR-lqR^ , and -CONRjqR^ are preferred for Ry.

In another of its preferred embodiments, the present invention provides compounds of the following formula (IV)

22״

R25 C00H wherein:

AR₂₆ is phenyl, substituted phenyl or biphenyl;

- 15

R₂ is hydrogen, hydroxyl, or C_t_₃ alkoxy;

R₂₂ is hydrogen, hydroxyl or halogen^.

R₂₅ is hydrogen, 3-methylenepyridyl, benzylidene, 4-methylenepyridyl or methylene; or

R₂₅ and R₂₂ together form a benzene ring fused to the flavonoid nucleus.

These compounds and their derivatives are particularily useful as antitumor agents, notably as antipancreat1c 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 com.oouncs in good yields.

In a first process, a compound of (ill) ^R 3 0 _כ u T T /ΑχΑ, ^Ri5~\ Br is reacted either with (1) alkaline nitrile component followed by hydrolysis, or (2) with an amine (NR^R^), or (3) with triethylphosphite followed by hydrolysis, or (4) with a compound of formula R3₂־SH, or R32-OH, wherein R32 ^can be -C^COOEt or -CH₂CH2־N(C2H5)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-amino thiazole, 2-methylpyridine, 2-aminothiazole, or ethoxycarbonyl acetamide.

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

Compounds of formula (II) can also be obtained from appropriate compounds of formula (II) wherein R^g is methyl and is COO^Hg) by reaction with methyl iodide followed by hydrolysis.

Compounds of formula (II) can also be obtained by reacting compounds of formula (II) wherein is hydrogen and R|g 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 CO8.

In the tests run by the inventors, in the inhibition of tumor PO3 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 CO8, 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 mice 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)

־19-

<img file="IL89840A_D0002.tif" />

R₂ ar₂₆ (IV) wherein:

AR₂6 j-⁵ Phenyl, substituted phenyl or biphenyl;

R₂ is hydrogen, hydroxyl, or C-^_2 alkoxy;

R₂₂ is hydrogen or hydroxyl;

R₂₂ is hydrogen, or fluoro:

R₂4 is hydrogen, or hydroxy;

R₂g is hydrogen, 2-methylpyridyl, benzylidene, 4methyLenepyrridyl, or methylene; or

R₂₅ and R₂4 form a benzene ring fused to the flavonoid nucleus.

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):

-סב822 (?

<img file="IL89840A_D0003.tif" />

Rtf (,7V (V) wherein AR2g, ^2224^ ׳23^ ^׳ ®^d ^25 3s defined above. The nitriles of formula (V) are obtained by the reaction of an alkali cyano compound*with a compound of formula (VI):

0 ?2?׳ «23 m «24

<img file="IL89840A_D0004.tif" />

0^AR2e (VI) «25 Br wherein AR 26׳ ^R2׳ ^R22' ^R23' ^24 ^and ^R25 ^{are as} defined above.

With compounds of formula (IV) when R₂g is methylene or arylidene, the compounds are obtained by the reaction of compounds of formula (IV) wherein R₂g is hydrogen, with Ν,Ν,Ν,Ν-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 BBSS 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 BBSS.

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 5% of FBS, pencillin (100 D/ml) streptomycin (100 pg/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 (ULjg): where is the quantity necessary to effectuate lysis of 1 x 10^ 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 animals 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.

/2

EXAMPLES

Example

a) OXO-1 PHENYL-3-1H-NAPHTO (2,l־b) PYRAN5-ACETQNITRILE ^C21^H13^NO2 MW=311,344

A mixture of 8.2 g (0.0224 mole) of bromomethyl-5phenyl-3-[lH]-naphto(2.1-b)pyranol-l, of 4.9 g (0.031 mole) of tetraethylammonium cyanide in 250 ml of dichloroethane is stirred for 13 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׳, Vc=N; 2160 and 2220 cm”^־.

b) OXO-l-PHENYL-3-( 1H)-NAPHTO (2.1-b) PYRAN-5-ACETIC ACID ¾1^14^4

MW=330.34

[Formula 1]

<img file="IL89840A_D0005.tif" />

COOH

A mixture of 6*9 g (0.022 mole) of oxo-l-phenyl-3[lH]־naphto(2.1-b)pyran-5-aceto-nitrile, 50 ml of acetic acid, 50 ml of water and 50 ml of HjSO^ 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%); PFq=291293°C; IR: Vc=o (acid)=1700 cm“¹, Vc־o (pyrone)=1638 cm¹; NMR (DMSO)fi in ppm in relation to TMS: 2H at 4.03 (s), 1H at 7.1 (s), 9H at 7.3 to 8.3 (η), 1H at 12.5 (exchangeable).

<td> Elemental analysis</td><td> c%</td><td> H%</td><td> 0%</td>

<td> calculated :</td><td> 76.35</td><td> 4.27</td><td> 19.37</td>

<td> found :</td><td> 73.85</td><td> 4.01</td><td></td>

Using the same technique the following compounds are prepared:

ΟΧΟ-4-ΡΗΕΝΥΡ2-4־Η־ΝΑΡΗΤΟ (2.3-b) PYRAN-l-ACETIC ACID ^C24^h14°4 (Formula 2)

MW = 330.34

<img file="IL89840A_D0006.tif" />

COOH

PF_g = 276-288°C; IR: Vc=o (acid) = 1720 cm¹־, VC=o (pyrone)=7610 cm; NMR (DMSOJ6 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 calculated :

found :

<td> c%</td><td></td><td> 0%</td>

<td> 76.39</td><td> ’ 4.27</td><td> 19.38</td>

<td> 79.89</td><td> 4.39</td><td></td>

OXO-4-PHENYL-2-4H-NAPHTO (1.2-b) PYRAN-10-ACETIC ACID ^C21^H14°4 ^MW 330.34 [Formula 3]

<img file="IL89840A_D0007.tif" />

PFq=259-261°C; IR: Vc=0 (acid)=1710 cm“¹, Vc=O (pyrone)=7630 cm¹; NMR (DMSO)i in ppm in relation to TMS: 2H at 4.45(3), 1 H at 6.9 (s), 10H at 7.3 to 8.3 (m), 1H at 12.2 (exchangeable).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated :</td><td> 76.39</td><td> 4.27</td><td> 19.38</td>

<td> found :</td><td> 76.24</td><td> 4.07</td><td></td>

METHOXY-3-0X0-4-PHENYL-2H-(1)-BENZ0PYRAN-8-ACETIC ACID

MW=310.292 [Formula 4]

<img file="IL89840A_D0008.tif" />

PF_G=187-I92°c; IR Vc=O (acid)=1720 cm¹, Vc=o (pyrone)=1610 cm¹; NMR (DMS0)6 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).

<td> Elemental analysis</td><td> C%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 69.67</td><td> 4.55</td><td> 23.78</td>

<td> found :</td><td> 69.90</td><td> 4.55</td><td></td>

METHOXY-5-QXQ-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID ^C18^H14°5

MW=310.292 [Formula 5]

<img file="IL89840A_D0009.tif" />

<td> PF_g=245-248’C; IR vc=o (acid)=1720 cm (pyrone) 1640 cm; NMR (DMSO)fi in ppm in</td><td>, Vc - O relation to</td>

<td> TMS: 5H at 4 (s), 1H at 7.2 (s), 7H at 7.7</td><td> to 8.7 (m)</td>

<td colspan="2"> 1H at 12.2 (exchangeable). Elemental analysis C% H% 0% calculated : 69.67 4.55 29.78 found : 69.50 4.57 (METHOXY-2-PHENYL)-2-OXO-4-4H-(1) BENZOPYRAN-8-ACETIC</td>

ACID ^cX8^h!4°5 MW=310.292 [Formula 6]

<img file="IL89840A_D0010.tif" />

־28PFq-203-205**C; IR vc=o (acid)=1730 cm*¹; Vc=o (pyrone)=1610 cm*¹; NMR (DMSO)0 in ppm in relation to TMS; 5H at 4 (S)_f 1H at ר (S)t 7H at 7.1 to 8.1 (m), 1H at 12.8 (exchangeable). Elemental

<td></td><td> Cl</td><td> HI</td><td> 0%</td>

<td> calculated :</td><td> 69.67</td><td> 4.55</td><td> 25.78</td>

<td> found :</td><td> 69.72</td><td> 4.39</td><td></td>

HYDROXY-3-QXQ-4-PHENYL-2-4H-(1)-BENZOPYRAN-8-ACETIC ACID

MW=296.266 [Formula 7]

<img file="IL89840A_D0011.tif" />

PF_G=221-223^eC; IR Vc=o (acid)=1700 cm’¹, Vc=0 (pyrone)=1610 cm’¹; NMR (DMSO)6 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).

<td> Elemental analysis</td><td> Cl</td><td> HI</td><td> 01</td>

<td> calculated :</td><td> 68.92</td><td> 4.08</td><td> 27.00</td>

<td> found :</td><td> 68.86</td><td> 4.01</td><td></td>

־29HYDROXY-5-OXO-4-PHENYL.2-4 ־H-(1)-BENZOPYRAN-8-ACETIC ACID ^c17^h12°5 MW=296.266 [Formula 8]

<img file="IL89840A_D0012.tif" />

PF_g=233-238’C; IR Vc=o (acid)=1700 cm¹, Vc=0 (pyrone)=1680 cm¹; NMR (DMSO)fi 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

Elemental analysis calculated :

found :

(exchangeable).

C% H% 0%

68.92 4.08 27.00

68.85 4.22

HYDROXY-7-OXO-4-PHENYL-2-4H1)־)-BENZOPYRAN-8-ACETIC

ACID ^C17^H12°5

MW=296.266

[Formula 9]

HO

<img file="IL89840A_D0013.tif" />

COOH

PF_g=227238°־C; IR Vc=o (acid)=1700 cm¹־, Vc=0

<td> (pyrone) =1630 cm^-^־; NMR (DMSO)fi in</td><td> ppm in relation to</td>

<td> TMS? 2H at 3.8 (3),.8H at 6.8 to 8.</td><td> 2 (m), 2H at 10.8 to</td>

<td> 11.1 (exchangeable).</td><td></td>

<td> Elemental analysis</td><td></td>

<td> C%</td><td> H% 0%</td>

<td></td><td> -</td>

<td> calculated : 68.92</td><td> 4.08 27.00</td>

<td> found : 68.92</td><td> .4.00</td>

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

MW=296.266 [Formula 10]

<img file="IL89840A_D0014.tif" />

PF_g=288-292״C; IR Vc=o (acid)=1700 cm“¹, Vc=0 (pyrone)=1640 cm; NMR (DMSOJ4 in ppm in relation to TMSi 2H at 4 (3), 1H at 7 (S), 1H at 7 (3), 7H at 7.2 to 8.2 (m), 2H at 10.8 to 12.9 (exchangeable).

<td colspan="4"> Elemental analysis</td>

<td colspan="2"> c%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 68.92</td><td> 4.08</td><td> 27.00</td>

<td> found :</td><td> 68.75</td><td> 3.88</td><td></td>

(HYDROXY-3-PHENYL) -2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID ^c17^h12°5 MW=296.266 [Formula 11]

<img file="IL89840A_D0015.tif" />

PF_G=259-288^eC; IR Vc=o (acid)=1720 cm, Vc=0 (pyrone)=1630 cm^-^־; NMR (DMSO)fi 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).

<td> Elemental analysis</td><td> c%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 68.92</td><td> 4.08</td><td> 27.00</td>

<td> found :</td><td> 68.91</td><td> 4.21</td><td></td>

(HYDR0XY-4-PHENYL)-2-QXO-4-4H-(1)-BENZ0PYRAN-8-ACETIC ACID ^c17^h12°5 MW296.266־ [Formula 12]

<img file="IL89840A_D0016.tif" />

OH

PF_g=261-268°C; IR Vc=o (acid)=1690 cm, Vc=0 (pyrone)=1620 cm^-־'־; NMR (DMSO)6 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

<td></td><td> C%</td><td> Hl</td><td> 01</td>

<td> calculated :</td><td> 68.92</td><td> 4.08</td><td> 27.00</td>

<td> found :</td><td> 68.61</td><td> 4.20</td><td></td>

CHLOROHYDRATE OF (DIETHYLAMINOETHOXY-3-PHENYL)-2-OXO-44H- BENZOPYRAN-8-ACETIC ACID ^C23^H26^C1NO3 MW=431.903 [Formula 13]

<img file="IL89840A_D0017.tif" />

COCH /2

PF_r=176-179^eC; IR Vc=o (acid)=1720 cm'¹, Vc=0

<td> {pyrone)=1640 cm ¹i NMR</td><td> (DMSO)5</td><td> in ppm</td><td> in</td><td colspan="2"> relation to</td>

<td> TMS; 3H at 1.4 (t), 11H</td><td> at 3 to</td><td> 4.6 (m,</td><td> of</td><td> which</td><td> 1H is</td>

<td colspan="2"> interchangeable), 1H at 7.1 (s), 1H at 13.2 (interchangeable). Elemental analysis</td><td> 6H at</td><td> 7.2</td><td> to 8.1</td><td> (m),</td>

<td> C%</td><td> H%</td><td> Cl%</td><td></td><td> N%</td><td> 0%</td>

<td>¹¹</td><td></td><td></td><td></td><td></td><td></td>

<td> calculated: 63.96 found : 63.69</td><td> 6.07 5.88</td><td> 8.21 8.09</td><td></td><td> 3.24 3.01'</td><td> 18.32</td>

(PHENOXY-2-PHENYL-2-OXQ-4-4H-( 1) -BENZOPYRAN-8-ACETIC ACID ^C23^H16°5'

MW=372.38 [Formula 14]

<img file="IL89840A_D0018.tif" />

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

<td> Elemental analysis</td><td> C%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 74.19</td><td> 4.33</td><td> 21.48</td>

<td> found :</td><td> 73.88</td><td> 4.56</td><td></td>

FLUORO-6-OXO-4-PHENYL-2-4H-(l)־BENZ0PYRAN-8-ACETIC ACID c₁₇h₁1F0₄

MW=298.26 [Formula 15]

<img file="IL89840A_D0019.tif" />

PF_G=225-239^eC; IR Vc=o (acid)=1720 cm¹, Vc0־ (pyrone)=1640 cm¹; NMR (DMSO)i in ppm in relation to TMS; 3H at 3 to 4 (m, of which 1H is interchangeable), 1H at 7 (s), 7H at 7, 1H at 8.4 (m).

<td> Elemental analysis</td><td> C%</td><td> 1^</td><td> F%</td><td> 0%</td>

<td> calculated :</td><td> 68.49</td><td> 3.72</td><td> 6.37</td><td> 21.46</td>

<td> found :</td><td> 68.42</td><td> 3.92</td><td> 6.28</td><td></td>

(FLUORO-2-PHENYL)-2-OXO-4-4H-(1) -BENZOPYRAN-8-ACETIC ACID ^C17^H11^FO4

MW=298.26

[Formula 16]

<img file="IL89840A_D0020.tif" />

PF_G193־-I99°c; IR Vc=o (acid)=1720 cm¹־, Vc=O (pyrone)=1610 cm“¹; NMR (OMSO)i in ppm in relation to

<td colspan="3"> TMS; 2H at 4 (s), 1H at 6.7 (s), 7H at 7.2</td><td> to 8.4</td><td> (m)r 1H</td>

<td> at 12.5 (interchangeable). Elemental analysis</td><td> C%</td><td></td><td> n</td><td> 0%</td>

<td></td><td></td><td></td><td></td><td></td>

<td> calculated :</td><td> 68.49</td><td> 3.72</td><td> 6.37</td><td> 21.46</td>

<td> found :</td><td> 68.42</td><td> 3.92</td><td> 6.28</td><td></td>

(FLUORO-PHENYL)-2-OXQ-4H-(1)-BENZ0PYRAN-8-ACETIC ACID

C17^HH^FO4

MW=298.26 [Formula 17]

<img file="IL89840A_D0021.tif" />

PF_g=2L5-217°C; IR Vc=o (acid)1720־ cm¹־, Vc=O

<td> (pyrone)=1640 cm¹־; NMR</td><td> (CF₃COOD)6</td><td> in ppm</td><td> in relation</td><td> to</td>

<td> TMS; 2H at 4 (s), 8H at</td><td> 7 to 9 (m).</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td></td><td> F%</td><td> 0%</td>

<td> calculated :</td><td> 67.49</td><td> 3.72</td><td> 6.37 24</td><td> .46</td>

<td> found :</td><td> 68.54</td><td> 3.80</td><td> 6.33</td><td></td>

<td> (FLUORO3־-PHENYL)-2-0X0־</td><td colspan="3">-4H-(1)-BENZ0PYRAN-8-ACETIC</td><td> ACID</td>

<td> C₁₇HnFO₄</td><td> MW297.26־</td><td></td><td> 'Formula 18]</td><td></td>

<img file="IL89840A_D0022.tif" />

PF_g=201-203°C; IR Vc=o (acid)=1700 cm¹־, Vc=0 (pyrone)=1640 cm; NMR (DMSO)6 in ppm in relation to TMS; 2H at 4 (3), 1H at 7.1 (3), 7H at 7.2 to 8 (m), 1H at 12.6 (interchangeable). Elemental analysis

<td></td><td> C%</td><td> H%</td><td> F%</td><td> 0%</td>

<td> calculated :</td><td> 68.49</td><td> 3.72</td><td> 6.37</td><td> 21.46</td>

<td> found :</td><td> 68.20</td><td> 3.69</td><td> 6.28</td><td></td>

־37־ (PHENYL-4-PHENYL)2-OXO-4-4H-(1)-BENZ0PYRAN-8-ACETIC ACID ^C23^H16°4

MW=356,36 [Formula 19]

<img file="IL89840A_D0023.tif" />

PF_G229-231°־C; IR Vc־o (acid)=1710 cm¹, Vc=0

<td> (pyrone)=1620 cm; NMR (</td><td> DMSO)4 in</td><td> ppm in</td><td> relation to</td>

<td> TMS; חי at 4 (s), 1H at 7</td><td> (s), 12H</td><td> at 7.2</td><td> to 8.4 (m), 1H</td>

<td> at 12.6 (interchangeable)</td><td> *</td><td></td><td></td>

<td> Elemental analysis</td><td></td><td></td><td></td>

<td></td><td> c%</td><td> H%</td><td> 0%</td>

<td></td><td></td><td></td><td>¹</td>

<td> calculated :</td><td> 77.51</td><td> 4.53</td><td> 17.96</td>

<td> found :</td><td> 77.42</td><td> 4.41</td><td></td>

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

C₁₇^h11C1°4

MW=314.71 [Formula 20]

<img file="IL89840A_D0024.tif" />

PF_g=238-242°C; IR Vc=o (acid)=1720 cm“¹, Vc=O (pyrone)=1620 cm; NMR (DMS0)6 in ppm in relation to TMS; 2H at 4 (5), 1H at 7 (s), 7H at 7.2 to 8.2 (m), 1H at 12.5 (interchangeable).

Elemental

<td></td><td> C%</td><td></td><td> Cl%</td><td> 0%</td>

<td> calculated :</td><td> 64.87</td><td> 3.52</td><td> 11.27</td><td> 20.34</td>

<td> found :</td><td> 64.83</td><td> 3.37</td><td> 11.55</td><td></td>

(CARBOXY-4-PHENYL)2-0 ־X0-4-4H-(1)-BENZOPYRAN-8-ACETIC

ACID ^C18^H12°6

MW=324.27 [Formula 21]

<img file="IL89840A_D0025.tif" />

PF_g=312-314°C; IR Vc=o (acid)=1700-1720 cm¹, Vc=0 (pyrone)=1640 cm“¹.

Elemental analysis

<td></td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated :</td><td> 66.67</td><td> 3.73</td><td> 29.69</td>

<td> found :</td><td> 66.76</td><td> 3.73</td><td></td>

(FLUORO-2-PHENYL) -4-PHENYL)-2-QXO-4-4H-(1) BENZOPYRAN-8ACETIC ACID ^C23^H15^FQ4 MW=374.35 [Formula 22]

<img file="IL89840A_D0026.tif" />

PF_g=226-228°C; IR Vc=O (acid)=L720 cm^-.¹, Vc=0

<td> (pyrone)=1630 cm¹; NMR</td><td> (DMSO)4 in</td><td> ppm in</td><td> relation</td><td> to</td>

<td> THS; 2H at 4 (S), L2H at</td><td> 7 to 8.4</td><td> (nt), 1H</td><td> to 12.8</td><td></td>

<td> (interchangeable).</td><td></td><td></td><td></td><td></td>

<td> Elemental analysis</td><td></td><td></td><td></td><td></td>

<td></td><td> C%</td><td> H%</td><td> F%</td><td> 0%</td>

<td></td><td> - </td><td></td><td></td><td></td>

<td> calculated :</td><td> 73.79</td><td> 4.04</td><td> 5.08</td><td> 17.10</td>

<td> found :</td><td> 73.80</td><td> 4.14</td><td> 4.87</td><td></td>

(NITRO-2-PHENYL)-2-QXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID ^c17^h11ⁿ⁰4 MW325.28־ (Formula 23]

<img file="IL89840A_D0027.tif" />

COOH

PF_G=180-182^eC; IR Vc=o (acid)=1700 cm ¹, Vc-0

<td> (pyrone)=1640 cm ¹,י NMR</td><td> (DMSO)fi</td><td> in ppm in</td><td> relation</td><td> to</td>

<td> TMS; 2H at 4 (s), 1H at</td><td> 6.8 (s),</td><td> 7H at’7.3</td><td> to 8.3</td><td> (m), 1H</td>

<td> at 12.8 (interchangeable</td><td> ) _t</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td></td><td></td><td></td><td></td>

<td></td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td></td><td></td><td></td><td>¹</td><td></td>

<td> calculated :</td><td> 62.77</td><td> 3.41</td><td> 4.31</td><td> 29.51</td>

<td> found :</td><td> 62.82</td><td> . 3.47</td><td> 4.20</td><td></td>

(NITRO-3-PHENYL)-2-OXQ-4-4H1)־)-BENZOPYRAN-8-ACETIC ACID ^C17^H11^NO6

MW=325.28 [Formula 24]

<img file="IL89840A_D0028.tif" />

PF_G203-208־^eC; IR Vc־o (acid)1720־ cm¹, Vc0־ (pyrone)=1630 cm¹; NMR (DMSO)i 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

<td></td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 62.77</td><td> 3.41</td><td> 4.31</td><td> 29.51</td>

<td> found :</td><td> 62.49</td><td> 3.40</td><td> 4,31</td><td></td>

(NITRO-4-PHENYL)-2-OXQ-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID ^C17^H11^NO6

MW=325.28 [Formula 25]

<img file="IL89840A_D0029.tif" />

PF_G=242-244’C; IR Vc=o (acid)=1720 cm“¹, Vc=0 (pyrone)=1620 cm“¹; NMR (DMSO)fi in ppm in relation to

<td rowspan="2"> TMS; 2H at 4 (s), 1H at 7 at 12.5 (interchangeable). Elemental analysis</td><td> (s), 7H at</td><td> 7.2 to</td><td> 8.3 (m)</td><td> 1, 1H</td>

<td> C%</td><td> Hl</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 62.77</td><td> 3.41</td><td> 4.31</td><td> 29.51</td>

<td> found :</td><td> 62.92</td><td> 3.38</td><td> 4.28</td><td></td>

(AMINO-3-PHENYL)-2-QXQ-4-4H1)־)-BENZOPYRAN-8-ACETIC ACID c_l7h₁₃no₄

MW=295.28

[Formula 26]

<img file="IL89840A_D0030.tif" />

COOH

PF_G=227-139°C; IR Vc=o (acid)=1720 cm¹־, Vc=O (pyrone)=1630 cm; NMR (DMS0)6 in ppm in relation to TMS; 2H at 4 (s), 9H at 6.8 to 8 (m), 1H at 12.6 (interchangeable). Elemental

<td></td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 69.14</td><td> 4.44</td><td> 4.74</td><td> 21.67</td>

<td> found :</td><td> 69.20</td><td> 4.70</td><td> 4.94</td><td></td>

(AMINO-2-4-PHENYL)-2-OXO-4-4H-(1)-BENZ0PYRAN-8-ACETIC ACID c₁₇h₁₃no₄

MW-295.28 [Formula 27]

<img file="IL89840A_D0031.tif" />

PF_G=189^eC; IR Vc=o (acid)=1700 cm¹־, Vc=0 (pyrone)=1620 cm¹־.

Elemental analysis

<td></td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 69.14</td><td> 4.44</td><td> 4.74</td><td> 21.67</td>

<td> found :</td><td> 69.00</td><td> 4.48</td><td> 4.66</td><td></td>

OXO-4-PHENYL-2-4H-(1)-BENZ0PYRAN-8-ACETIC ACID ^c17^h12°4 MW=280.28 [Formula 28]

<img file="IL89840A_D0032.tif" />

PF_G=240-242^eC; IR Vc־o (acid)1740־ cm‘¹, Vc=0 (pyrone)=1640 cm; NMR (DMSO)6 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).

<td> Elemental analysis</td><td> C%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 72.85</td><td> 4.32</td><td> 22.83</td>

<td> found :</td><td> 73.00</td><td> 4.16</td><td></td>

<td> OXO-4-PHENYL-2-4H-( 1)</td><td> BENZOPYRAN-</td><td> 7-ACETIC</td><td> ACID</td>

^C17^H12°4 MW-280.28 [Formula 29]

<img file="IL89840A_D0033.tif" />

PF_g=237-239°C; IR Vc=o (acid)=1740 cm, Vc=O (pyrone)=1620 cm”¹; NMR (DMSO)S in ppm in 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

<td></td><td> C%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 72.85</td><td> 4.32</td><td> 22.83</td>

<td> found :</td><td> 72.73</td><td> 4.33</td><td></td>

TRIFLUOROMETHYL-2-OXO-4-4H-(1)-BENZOPYRAN-8-ACETIC ACID ^C12^H7^F3°4 MW=272.17 [Formula 30]

<img file="IL89840A_D0034.tif" />

PF_G=141-143^eC; IR Vc=o (acid)=1700 cm'¹, Vc=0 (pyrone)-1650 cm¹.

Elemental analysis

<td></td><td> C%</td><td></td><td> n</td><td> 01</td>

<td> calculated :</td><td> 52.95</td><td> 2.59</td><td> 20.94</td><td> 23.52</td>

<td> found :</td><td> 52.72</td><td> 2.64</td><td> 20.35</td><td></td>

OXO-4-PHENYL-2-4H-(1)-BENZ0THI0PYRAN-8-ACETIC ACID ^C17^H12°3^S

MW=296.34 [Formula 31]

<img file="IL89840A_D0035.tif" />

<td colspan="2" rowspan="2"> PF_G=198-200°C; IR Vc=o (acid)= (pyrone)=1610 cm^-^־; NMR (DMSO)fi in</td><td rowspan="2"> 1720 cm ppm in</td><td colspan="2">¹, Vc=0</td>

<td> relation</td><td> to</td>

<td> TMS; 2H at 4 (s), 1H at</td><td> 7.3 (s), 7H</td><td> at 7.3</td><td> to 8.4</td><td> (m), 1H</td>

<td> at 12.5 (s), 1H at 7.3</td><td> (s), 7H at 7</td><td> .3 to 8</td><td> .4 (m),</td><td> 1H at</td>

<td> 12.5 (interchangeable).</td><td></td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> 0%</td><td> S%</td>

<td> calculated :</td><td> 68.40</td><td> 4.08</td><td> 16.20</td><td> 10.82</td>

<td> found :</td><td> 69.04</td><td> 4.29</td><td></td><td> 11.04</td>

OXO-4-PHENYL-2-4H-(1)-BENZOTHIQPYRAN-8-ACETIC ACID ^c17^h12°5^s MW=328.34 (Formula 32]

<img file="IL89840A_D0036.tif" />

PF_G=184-187^eC; IR Vc=o (acid)=1700 cm¹־, Vc=O (pyrone)=1660 cm’¹; NMR (DMSO)S 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).

<td> Elemental analysis</td><td> C%</td><td></td><td> 0%</td><td> S%</td>

<td> calculated :</td><td> 62.18</td><td> 3.68</td><td> 24.36</td><td> 9.77</td>

<td> found :</td><td> 62.29</td><td> 3.68</td><td></td><td> 9.65</td>

ΟΧΟ-4-ΡΗΕΝΥϋ-2-ΡΙΗΥΡΗΟ-1-4-ΟϋΙΝΟΕΙΝΕ-9-Α€ΕΤΙΟ ACID

C17H13NO3

MW=279.29 [Formula 33]

<img file="IL89840A_D0037.tif" />

PF_G=236-238°C; IR Vc=o (acid)=1680 cm¹־, Vc=0 (pyrone)=1620 cm¹־; NMR (DMSO)4 in ppm in relation to

<td> TMS; 2H at 4 (s), 8H at 7 (interchangeable).</td><td> to 8.3</td><td> (m), 1H at</td><td colspan="2"> 8.5</td>

<td> Elemental analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td></td><td></td><td></td><td></td><td></td>

<td> calculated :</td><td> 73.11</td><td> 4.69</td><td> 5.01</td><td> 17.13</td>

<td> found :</td><td> 73.10</td><td> 4.62</td><td> 5.04</td><td></td>

־47OXO-4-PHENYL-2-4H-(1)-BENZ0SELEN0PYRAN-8-ACETIC ACID ^C17^H12°3^Se

MW=343.24 (Formula 34]

<img file="IL89840A_D0038.tif" />

PF_g=182-184°C; ir Vc=o (acid)=1700 cm¹, Vc=0 (pyrone)=1600 cm¹; NMR (DMSO)5 in ppm in relation to TMS; 2H at 4 (s), 8H at 7.4 to 8.6 (m), 1H at 12.5 (interchangeable). Elemental C% H% 0¾ Se% calculated : 59.49 3.52 13.98 23.00 found : 59.30 3.26 22.91

OXO-7-7H-BENZO(C)XANTHENYL-ll-ACETIC ACID ^c19^h12°4 MW=304.31 [Formula 35]

<img file="IL89840A_D0039.tif" />

C0Qh

PFg=270-272^eC; IR Vc=o (acid)=1720 cm, Vc=O (pyrone)=1620 cm; NMR (DMSO)S 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 calculated :

74.99

3.97

21.03 found

74.34

3.93

OXO-4-7-7H־DIBENZO(C,h)XANTHENYL-l-ACETIC ACID ^C23^H14°4

MW=354.37

[Formula 36] coo H

PF_G=276-278’C; IR Vc־o {acid)=1700 cm¹־, Vc=0 (pyrone)=1620 cm“¹; NMR (DMSO)5 in ppm in relation to TMS; 2H at 4 (s), 11H at 7.4 to 8.8 (in), 1H at 12.5 (interchangeable). Elemental analysis calculated

77.96

3.98

18.06 found

77.94

3.97

CARBOXYMETHYL-4-PHENYL)-2-4H1)־) BENZOPYRANONE-4 ^C17^H12°4

MW=280.17 [Formula 37]

<img file="IL89840A_D0040.tif" />

<td> PF_g=204°C; IR Vc=o (pyrone)=1640 cm.</td><td colspan="3"> (acid)=1720 cm“¹, Vc=0</td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated :</td><td> 72.84</td><td> 4.32</td><td> 22.84</td>

<td> found :</td><td> 72.08</td><td> 4.33</td><td></td>

(CARB0XYMETHYL-3-PHENYL)-2-4H-(-ll BENZOPYRANONE-4 ^C17^H12°4

MW=280.27 [Formula 38]

<img file="IL89840A_D0041.tif" />

־50PFr-=181183־^eC; IR Vc=o (acid)=1720 cm¹, Vc=0 kJ (pyrone)=1620 cm¹; NMR (DMSO)6 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).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated :</td><td> 72.84</td><td> 4.32</td><td> 22.84</td>

<td> found :</td><td> 73.08</td><td> 4.41</td><td></td>

(CARBOXYMETHYL-2-PHENYL)2-4־H-(1) BENZOPYRANONE-4 ^C17^H12°4

MW=280.27 [Formula 39]

<img file="IL89840A_D0042.tif" />

PF_G=179-181°C; IR Vc=o (acid)=1730 cm¹, Vc=0 (pyrone)=1630 cm¹; NMR (DMSO)5 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 ' C% H% 0% calculated : 72.84 4.32 22.84 found

73.79

4.34 ־51((QXO-4-PHENYL-2-4H-(!) BENZ0PYRAN-8-YL) METHYL) PHOSPHONATE OF DIETHYL

[Formula 40]

PF_g=107-109’C; IR Vc=0 (pyrone)=1640 cm; NMR (CDC13)6 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 calculated :

64.51

5.69

21.48

8.32 found

64.59

5.67

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

MW=316.24

[Formula 41]

PF_g=331-334’C; IR V OH = 3400 to 2200 cm¹, Vc=0 (pyrone)=1620 cm¹; NMR (DMSO)6 in ppm in relation to TMS; 2H at 3.45 (d), 1H at 7.03 (3), 8H at 7.2 to 8.4 (m), 2H at 9.7 (interchangeable).

<td> Elemental analysis</td><td rowspan="2"> C%</td><td rowspan="2"></td><td rowspan="2"> 0%</td><td rowspan="2"> P%</td>

<td></td>

<td> calculated :</td><td> 60.76</td><td> 4.14</td><td> 29.30</td><td> 9.80</td>

<td> found :</td><td> 60.77</td><td> 4.17</td><td></td><td> 9.83</td>

Example (PHENYL-2-OXO-4-4H-(!) BENZOPYRAN-8-YL)2־-ACRYLIC ACID ^C18^H12°4

MW=292.27 [Formula 42]

<img file="IL89840A_D0043.tif" />

8.4 g (0.03 mole) of oxo-4-phenyl-2-4H-{4}benzopyran-8-acetic and 81 ml of Ν,Ν,Ν',Ν' tetramethyldiaminomethane 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^eC. 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%); PFq=240-247°C; IR Vc=o (acid)=1689 cm, Vc=0 (pyrone)=1620 cm¹; NMR (DMSO)« in ppm in relation to TMS; 2H at 6.3 (d), 1H at 7 (3), 8H at 7.3 to 8.2 (m), 1H at 13 (interchangeable).

Elemental analysis calculated :

found :

<td> c%</td><td> H%</td><td> 0%</td>

<td> 73.96</td><td> 4.14</td><td> 21.90</td>

<td> 74.21</td><td> 4.05</td><td></td>

Example

PHENYL-3-(PHENYL-2-OXO4-4־H-[l]

ACRYLIC ACID ^c24^h16°4 MW=368.36 [Formula 43]

<img file="IL89840A_D0044.tif" />

A mixture of 9.2 g (0.087 mole) of benzaldehyde,

16.8 g (0.06 mole) of oxo-4-phenyl-2-4H-[l]-benzopyranacetic 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^eC; IR Vc=o (acid)=1680 cm, Vc=0 (pyrone)=1630 cm; NMR (DMSO)4 in ppm in relation to TMS; 15H at 6.8 (m), 12.5 (interchangeable).

־,א

<td> Elemental analysis</td><td> Cl</td><td> HI</td><td> 01</td>

<td> calculated :</td><td> 78.25</td><td> 4.39</td><td> 17.31</td>

<td> found :</td><td> 77.90</td><td> 4.11</td><td></td>

Using the same technique, the following compounds were prepared:

(BROMO-2-PHENYL)-3-( PHENYL-2-OXQ-4-4H-[1] BEN2OPYRAN-8 ־

YL)-3-ACRYLIC ACID ^c24^H15^BrO4 MW=447.27 [Formula 44)

<img file="IL89840A_D0045.tif" />

PF_G=217-219״C; IR Vc=o (acid)=1680 cm¹, Vc=O (pyrone)=1640 cm¹; NMR (DMSO)« in ppm in relation to TMS; 14H at 6.8 to 8.1 (m), 1H at 12.8 (interchangeable).

<td> Elemental analysis</td><td> Cl</td><td> HI</td><td> Brl</td><td> 01</td>

<td> calculated :</td><td> 64.44.</td><td> 3.3a</td><td> 17.87</td><td> 14.31</td>

<td> found :</td><td> 64.29</td><td> 3.37</td><td> 17.58</td><td></td>

(PYRIDINYL-4)-3-(PHENYL-2-OXO-4-4H-[1] BENZ0PYRAN-8-YL)-

3-ACRYLIC ACID ^c23^h15^NO4 MW=369.36 [Formula 45]

<img file="IL89840A_D0046.tif" />

<td colspan="2" rowspan="2"> PF_g=272-283°C; IR Vc=o (acid) (pyrone)-1640 cm ¹, NMR (DMSO)S in</td><td colspan="3"> 1700־ cm¹־, Vc=0</td>

<td> ppm in</td><td colspan="2"> relation to</td>

<td> TMS; 14H at 6.8 to</td><td> 8.4 (m), 1H at</td><td colspan="3"> 12.8 (interchangeable).</td>

<td> Elemental analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 74.79</td><td> 4.09</td><td> 3.79</td><td> 17.33</td>

<td> found :</td><td> 74.54</td><td> 4.00</td><td> 3.79</td><td></td>

(PYRIDINYL-3)-3-(PHENYL-2-OXO4-4־H-[lj ACRYLIC ACID ^C23^H15^NO4 MW=369.36 [Formula 46]

<img file="IL89840A_D0047.tif" />

PF_G=118124־^eC; IR Vc=o (acid)=1720 cm’¹, Vc=O (pyrone)=1630 cm; NMR (DMSO)fi in ppm in relation to TMS; 14H at 7 to 8.5 (m), 12.5 (interchangeable).

Elemental

<td></td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 74.79</td><td> 4.09</td><td> 3.79</td><td> 17.33</td>

<td> found :</td><td> 74.36</td><td> 4.09</td><td> 3.50</td><td></td>

Example

CHLOROHYDRATE OF [(METHYL-4-PIPERAZINYL) METHYL]-8PHENYL-2-4H-[1] 3ENZOPYRANONE>4

C₂₁H₂₃C1N₂O₂ MW=370.87 [Formula 47]

<img file="IL89840A_D0048.tif" />

18.9 g (0.06 mole) of Bromomethyl-8-oxo-4־phenyl-24H-[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^eC; IR Vc=0 (pyrone)=1640 cm”¹. Using an HC1 treatment in CHC1₃, the chlorohydrate is obtained: PF_G^a244-246°C.

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> Cl%</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 58.00</td><td> 6.25</td><td> 9.56</td><td> 7.56</td><td> 8.63</td>

<td> found :</td><td> 68.34</td><td> 5.86</td><td> 9.80</td><td> 7.61</td><td></td>

Using the same technique, the following compounds were prepared:

BROMOHYDRATE OF N[IMIDAZOLINYL-2], N [(OXO-4-PHENYL-2-4H[1] BENZQPYRAN-8-YL) METHYL]-DICHLORQ-2-6-ANILINE ^c25^H20^SrC12^N3°2

MW-545.26 [Formula 48]

<img file="IL89840A_D0049.tif" />

PF_g=289-290*C; IR Vc=o (pyrone)=1640 cm*¹; V

<td colspan="4"> NH3000-3200־ cm¹; NMR (DMS0)5 in ppm</td><td colspan="2"> in relation</td><td> to TMS</td>

<td> 4H at 3.4 (s), 2H</td><td> at 5.</td><td> 5 is),</td><td> 1H at 7</td><td> (s),</td><td> 11H at</td><td> 7.2 to</td>

<td> 8.3 (m), 2H at 8.5</td><td> to 9</td><td colspan="3"> .5 (interchangeable)</td><td> •</td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> .Br%</td><td> Cl%</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 55.06</td><td> 3.70</td><td> 14.66</td><td> 13.00</td><td> 7.71</td><td> 5.87</td>

<td> found :</td><td> 55.14</td><td> 3.63</td><td> 14.56</td><td> 13.09</td><td> 7.07</td><td></td>

־58[(OXO4־-PHENYL2-4־H-(1) BENZ0PYRAN-8-YL0 METHYL AMINO]-4BENZOIC ACID ^c23^h17^NO4 MW=371.396 [Formula 49]

<img file="IL89840A_D0050.tif" />

PFr-269-271°C; IR Vc=o (acid)1710־ cm”¹, Vc=0 (pyrone)=1640 cm¹; NMR (DMSO)4 in ppm in relation to TMS; 2H at 4.8 (m), 13H at 6.9 to 8.27 (m), 1H at 12.6 (interchangeable).

<td> Elemental analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 74.38</td><td> 4.61</td><td> 3.77</td><td> 17.24</td>

<td> found :</td><td> 74.08</td><td> 4.59</td><td> 3.91</td><td></td>

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

C24^H19^NO4

[Formula 50]

MW=385.424

<img file="IL89840A_D0051.tif" />

PF260-262=>-״^oC; IR Vc=o (acid)=1710 cm'¹, Vc=O (pyrone)=1640 cm'¹; NMR (DMSO)« in ppm in relation to

<td> TMS; 3H at 3.2 (s), 2H at 5 (S),</td><td> 13H at 6.8</td><td> to 8.4</td><td> (m),</td>

<td> 1H at 12.6 (interchangeable).</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td></td><td></td><td></td>

<td> C%</td><td></td><td> N%</td><td> 0%</td>

<td></td><td></td><td></td><td></td>

<td> calculated : 74.79</td><td> 4.97</td><td> 3.63</td><td> 16.60</td>

<td> found : 74.51</td><td> '4.81</td><td> 3.47</td><td></td>

[(ΟΧΟ-4־ΡΗΕΝΥΙ-2-4Η1]־] BENZOPYRAN-8-YLO METHYLAMINO]-3, METHYL-3, PROPANEDIOL-13־ ^C20^H24^NO4

MW=339.398 [Formula 51]

<img file="IL89840A_D0052.tif" />

PF_g=150-152°־C; IR Vc=o {pyrone) = 1630 cm¹, V OH=3380 cm“¹; NMR (DMSO)i 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).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 70.78</td><td> 6.24</td><td> 4.13</td><td> 18.25</td>

<td> found :</td><td> 70.51</td><td> 6.42</td><td> 4.37</td><td></td>

CHLOROHYDRATE OF (AMINOMETHYL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4 ^c16^H14^C1NO4 MW=287.19 [Formula 52]

<img file="IL89840A_D0053.tif" />

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

<td></td><td> C%</td><td> H%</td><td> Cl%</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 64.76</td><td> 5.1</td><td> 11.95</td><td> 4.72</td><td> 13.48</td>

<td> found :</td><td> 65.05</td><td> 4.73</td><td> 12.08</td><td> 4.46</td><td></td>

PHENYL-2-(TRIMETHOXY-3,4,5-PHENYLAMINOMETHYL)8-4־H1]־] BENZOPYRANONE-4

C24H23NO5 MW=417.47 [Formula 53]

<img file="IL89840A_D0054.tif" />

PF219-2221=״C; IR V NH=3350 cm¹, Vc=o (pyrone)=1620 (j cm¹; NMR (CF-jCOOD)6 in ppm in relation to TMS; 6H at

<td> 3.15 (s), 3H at 3.35 (s),</td><td> 2H at 4.93</td><td> (S),</td><td> 1H at 6.1 (s),</td>

<td> 11H at 7 to 8.3 (m).</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> N% 0%</td>

<td> calculated :</td><td> 74.93</td><td> 5.55</td><td> 3.35 19.16</td>

<td> found :</td><td> 71.65</td><td> 5.58</td><td> 3.35</td>

Example (ACETYLOXY-l-ETHYL)-8-PHENYL2-4־H-[1] BENZOPYRANONE-4 ^C19^H16°4 MW=308.32 [Formula 54]

<img file="IL89840A_D0055.tif" />

61.2 g (0.186 mole) of (bromo-l-ethyl)-8-phenyl-24H-[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%);

PFr=137’C; IR Vc=o (ester) = 1740 cm’¹, Vc=o (pyrone)=1640 cm’¹; NMR (CDC!₃)4 in ppm in relation to TMS; 3H at 1.7 (d)33 _׳ at 2.1 (s), 13 at 6.6 (g), 1H at 6.8, 8H at 7.2 to 8.4 (m).

Example (HYDROXY-l-ETHYL)8־-PHENYL-2-4H-[1] BENZOPYRANONE-4 ^C17^H14°3 MW=266.3 [Formula 55]

194.3 g (0.63 mole) of (acetoloxy-l-ethyl)-8-phenyl2-48-(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 mikture is heat-filtered, the filtrate is evaporated in a vacuum, the residue is takan up in water and recrystallized in toluene. Weight obtained: 152.9 g (yield: 91%);

PF_G=154157־^OC; IR V OH=3350 cm’¹, Vc=O (pyrone)=1620 cm; NMR (CDC13)5 in ppm in relation to TMS; 3H at 1.62 (d), 1H at 2.8 (interchangeable).

Elemental

<td></td><td> c%</td><td></td><td> 0%</td>

<td> calculated :</td><td> 76.67</td><td> 5.30</td><td> 18.03</td>

<td> found :</td><td> 76.50</td><td> 5.19</td><td></td>

Example 7

ACETYL-8-PHENYL-2-4H-1 BENZOPYRANONE-4 ^C17^H12°3 MW=264.28

[Formula 56]

<img file="IL89840A_D0056.tif" />

59.5 g (0.223 mole) of (hydroxy-l-ethyl)-8-phenyl-24H-[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 CrO3, 50 ml of water, 13.6 ml of concentrated H₂^SO4 ^{13 a}^ded 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-I26^ec; IR Vc=o (cetone)=1675 cm, Vc=0 (pyrone)=1690 cm¹; NMR (CDC1₃)5 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 ---------------- C% ־H% 0% calculated : 77.26 4.58 18.16 found : 77.23 4.53

Example (BROMOACETYL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4 ^c17^Hll^SrO3 MW=343.18 [Formula 57]

<img file="IL89840A_D0057.tif" />

To a solution of 40 g (0.19 mole) of acetyl-8phenyl-2-4H-[l] 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&lt;-.=142°C; IR Vc=o -1630 cm'¹, NMR (CDC1₃)&lt;5 in ppm in relation to TMS; 2H at 4.64 (s), 1H at 6.8 (s), 8H at

7.2 to 8.6 (m).

Example (AMINO-2-THIAZOL-4-YL)-8-PHENYL-2-4H-[1] BENZOPYRANONE-4 ^C18^H12^N2°2^S MW=320.37 [Formula 58]

<img file="IL89840A_D0058.tif" />

A mixture of 5 g (0.0146 mole) of (bromoacetyl.)-8phenyl-2-4H-[l] 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 cm¹־Vc=o=1630 cm'¹; NMR (CDCl₃)i in-ppm in relation to TMS; 2H at 3.34 (interchangeable).

Elemental analysis calculated : 67.48 3.78 8.74 9.99 10.01 found

67.57

3.65

8.84

10.06

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]

PF_g=148-153®C; IR Vc=o (acid)=1639 cm, NMR (CDC1₃)4 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 —־ Cl HI Nl 0% SI calculated : 71.45 4.10 4.39 10.02 10.04 found : 71.39 4.03 4.36 10.30 (IMIDAZO [2,1-B] THIAZOL-6-YL)8־-PHENYL-2-4H-[1]

BENZOPYRANONE-4 ^c20^H12^N2°2 ^S MW=344.39 [Formula 60]

<img file="IL89840A_D0059.tif" />

<td rowspan="2"> PF_G229-233־^dC; CF₃COOD)6 in ppm in</td><td colspan="3"> IR Vc=o = 1630 cm, NMR</td><td rowspan="2"> (DMSO + (s)r 11H at</td>

<td> relation</td><td> to TMS;</td><td> 1H at Ί</td>

<td> 7.4 to 8.8 (m). Elemental analysis</td><td> C%</td><td> H%</td><td> N%</td><td> 0% s%</td>

<td> calculated ;</td><td> 69.75</td><td> 3.51</td><td> 8.14</td><td> 9.28 9.31</td>

<td> found :</td><td> 69.50</td><td> 3.53</td><td> 8.01</td><td> 9.37</td>

[IMIDAZO [1,2-A] PYRIDIN-2-YL]8־-PHENYL2-4־H-[1] BENZOPYRANONE-4 ^c22^H14^N2°2 MW338.35־ [Formula 61]

<img file="IL89840A_D0060.tif" />

<td> PF/-=203-205°C; IR Vc=o = 1635 Li</td><td> cm¹־, NMR</td><td> (CDC1</td><td> ^)5 in</td>

<td> ppm in relation to TMS; 1H at 6.8</td><td> (s), 13H at</td><td> 7 to</td><td> 8.7</td>

<td> (m).</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td></td><td rowspan="2"> N%</td><td rowspan="2"> 0%</td>

<td> c%</td><td> H%</td>

<td> calculated : 78.09</td><td> 4.17</td><td> 8.28</td><td> 9.46</td>

<td> found : 78.16</td><td> 4.12 ־</td><td> 8.26</td><td></td>

(INDOLIZIN-2-YL)-8-PHENYL-2-4H-{1] BENZOPYRANONE-4 ^C23^H15^NO2

MW=337.36

[Formula 62]

<img file="IL89840A_D0061.tif" />

<td> PF_G=204-207^eC;</td><td> IR Vc=o 1639</td><td> cm¹־, NMR</td><td> (CDC1₃)4</td><td> in</td>

<td> ppm in relation to</td><td> TMS; IB at 6.8</td><td> (9)1 ׳H</td><td> at 7.3 to</td><td> 8.3</td>

<td> (m).</td><td></td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> Hl</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 81.88</td><td> 4.48</td><td> 4.15</td><td> 9.49</td>

<td> found :</td><td> 82.03</td><td> 4.60</td><td> 4.16</td><td></td>

־69PHENYL-2-(PHENYL-2-THIAZOL-4-YL)-8-4H ^C24^H15°2^S

MW=381.46

[1] BENZOPYRANONE-4

[Formula 63]

<img file="IL89840A_D0062.tif" />

PF_G=199202°־C; IR Vc=o 1650 ־־ cm in ppm in relation to TMS; 15H at 7.4 Elemental C% H% calculated : 75.57 3.96 found : 75.42 4.03 (DIHYDRO-2-3-IMIDAZO [2,1-B] TEIAZOL[1] BENZOPYRANONE-4 ^C20^H14^N2°2 ^S MW346.40־ ¹, NMR (CF₃COOD)i to 8.8.

N% 0% S% .67 8.39 8.41 .64 8.15

-YL)-8-PHENYL-2-4H[Formula 64]

<img file="IL89840A_D0063.tif" />

<td> PF_G=226-230°C; ppm in relation to at 7.4 to 8.3 (m).</td><td colspan="4"> IR Vc=O = 1635 cm¹־, NMR (DMSO)« TMS; 4H at 4 to 5 (m), 1H at 7 (S</td><td> in ), 9H</td>

<td> Elemental analysis</td><td> C|</td><td></td><td> N%</td><td> 0%</td><td> S%</td>

<td> calculated :</td><td> 69.34</td><td> 4.07</td><td> 8.09</td><td> 9.24</td><td> 9.26</td>

<td> found :</td><td> 69.21</td><td> 4.19</td><td> 8.32</td><td></td><td> 9.02</td>

EXAMPLE

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

C₂₂H_l6O₄ MW = 334.37 [FORMULA 65]

<img file="IL89840A_D0064.tif" />

A mixture of 19.8 g (0.054 mole) of bromomethyl-10phenyl-2-4H-naphto[l,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

־71־ obtained is then filtered and used in the following step, without further purification. Weight obtained: 18.5 g (quantitative yield); PFq = 170°C; IR Vc = 0 (ester) = 1740 cm, Vc = 0 (pyrone) = 1635 cm; NMR (CDCI3) 5 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-2-4 H-NAPHTO(1,2-b]PYRANONE-4 ^C20^H14°3 ^{MW = 302}.³³ [FORMULA 66]

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 HC1. 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 = ο = 1630 cm¹; NMR (DMSO) δ in ppm in relation to TMS: 1H at 3.5 (5, large), 2H at 5.4 (s), 1H at 7 (s), 10H at 7.2 to 8.4.

QXO-4-PHENYL-2-4H-NAPHTO[1,2־b]PYRANONE-4 ^C20^H12°4

MW = 316.31

[FORMULA 67]

<img file="IL89840A_D0065.tif" />

A mixture of 16.2 g (0.0536 mole) of hydroxymethyl10-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 HC1. The precipitate obtained is filtered and recrystallized in acetic acid. Weight obtained: 1.1g (yield 6.5%); mp = 278-280°C; IR Vc = 0 (acid) = 1700 cm”¹, Vc = 0 (pyrone) - 1620 cm ¹: NMR (DMSO) 6 in ppm in relation to TMS: 1H at 7.15 (3), 10H at 7.4 to 8.4 (m), 1H at 13.5 (interchangeable).

<td> Elemental Analysis</td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated</td><td> 75.96</td><td> 3.82</td><td> 20.24</td>

<td> found</td><td> 75.58</td><td> 3.77</td><td></td>

EXAMPLE

OXO-4-PHENYL-1-4H-[1]-BENZOPYRAN-8-ACETATE (ETHOXYCARBONYL)-1-ETHYL ^C20^H20°6

MW = 380.38

[FORMULA 68]

<img file="IL89840A_D0066.tif" />

To a suspension of 30.6 g (0.109 mole) of oxo-

4-phenyl-2-4H-l-benzopyran-8-acetic acid in 1.9 1 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. Heatfiltratioin 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^eC; IR Vc = 0 (pyrone) = 1730 cm'¹, Vc = 0 (pyrone) - 1640 cm¹; NMR (CDClg) δ in ppm in relation to TMS: 3H at 1.2 (t), 3H at 1.46 (d), 2Ξ at 4.1 (s), 2H at

4.18 (g), 1H at 5.18 (q), 1H at 6.8 (s), 8H at 7.2 to 8.4 (m). (interchangeable).

־75־

HYDROXY-4-METHYL-5-(OXQ-4-PHENYL-2-4H-[11-BENZOPYRAN-8YL)-3-5H-FURANONE-2 ^C20^H14°5

MW = 334.31 [FORMULA 69]

O

<img file="IL89840A_D0067.tif" />

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-[l]benzopyran-8־acetate of (ethylcarbonyl)-l-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 1 of 6N HC1. The precipitate obtained is filtered and recrystallized. Weight obtained: 28.3 g (yield 77%); mp = 265-268®C; IR V OH = 3400 to 2200 cm, Vc = o (lactone) = 1740 cm; Vc = o (pyrone) = 1600 cm“¹; NMR (DMSO) « in ppm in relation to TMS: 3H at 1.6 (d), 1H at 5.2 (q), 1H at 7.1 (s), 9H at 7.2 to 8.6.

<td> Elemental Analysis</td><td> Cl</td><td> HI</td><td> 01</td>

<td> calculated</td><td> 71.85</td><td> 4.22</td><td> 23.93</td>

<td> found</td><td> 71.55</td><td> 4.11</td><td></td>

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 ^C25^H15^C105 ^{MW = 430}.S3 [FORMULA 70]

<img file="IL89840A_D0068.tif" />

mp = 265-273״C; IR Vc = 0 (lactone) 1750 ־ cm’¹, Vc = 0 (pyrone) = 1660 cm’¹; NMR (DMSO) δ in ppm in relation to

<td> TMS: 1H at 6.16 (s), 1H at</td><td> 7(s), 13H at</td><td> 7.1 to 8.4.</td>

<td> Elemental Analysis</td><td> Cl</td><td> HI Cll 01</td>

<td> calculated</td><td> 69.69</td><td> 3.51 8.23 18.57</td>

<td> found</td><td> 69.41</td><td> 3.52 8.27</td>

METHYL-3-HYDROXY-4-(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8YL)-5-5H-FURANONE-2 ^C20^H14°5

MW = 334.31

[FORMULA 71]

<img file="IL89840A_D0069.tif" />

mp = 160* C; I_R v c = 0 (lactone) = 1760 cm,

<td> Vc=o (pyrone) = 1640 cm ¹,י</td><td> NMR (DMSO) δ</td><td> in ppm</td><td> in</td>

<td> relation to TMS: 3H at 1.</td><td> 8 (s), 1H at</td><td> 6.55 (s)</td><td> 1, 1H at</td>

<td> 7.75 (S), 8H at 7.5 to 8.3</td><td> (m) .</td><td></td><td></td>

<td> Elemental Analysis</td><td> C%</td><td></td><td> 0%</td>

<td> calculated</td><td> 71.85</td><td> 4.22</td><td> 23.93</td>

<td> found</td><td> 71.80</td><td> 4.22</td><td></td>

EXAMPLE

CHLORHYDRATE OF [(N,N-DIETHYLAMINO)-2-ETHOXY]-4-METHYL-

5-(0X0-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL]-3-5H-

FURANONE-2

C₂₆H₂₈C1N°5 MW = 469.95 [FORMULA 72]

<img file="IL89840A_D0070.tif" />

A mixture of 20 g (0.06 mole) of hydroxy-4-methyl5-(oxo-4-phenyl-2-4H-(1]-benzopyran-8-yl)-3-5Hfuranone-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(diethylainino)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

־79־ is dissolved in 200 ml of ethanol. This product is cooled in an ice bath and HC1 is bubbled through until a pH of 2 is achieved. 0y 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 = 0 (lactone) = 1740 cm'¹, Vc = 0 (pyrone) = 1640 cm'¹; NMR (DMSO-CDC1₃) δ 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.

<td rowspan="2"> Elemental Analysis calculated</td><td> C%</td><td> H%</td><td> Cl%</td><td> N%</td><td> 0%</td>

<td> 66.45</td><td> 6.00</td><td> 7.55</td><td> 2.98</td><td> 17.02</td>

<td> found</td><td> 66.30</td><td> 6.20</td><td> 7.55</td><td> 2.83</td><td></td>

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^H20°7

420.4 ־־ MW

[FORMULA 73]

<img file="IL89840A_D0071.tif" />

mp = 153°C; IR Vc = 0 NMR (ester and lactone) = 1755 cm”¹, Vc = 0 (pyrone) = 1640 cm¹ NMR (CDCI3) 5 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), 1H at 6.9 (s), 8H at 7.2 to 8.5.

[DIHYDRO-2-5-METHYL-5-OXQ-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-3-FURAN-4-YL] OXYACETIC ACID ^C22^H16°7 ^{MW = 392}‘³⁹ [FORMULA 74)

<img file="IL89840A_D0072.tif" />

mp = 257-259°C; IR V OH = 2400 cm¹, Vc = 0 (lactone) = 1740 cm, Vc = 0 (acid) = 1710 cm¹, Vc = 0 (pyrone) = 1620 cm¹; 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 (3), 8H at 7.2 to 8.4 (m).

<td> Elemental Analysis</td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated</td><td> 67.34</td><td> 4,11</td><td> 28.55</td>

<td> found</td><td> 67.20</td><td> 4.00</td><td></td>

DIMETHYL CARBAMOTHIOATE OF 0־[DIHYDRO-2,5-METHYL-5-0X0־ 2-(OXQ-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-3-FURN-4-YL)

C₂₃H₁₉NO₅S

MW = 421.46 (FORMULA 751

<img file="IL89840A_D0073.tif" />

mp = 173175°־C; IR Vc = 0 (lactone) = 1740 cm¹, Vc = o (pyrone) = 1630 cm; NMR (CDC1₃) 4 in ppm in relation to TMS: 3H at 1.66 (d), 6H at 2.8 (s), 1H at

<td> 6.16 (q), 1H at 6.8</td><td> (s), ΘΗ at</td><td> 7.2 to 8.4</td><td> (m).</td><td></td><td></td>

<td> Elemental Analysis</td><td></td><td> Ht</td><td></td><td> 0%</td><td> S%</td>

<td> calculated</td><td> 65.54</td><td> 4.70</td><td> 3.32</td><td> 18.98</td><td> 7.61</td>

<td> found</td><td> 65.42</td><td> 4.52</td><td> 3.32</td><td></td><td> 7.64</td>

EXAMPLE

AC ETYLTHIMETHYL-8-QXO-4-PHENYL-2-4H-[1]-BENZOPYRANE ^C18^H14°3^S

MW = 310.38

[FORMULA 76]

<img file="IL89840A_D0074.tif" />

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-[l]-benzopyranone-4, by portions while being stirred. This is stirred for 1 hour at room temperature and then poured into a waterice 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, Vc = o (pyrone) = 1655 cm; NMR (CDC1₃) δ in ppm in relation to TMS: 3H at 2.4 (s), 2H at 4.5 (s), 1H at 6.9 (3), 8H at 7.2 to 8.4 (m).

EXAMPLE

MERCAPTOMETHYL-8-PHENYL-2-4H־[!]-BENZOPYRANONE-4 ^C16^H12°2^S

MW = 268.34 [FORMULA 77]

<img file="IL89840A_D0075.tif" />

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 HC1. 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%) ן mp = 162°CJ; IR Vc ־ o 1640 ־ cm; NMR (CDC1₃) δ 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).

<td> Elemental Analysis</td><td> C%</td><td> H%</td><td> 0% S%</td>

<td> calculated</td><td> 71.62</td><td> 4.51</td><td> 11.92 11.95</td>

<td> found</td><td> 71.45</td><td> 4.48</td><td> 11.84</td>

Using the same technique, the following compounds were prepared:

(OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN־8־YL)־METHYL 1 METHYL THIOACETATE ^C19^H16°4^S

MW = 340.4

[FORMULA 78] mp = 110⁴C; IR Vc = 0 (ester) = 1720 cm“¹, Vc = 0 (pyrone) = 1650 cm”¹ NMR (CDC1₃) s 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 ^C18^H14°4^S ™ ^{= 326}.³⁷ [FORMULA 79]

<img file="IL89840A_D0076.tif" />

<td colspan="6"> mp = 202-204°C; IR V OH = 3100-2400 cm \ IR Vc =</td>

<td> 0 (acid) (DMSO) δ</td><td> = 1720 in ppm</td><td> cm'¹, Vc = 0 in relation</td><td> (pyrone) to TMS:</td><td> = 1640 cm 2H at 3.2</td><td>¹, NMR (s), 2H</td>

<td colspan="3"> at 4.25 (s), 1H at 6.8 (s), Elemental Analysis calculated found</td><td> 9H at 7.2 C% 66.24 66.51</td><td> to 8.4 (m Hi 4.32 4.34</td><td> ). 0% Si 19.61 9.81 10.11</td>

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

C₂₄H₂₇NO₇ MW = 441.48 [FORMULA 80] mp = 162-164°C; IR Vc = 0 = 1660 cm’¹; NMR (DMSO) 5 in ppm in relation to TMS: 3H at 1.2 (t), 6H at 2.95 to 3.5 (m), 1H at 3.8 to 4.2 (ra), 2H at 5.05 (s), 2H at 5.4 (interchangeable), 1H at 7.1 (s), 8H 7.5 to 8.5 (m).

<td> Elemental Analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated</td><td> 65.29</td><td> 6.16</td><td> 3.17</td><td> 25.37</td>

<td> found</td><td> 65.18</td><td> 6.10</td><td> 3.07</td><td></td>

[[HYDROXY2־-(HYDROXYMETHYL)-1-ETHOXY] METHYL]-8-PHENYL2-4H-[l]-BENZOPYRANONE-4 ^C19^H18°5 ^{MW = 326}.³³ [FORMULA 81]

<img file="IL89840A_D0077.tif" />

mp 162° ־C; IR V OH = 3300 cm ¹: IR Vc = 0 1620 cm¹, 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), 13 at 6.93 (s), 8H at 7.2 to 8.2 (m).

<td> Elemental Analysis</td><td> Cl</td><td> Hl</td><td> 0%</td>

<td> calculated :</td><td> 69.93</td><td> 5.56</td><td> 24.51</td>

<td> found :</td><td> 70.00</td><td> 5.57</td><td></td>

EXAMPLE

OXO-4-PHENYL-2-4H-[1]-BENZ0PYRAN-8-ACETAMIDE ^c1₇H₁₃N°₃

MW = 279.28 [FORMULA 82]

<img file="IL89840A_D0078.tif" />

A suspension of 5 G (0.0178 mole) of oxo-4-phenyl2-4H-[l]-benzopyran-8-acetic acid in 180 ml of dioxane is heated until it dissolves. A solution of 3.5 g (0.0124 mole) of Ν,Ν'-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; IR vc = 0 (acid) = 1660 cm“¹, Vc = 0 (pyrone) = 1630 cm; NMR (CDC1₃ + CF₃COOD) 6 in ppm in relation to TMS: 2H at 4.33 (s), 9H at 7.5 to 8.7 (m), 2H at 11.5.

<td> Elemental Analysis</td><td> C%</td><td> H%</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 73.13</td><td> 4.69</td><td> 5.01</td><td> 17.19</td>

<td> found :</td><td> 73.13</td><td> 4.69</td><td> 5.00</td><td></td>

EXAMPLE

OXO-4-PHENYL-2-4H-(1]-BENZOPYRAN-8-THIOACETIMIDE ^C17^H13^NO2^S MW ^{= 295}* ³⁵ [FORMULA 83 J

In a mixture of 60 g (0.229 mole) of oxo-4-phenyl-2-4H(l]-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 1 of ice water, acidified to a pH 5-6 with HC1, 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

<td> cm’¹; IR Vc = 0 = 1620</td><td> cm; NMR</td><td> (DMSO)</td><td> 6 in ppm in relation</td>

<td> to TMS: 2H at 4.15 (s] 2H at 9.4 (s).</td><td> ), 1H at 6.</td><td> 9 (S),</td><td> 8H at 7.2 to 8.4 (m),</td>

<td rowspan="2"> Elemental Analysis calculated :</td><td> C%</td><td> H%</td><td> N% 0% S%</td>

<td> 69.13</td><td> 4.44</td><td> 4.74 10.83 10.86</td>

<td> found :</td><td> 69.22</td><td> 4.38</td><td> 4.80 10.68</td>

EXAMPLE

PHENYL-2-[

9ENZOPYRANONE-4

C-,ςΗ,ηΝΟ׳, MW = 395.46 [FORMULA 84] £ O A / 4*

<img file="IL89840A_D0079.tif" />

־90A mixture of 5 g (0.0169 mole) of oxo-4-phenyl-24H-[l]-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 cm¹; NMR

<td colspan="2"> (CDC1₃) δ in ppm in relation to TMS: 2H at 4,7</td><td rowspan="2"> (s), 1H</td>

<td> at 6.75 (s), 14 H at 7.1 to 8.3</td><td> (m).</td>

<td> Elemental Analysis C%</td><td> H% Nt</td><td> O% St</td>

<td> calculated 75.92</td><td> 4.33 3.54</td><td> 8.09 8.11</td>

<td> found 75.73</td><td> 4.23 3.52</td><td> 8.31</td>

Using this same technique, the following compounds were prepared:

[(OXO-4-PHENYL-2-4H-[l]-BENZOP¥RAN-8-YL) METHYL]-2THIAZOL-4-ETHYL CARBOXYLATE ^C22^H17^NO4^{S MW = 391}.⁴³ [FORMULA 85]

<img file="IL89840A_D0080.tif" />

־91־ mp = 152-153°C; IR Vc = 0 (ester) = 1710 cm¹־, Vc = o (pyrone) = 1640 cm ¹j NMR (CDC12) 6 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-PHENYL4~2־H-{12}~BENZOPYRAN-8-YL) METHYL-2THIAZOL־4־CARBOXYLIC ACID ^C20^H15^NO4^{S MW = 362}.³⁸ [FORMULA 86)

<img file="IL89840A_D0081.tif" />

mp = 237-240’C; IR V OH = 3100 to 2400 cm¹־; IR

Vc = o (acid) = 1720 cm¹־, Vc = 0 (pyrone) = 1620 cm‘

NMR (DMSO) S in ppm in relation to TMS: 1H at 4.7 (s),

<td colspan="2"> 1H at 6.9 (s)_r 8H at 7.2 to 8.15</td><td colspan="2"> (m), 1H at 8.2</td><td colspan="2"> (s).</td>

<td> Elemental Analysis</td><td> C%</td><td> H%</td><td> N%</td><td> 0%</td><td> S%</td>

<td> calculated :</td><td> 66.10</td><td> 3.61</td><td> 3.85</td><td> 17.61</td><td> 8.82</td>

<td> found :</td><td> 69.83</td><td> 3.60</td><td> 3.87</td><td></td><td> 8.60</td>

EXAMPLE

[ OXO-4-PHENYL-2-4H- [1 ] -BENZ0PYRAN-8-YL) METHYLENE ] -2HYDRAZINE CARBOTHIOAMIDE ^C17^H13^N3°2^S

MW = 323.36

[FORMULA 87]

A suspension of 5 g (0.02 mole) of (oxo-4-phenyl2-4H-[1J-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 = 0: 7640 cm¹.

Elemental Analysis C% H% N% 8% calculated : 63.14 4.05 13.00 9.90 9.92 found : 63.12 4.04 13.00 9.87

Using the same method, the following compound was prepared;

DIHYDRO-4,5-[1H]-IMIDAZO9LE-2־YL־HYDRA2ONE BROMHYDRATE (OXO-4PHENYL-2-4H-[11-BENZ0PYRAN-8-YL) CARBOXALDEHYDE ^C19^H17^3rN4°4 ^{MW = 413}’²⁸ [FORMULA 88]

<img file="IL89840A_D0082.tif" />

mp = 301-303’C; IR:

V NH = 3300 cm¹; VC = N - C = 0 =

1660 and 1640 cm¹; NMR (DMSO) 5 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).

<td> Elemental Analysis</td><td> C%</td><td> H%</td><td> Br%</td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 55.21</td><td> 4.15</td><td> 19.34</td><td> 13.56</td><td> 7.74</td>

found

54.96

4.09

13.62

Example (0X0-4־TETRAHYDRO-2,3,5,6-4H-PYRAN-2-YL)-8-PHENYL-2-4H[1]-BENZOPYRANONE-4 ^C20^H16°4

MW = 320.33

[FORMULA 89}

O

<img file="IL89840A_D0083.tif" />

g (0.08 mole) of oxo-4-phenyl-2-4H-[1]-benzopyran-8carboxaldehyde were added in parts to a mixture of 22.8 g (0.16 mole) of trimethylsilyloxy-2-butadiene-l-3 and 12 g (0.088 mole) of anhydrous ZnC12 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^eC, 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, V C = 0 (pyrone) = 1640 cm; NMR (CDCI3) δ in ppm in relation to TMS: 4H from

<td> 2.3 to 3.2 (m), 2H from</td><td> 3.7 to 4.7 (m),</td><td> 1H to 5.3 (dd)</td>

<td> 1H to 6.8 (s), 8H from 7</td><td> .1 to 8.3 (m).</td><td></td>

<td> Elemental Analysis</td><td> C%</td><td> H% 0%</td>

<td> calculated :</td><td> 74.98</td><td> 5.03 19.98</td>

<td> found :</td><td> 75.03</td><td> 4.81</td>

EXAMPLE (HYDROXY-4-TETRAHYDRO-3,4,5,6-2H-PYRAN-2-YL)-8-PHENYL2-4H-[1]-BENZOPYRANONE-4 ^C20^H18°4 MW ’ ³²².³⁴ [FORMULA 901

<img file="IL89840A_D0084.tif" />

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 NABH^ 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; Vc = O = 1610 cm'¹

<td colspan="2"> NMR CDCP^) 6 in ppm in relation to TMS:</td><td> 4H at 1 to</td>

<td> 2.76 m; 4H from 3.2 to 4</td><td> .4 (m, of which</td><td> 1H is</td>

<td> exchangeable), 1H to 4.9 7.2 to 8.2 (m).</td><td> (dd) 1H to 6.8</td><td> (s), 8H from</td>

<td> Elemental Analysis</td><td> C%</td><td> H% 0%</td>

<td> calculated :</td><td> 74.52</td><td> 5.63 19.85</td>

<td> found :</td><td> 74.82</td><td> 5.52</td>

EXAMPLE

OXO-4-(OXQ-PHENYL-2-4B-[1]-BENZOPYRAN-8-YL)-4-BUTEN-2QIC ACID ^C19^H12°5 ²⁹.^{320 =} *®י [FORMULA 91]

<img file="IL89840A_D0085.tif" />

A mixture of 2 g (0.0076 mole) of acetyl-8-phenyl2-4H-[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% NaHCO₃ and acidified using acetic acid. The precipitate was filtered, washed with water and recrystallized in the dioxanehexane mixture. Weight obtained: 0.5 g (yield: 20.6%); mp = 217-218“C; IR V C = 0 (acid) 1710 cm, V C = 0 (ketone) = 1760 cm’¹, VC = 0 (pyrone) = 1620 cm; NMR (DMSO) 6in ppm in relation to TMS 1H to 3.8

<td> (exchangeable), 11H from 6.5</td><td> to 8.5 (m).</td><td></td>

<td> Elemental analysis</td><td> C% H%</td><td> 0%</td>

<td> calculated :</td><td> 71.24 3.78</td><td> 24.98</td>

<td> found :</td><td> 71.17 3.52</td><td></td>

EXAMPLE (OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)2־-HYDROXY-2ACETIC ACID ^C17^H12°5 ^{MW = 296}*²⁸ [FORMULA 92]

<img file="IL89840A_D0086.tif" />

eoeH

A mixture of 8.75 g (0.134 mole) of potassium cyanide, 125 ml of water, 1.25 1 of dioxane, 53 g (0.5 mole) of Na₂CO₃ and 15.32 g (0.061 mole) of oxo-4phenyl-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, V C = 0 (acid) = 1720 cm”¹, V C ־ O (pyrone) = 1620 cm; NMR (DMSO) 6in ppm in relation to TMS: 1H at 3.4 (interchangeable), 1H at 5.6 (s), 1H at 7(3), 9H at 7.3 to 8.3 (m, of which 1H is interchangeable).

Elemental analysis Cl HI 0% calculated : 68.92 4.08 27.00 found

68.98־

4.19

Example (OXO-4-PHENYL-2-4H-[1]-BENZOPYRAN-8-YL)-2~HYDROXY-2-ETHYLr

ACETATE ^C19^H16°5

MW=324.32

[Formula 93]

A mixture of 29 g (0.098 mole) of (oxo-4-phenyl-24H-[l]-benzopyran-8-yl)-2-hydroxy-2 acetic acid and 35 ml of concentrated H2SO4 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 MIBKhexane. Weight obtained: 20.3 g (Yield: 64%); MP^=135^eC; IR: V OH=3420 cm“¹, V C=O (ester)-1730 cm¹, V C=O (pyrone)=1640 cm¹.

Example (OXO-4-PHENYL-2-4H-[11BENZQPYRAN-8-YL)-2-OXO-2-ETHYL

ACETATE ^C19^H14°5

MW=322.3 [Formula 94]

<img file="IL89840A_D0087.tif" />

0.79 g (0.0077 mole) of CrO₃ 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-[l]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 CHC1₃. This was evaporated and the residue was recrystallized in hexane. Weight obtained: 0.9 g (Yield! 36.3%); MP_K=8590°C; IR V C=O (ester)1730־ cm¹, V C=O (ketone)=1690 cm ¹, V C=0 (pyrone)=1640 cm, NMR (CDC1₃), 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 (OXO-4-PHENYL-24־H[l]BENZOPYRAN-8-YL)-2־OXO-2־ACETATE

ACID ^C17^H10°5

MW=294.25

[Formula 95]

O

<img file="IL89840A_D0088.tif" />

The mixture of 9.3 g (0.0288 mole) of (oxo-4-phenyl2-4H-[l]benzopyran-8-yl)-2־oxo2־-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 HC1 and the precipitate obtained was filtered and recrystallized in dioxane. Weight obtained: 2.3 g (Yield 27%), MP_G=232235’C, IR V C־O (acid)=1740 cm¹, V C=O (ketone)־ 1690 cm¹, V C=O (pyrone)=1660 cm¹. NMR (DMSO) 4 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

C% H% 0%

<td> calculated :</td><td> 69.39</td><td> 3.91</td><td> 27.19</td>

<td> found :</td><td> 69.11</td><td> 3.95</td><td></td>

Example

METHYL-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-Y)-2-METHYL PROPANOATE ^C20^H18°4

MW=322.34

[Formula 96]

<img file="IL89840A_D0089.tif" />

A solution of 6.7 g (0.023־ mole) of oxo-4-phenyl-24H-[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 CIH₃ in 5 ml of DMF 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, V C=O (pyrone)=1650 cm¹; NMR (CDC1₃) δ 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

METHYL-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-2PROPIONIC ACID ^c19^h16°4 MW=308.318 [Formula 97] ccoH

A mixture of 5.7 g (0.0177 mole) of methyl-2-(oxo-4phenyl-2-4H-[l]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 HC1 and the precipitate was dried, washed with water and recrystallized in acetic acid.

Weight obtained: 3.1 g (Yield: 56.8%); MPq=255-260; IR V C=O (acid)=1720 cm¹, V CO (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).

<td> Elemental analysis</td><td rowspan="2"> Cl</td><td rowspan="2"> Hl</td><td rowspan="2"> 0%</td>

<td></td>

<td> calculated :</td><td> 74.01</td><td> 5.23</td><td> 20.76</td>

<td> found :</td><td> 73.93</td><td> 5.25</td><td></td>

Example

OXQ-4-PHENYL-2-4H[l]־BENZOPYRAN-8-CARBOXALDEHYDE OXIME ^c16^h11^NO3 MW=265.256 [Formula 98]

<img file="IL89840A_D0090.tif" />

A.mixture of 10 g (0.04 mole) of oxo-4-phenyl-2-4H[l]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 cm¹, V C־=O; NMR (CF₃COOD), ό in ppm in

<td> relation to TMS: 10</td><td> H from 7.8 to</td><td> 9.5 (m).</td><td></td>

<td> Elemental analysis</td><td></td><td></td><td></td>

<td></td><td> C% H%</td><td> N%</td><td> 0%</td>

<td></td><td></td><td>^-</td><td> י</td>

<td> calculated :</td><td> 72.44 4.18</td><td> 5.28</td><td> 18.10</td>

<td> found :</td><td> 72.74 4.24</td><td> 5.03</td><td></td>

Using the same method, the following compound was prepared:

ACETYL-8-PHENYL-2-4H-[1]-BENZOPYRANONE-4- OXIME (8) ^c17^h13^nO3 MW279.282־ [Formula 99]

<img file="IL89840A_D0091.tif" />

Elemental analysis

<td></td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated :</td><td> 73.10</td><td> 4.69</td><td> 5.02</td><td> 17.19</td>

<td> found</td><td> 73.00</td><td> 4.70</td><td> 4.99</td><td></td>

Example (MORPHOLIN-4-YL)-3-(OXQ-4-PHENYL-2-4H-[1]-BENZOPYRAN-8YL)-2-GLUTARONITRILE ^C24^H21^N3°3 MW=399.43 [Formula 100]

<img file="IL89840A_D0092.tif" />

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[l]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 cm¹, V 0=1640 cm¹; NMR (CDC1₃) 5 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).

־107Example

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

ACID ^C19^H14°5

MW=322.3

[Formula 101]

A mixture of 3 g (0.0075 mole) of the corapounf 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% NaHCO^ and acidified. The precipitate formed was dried and recrystallized in the MIBK-dioxane mixture. Weight obtained: 1.1 g (Yield: 45.5%); MP_F=207209°־C; IR V C= ) (acid=1720 cm¹, V C=0 (ketone)=1680 cm, V C=0 (pyrone)=1620 cm; NMR (DMSO) δ 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).

<td> Elemental analysis</td><td rowspan="2"> C%</td><td rowspan="2"></td><td rowspan="2"> 0%</td>

<td></td>

<td> calculated :</td><td> 70.80</td><td> 4.38</td><td> 24.82</td>

<td> found :</td><td> 70.50</td><td> 4.43</td><td></td>

Example

HYDROXY-4-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-Y)-BUTYRIC ACID ^c19^s16°5 MW=324.32 [Formula 102]

<img file="IL89840A_D0093.tif" />

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 MPr=198-202^eC; IR V OH=3350 cm¹, V C־O (acid)=1700 cm¹, V C=O (pyrone)=1620 cm¹; 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 (3), 8H from 7.4 to

8.4 (nt), 1H to 11.8 (exchangeable).

Elemental analysis C% . 0% calculated : 70.36 4.97 24.67 found : 70.56 4.72

Example

ACETAMIDO-2-ETHOXYCARBONYL-2-(0XQ-4-PHENYL-2-4H[l]BENZ0PYRAN-8-YL)2־ ETHYL PROPIONATE ^c25^h25ⁿ⁰7 MW=451.46 [Formula 103]

O e

H

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-[l]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_R=200^eC; IR V NH=3370 cm V C=O (ester)=1720 ent¹ and 1760 cm, V C=O (amide)=7670 cm, V C=O (pyrone)=1640 cm¹.

Example

AMINO-2-(OXO-4-PHENYL-2-4H-[1]BENZOPYRAN-8-YL)-3PROPIONIC ACID HYDROCHLORATE ^C18^H16^C1NO4 MW345.78־ [Formula 104]

C00W

A mixture of 10 g (0.022 mole) of the compound of Example 32 and 400 ml of 1/2 HC1 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%), MPq=243°C; IR V OH, NH₃⁽⁺⁾=3500-2500 cm’¹, V C=O (acid)=1740 cm“¹, V C=0 (pyrone)=1625 cm; NMR

<td> (DMSO) 6 in ppm in</td><td> relation to TMS:</td><td> 3H from 3.4 to 4.4</td>

<td> (m), 1H to 7.1 (s), are exchangeable). Elemental analysis</td><td> 1H from 7.4 to C% H%</td><td> 10 (m, of which 4H Cl% N% 0%</td>

<td> calculated : found :</td><td> 62.52 4.66 62.66 4.89</td><td> 10.26 4.05 18.51 10.35 4.11</td>

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

2-(2-AMINOPHENYL)-4-OXO4־H-[1]BENZOPYRAN-8-ACETIC ACID ^C17^H13^NO4 ^MW ~ ^295,28 [Formula 105]

<img file="IL89840A_D0094.tif" />

PFq = 189® vC; IR vC = 0 (acid) 1710 cm, vC = 0 (pyrone) = 1610 cm

<td> Elemental analysis</td><td> C%</td><td></td><td> Ν» 0%</td>

<td> calculated:</td><td> 69.14</td><td> 4.44</td><td> 4.74 21.61</td>

<td> found:</td><td> 68.92</td><td> 4.25</td><td> 4.45</td>

-(2-CHLOROPHENYL)-4-OXO-4H-[1]-BENZ0PYRAN-8-ACETIC ACID ^C17^H11^C1O4

MW = 314.715 [Formula 106]

<img file="IL89840A_D0095.tif" />

PF169 = ״^eC; IR \)C = 0 (acid) = 1710 cm’¹; vC = 0 b (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).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> Cl%</td><td> 0%</td>

<td> calculated:</td><td> 64.87</td><td> 3.52</td><td> 11.27</td><td> 20.34</td>

<td> found:</td><td> 65.09</td><td> 3.48</td><td> 11.53</td><td></td>

2-(2-CHLOROPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C17^H11^C1O4

MW = 314.715

[Formula 107]

<img file="IL89840A_D0096.tif" />

PF220-222 = ״^oC; IR vC = 0 (acid) = 1730 cm; vC = 0

G (pyrone) = 1620 cm¹; NMR (DMSO) s in ppm relative to

TMS: 2 H at 4 (s), 1 H from 7.5 (s), 7 H from 7.3 to

<td colspan="4"> 8.3 (m), 1 H at 13 (exchangeable).</td><td rowspan="2"> 0%</td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> Cl*</td>

<td> calculated:</td><td> 64.87</td><td> 3.52</td><td> 11.27</td><td> 20.34</td>

<td> found:</td><td> 64.59</td><td> 3.53</td><td> 11.28</td><td></td>

22)־-ACETAMIDOPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C19^H15^NO5

MW = 337.318 [Formula 109]

<img file="IL89840A_D0097.tif" />

PF196-201 = ״’C; IR vC = 0 (acid) = 1720 cm¹; vC = 0 b (amide) = 1660 cm¹; υϋ = 0 (pyrone) = 1620 cm¹; NMR (DMSO) ί in ppm relative to TMS: 3 H at 2 (3), 2 H at 3.8 (3), 1 H at 6.5 (3), 7 H from-7.3 to 8.2 (m), 1 H

<td> at 8.8 (exchangeable),</td><td> 1 H at</td><td colspan="2"> 11.5 (exchangeable).</td>

<td> Elemental analysis</td><td> C%</td><td> H*</td><td> Cl* 0*</td>

<td> calculated:</td><td> 67.65</td><td> 4.48</td><td> 4.15 23.72</td>

<td> found:</td><td> 67.42</td><td> 4.24</td><td> 4.11</td>

-(4-ACETYLPHENYL)-4-QXQ-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C19^H14°5

MW = 322.302 [Formula 110]

<img file="IL89840A_D0098.tif" />

PF_g = 253-255°C; IR vC = 0 (pyrone) = 1620 cm; NMR

<td colspan="4"> (CF-jCOOD) 4 in ppm relative to TMS: 3 H at 2.8 at 4.3 (m), 8 H from 7.7 to 8.5 (m).</td><td rowspan="2"> (S), 2 H</td>

<td colspan="2"> Elemental analysis C%</td><td> H%</td><td> O%</td>

<td> calculated:</td><td> 70.80</td><td> 4.38</td><td> 24.82</td><td></td>

<td> found:</td><td> 70.61</td><td> . 4.31</td><td></td><td></td>

2-(3-ACETAMIDOPHENYL)-4-OXO-4H1]־]-BENZOPYRAN-8-ACETIC ACID ^C19^H15^NO5 ^{MW = 337}.³¹⁸ [Formula 111]

<img file="IL89840A_D0099.tif" />

־115PF284-288 = ״^eC IR vC = 0 (acid) = 1720 cm“¹; vC = 0 u (amide + pyrone) = 1630 cm ¹j NMR (DMSO) δ 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).

Elemental analysis C% Hi Ni 0% calculated: 67.65 4.48 4.15 23.72 found: 67.70 4.40 4.12

2-(2-DlETHYLAMINOETHOXYPHENYL)-4-OXO-4H-(1]-BENZOPYRAN8-ACETIC ACID

C,oH״cClNOc MW = 431.903 [Formula 112] (chlorhydrate) (CH,),-N:

(CH,

PF_g = 1780-182°C Cj_(chlorhydrate); IR vC = 0 (acid) = 1720 cm“¹; vC = 0 (pyrone) = 1640 cm¹; 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).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> Cl%</td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> ' 63.96</td><td> 6.07</td><td> 8.21</td><td> 3.24</td><td> 18.52</td>

<td> found:</td><td> 63.96</td><td> 6.12</td><td> 8.19</td><td> 3.24</td><td></td>

2-(3-NITRO-4-CHLOROPHENYL)-4-QXO-4H-[l]-BENZOPYRAN-8ACETIC ACID

C₁₇H₁₀ClNO₄ MW = 359.715 [Formula 113]

<img file="IL89840A_D0100.tif" />

PF_g = 232 - 234^eC; IR vC = 0 (acid) = 1720 cm; vC = 0 (pyrone) = 1640 cm; 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).

<td> Elemental analysis</td><td> C%</td><td></td><td> Clt</td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> 56.76</td><td> 2.80</td><td> 9.86</td><td> 3.89</td><td> 26.69</td>

<td> found:</td><td> 56.82</td><td> 2.69</td><td> 9.78</td><td> 3.90</td><td></td>

-{2,4-DIMETH0XYPHENYL)-4-OXQ-4H-(1]-BENZOPYRAN-8ACETIC ACID ^C19^H16°6

MW = 340.185

[Formula 114]

<img file="IL89840A_D0101.tif" />

PF_g = 225-227°C; IR vC = 0 (acid) = 1710 cm¹־; \>C 0 ־ (pyrone) = 1620 cm; NMR (DMSO) δ in ppm relative to

TMS: 2 H at 3.5 (s), 3 H at 3.9 (s), 3 H at 4 (3), 7H from 6.8 to 8, 1 H at 12.2 (exchangeable).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> 0%</td>

<td> calculated:</td><td> 67.05</td><td> 4.74</td><td> 28.21</td>

<td> found:</td><td> 67.23</td><td> 4.63</td><td></td>

2-(4-DIMETHYLAMINOETHOXYPHENYL)-4-OXO-4H-[1]BENZOPYRAN-8-ACETIC ACID ^C23^H26^C1NO2

MW = 431.92

[Formula 115] (chlorhydate)

<img file="IL89840A_D0102.tif" />

PFq = 194-199’C (chlorhydate); IR vC = 0 (acid) = 1720 cm“¹; \)C = 0 (pyrone) = 1630 cm; NMR (DMSO) S 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).

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> Cl*</td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> 63.96</td><td> 6.07</td><td> 8.21</td><td> 3.24</td><td> 18.57</td>

<td> found:</td><td> 63.50</td><td> 6.04</td><td> 8.30</td><td> 3.45</td><td></td>

2-(4-CARBAMOYLPHENYL)-4-OXO4־H-[1]-BENZOPYRAN-8-ACETIC ACID ^C18^H13^N^5

MW = 323.292 [Formula 116]

<img file="IL89840A_D0103.tif" />

<td> PF_g = 228-290^QC; IR vC</td><td> = 0 (ac</td><td> :id) =</td><td> 1710 cm“¹; vC =</td>

<td> (amide + pyrone) = 1640</td><td> cm“¹</td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> N% 0%</td>

<td> calculated:</td><td> 66.87</td><td> 4-.05</td><td> 4.33 24.75</td>

<td> found: .</td><td> 66.35</td><td> 4.35</td><td> 4.46</td>

־119[ [methyl-2-thiazolyl-4]-4-phenyl]-2-0X044H[1]BENZOPYRAN-8-ACETIC ACID ^C21^H15^NO4^S

MW = 377.398 [Formula 117]

<img file="IL89840A_D0104.tif" />

PF_g = 246-248’C; IR vC = 0 (acid) = 1720 cm¹־; vC = 0 (pyrone) = 1620 cm”¹; NMR (DMSO) 6 in ppm relative to

TMS: 3 3 at 4 (s), 13 at 7 (s), 83 from 7.1 to 8.1 (m), 13 at 12.6 (exchangeable).

<td> Elemental analysis</td><td> C%</td><td> Hi</td><td> N%</td><td> 0%</td><td> S%</td>

<td> calculated:</td><td> 66.83</td><td> 4.01</td><td> 3.71</td><td> 16.96</td><td> 8.50</td>

<td> found:</td><td> 66.73</td><td> 3.95</td><td> 3.66</td><td></td><td> 8.56</td>

2-(2-C3L0R0PBENYL)-4-OXO-4B-[1]-BENZ0PYRAN-8-ACETIC ACID ^C19^H17^N3°4

MW = 351.35

[Formula 118]

HOOC

<img file="IL89840A_D0105.tif" />

<img file="IL89840A_D0106.tif" />

_ZCH

CH,

PF173-175° = ״C; IR \>C = 0 (acid) = 1710 cm¹; vC = 0 b (pyrone) = 1620 cm; 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).

<td> Elemental analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> 64.95</td><td> 4.88</td><td> 11.96</td><td> 18.22</td>

<td> found:</td><td> 64.72</td><td> 4.85</td><td> 12.04</td><td></td>

2-(2-AMINQ-4-THIAZOLYLPHENYL)-4-QXQ-4H-[1]-BENZOPYRAN8-ACETIC ACID ^c20^H14°4^S^378,388 ־ [Formula 119]

<img file="IL89840A_D0107.tif" />

PF_g = 263-265®C; IR vC = 0 (acid) = 1710 cm¹־; uC = 0 (pyrone) = 1620 cm; NMR (DMSO) δ 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).

<td> Elemental analysis</td><td> C%</td><td></td><td> 0%</td>

<td> calculated:</td><td> 67.05 ’</td><td> ,4.75</td><td> 28.21</td>

<td> found:</td><td> 67.70</td><td> 4.54</td><td> 7.12</td>

-(3,5-DIMETHOXYPHENYL)-4-0X0-4Η-[1]-BENZ0PYRAN-8ACETIC ACID ^C19^H16°6 ^{MW = 340}.³¹⁸ [Formula 120]

<img file="IL89840A_D0108.tif" />

PF_r = 261-263°C; IR vC = 0 (acid) = 1720 cm¹־; vC = 0 kJ (pyrone) = 1530 cm¹; 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).

<td> Elemental analysis</td><td> c%</td><td> H%</td><td> 0%</td>

<td> calculated:</td><td> 67.05</td><td> . 4.74</td><td> 28.21</td>

<td> found:</td><td> 67.20</td><td> 4.54</td><td></td>

2-(4-PYRIDYL)-4-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C16^H11^NO4

MW = 281.256 [Formula 121] ־122PF275-277 = ״^eC; IR vC = 0 (acid) = 1720 era“¹; vC = 0

<td> (pyrone) = 1600 era“¹;</td><td> NMR (DMSO</td><td colspan="2"> + CF₃COOD) s</td><td> in ppm</td>

<td> relative to TMS: 2 H</td><td> at 4 (s),</td><td> 8 H from</td><td> 7.3</td><td> to 8.8</td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> 68.32</td><td> 3.94</td><td> 4.98</td><td> 22.76</td>

<td> found:</td><td> 67.94</td><td> 4.09</td><td> 5.12</td><td></td>

2-(2-PYRIDYL)-4-OXO-4H1]־]-BENZOPYRAN-8-ACETIC ACID

Ci/Η,,ΝΟ, MW = 281.256 [Formula 122]

11 9

<img file="IL89840A_D0109.tif" />

PF223°־221 = ״C; IR vC = 0 (acid) = 17201740־ kJ

<td> cm; vC = 0 (pyrone) =</td><td> 1640 c:</td><td> ra¹; NMR</td><td> (DMSO)</td><td> δ in ppm</td>

<td> relative to TMS: 2 H at</td><td> 4.1 (s</td><td> ), 1 H at</td><td> 7.2 (</td><td> s), 8 H</td>

<td> from 7.25 to 9 (m), 1 H</td><td> at 13</td><td> (exchange</td><td> able).</td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> N%</td><td> 21</td>

<td> calculated:</td><td> 68.32</td><td> 3.94</td><td> 4.98</td><td> 22.76</td>

<td> found:</td><td> 68.50</td><td> 3.89</td><td> 4.86</td><td></td>

-(4-HEXYLPHENYL.)-4-0X04־H-[1]-BENZ0PYRAN-8-ACETIC ACID ^C23^H24°4

MW = 364.422

[Formula 123]

<img file="IL89840A_D0110.tif" />

PF_G = 154-156’C; IR vC = 0 (acid) = 1720 cm“¹; vC = 0 (pyrone) = 1620 cm¹; NMR (DMSO) δ in ppm relative to

TMS: 13 H from 0.7 to 2.8 (m), 2 H at 4 (s), 1 H at

<td> 7 (s), 7 H from 7.2</td><td> to 8.1 (m)</td><td> , 1 H at</td><td> 12.9</td>

<td> (exchangeable).</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> O%</td>

<td> calculated:</td><td> 75.80</td><td> 6.64</td><td> 17.56</td>

<td> found:</td><td> 75.50</td><td> . 6.49</td><td></td>

23)־-METHYLPHENYL)-4-0X0-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C18^H14°4

MW = 294.292

[Formula 124]

HOOC

<img file="IL89840A_D0111.tif" />

PF- = 252-254°C; IR \)C = 0 (acid) = 1720 cm¹; vC = 0

G

<td> (pyrone) = 1620 cm ־*</td><td> .; NMR (CF^COOD) 6 in ppm</td><td> relative</td>

<td> to TMS: 2 H at 2.55 to 8.6 (m). Elemental analysis calculated: found:</td><td> (s), 2 H at 4.5 (m), 8 H C% H% 0% 73.46 4.80 21.75 73.74 4.86</td><td> from 7.5</td>

2-{4-BENZOYLPHENYL)-4-OXQ-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C24^H16°4

MW - 384.368 [Formula 125]

<img file="IL89840A_D0112.tif" />

PF- = 257-259^eC; IR vC = 0 (acid) = 1720 cm; vC = 0 b (benzoyl) = 1650 cm; vC 0 ־ (pyrone) = 1620 cm¹; NMR

<td> (CF₃COOD) ί in ppm</td><td> relative to</td><td> TMS: 2</td><td> H at 4.5 (s)</td>

<td> 13 H from 7.5 to 8.</td><td> 7 (m).</td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> Hl</td><td> 01</td>

<td> calculated:</td><td> 74.99</td><td> 4.20</td><td> 20.81</td>

<td> found:</td><td> 75.11 .</td><td> 4.09</td><td></td>

-(4-UNDECYLPHENYL)4־-OXO-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C28^H34°4

MW = 434.552

[Formula 126] ^(CH2\q^CH3

PF_g = 150-152^eC; IR uC = 0 (acid) = 1710 cm; vC = 0 (pyrone) = 1620 cm*¹; NMR (CFjCOOD) 5 in ppm relative to TMS: 23 H from 0.6 to 1.7 (tn), 2 H at 4.5 (s), 8 H from 7.5 to 8.4 (m).

Elemental analysis C* H* 0% calculated: 77.39 7.89 14.73 found: 77.34 7.87

NITRO-3,

ACETIC ACID

C-i-1H1eN0_c MW = 401.358 [Formula 127]

ם כ1

Ν0₂

PF270-272 = ״’C; IR vC = 0 (acid) = 1720 cm; vC = 0 u

<td> (pyrone) = 1620 cm¹;</td><td> NMR (DMSO)</td><td> 5 in</td><td> ppm relative to</td>

<td> TMS: 2 H at 4 (s), 12</td><td> H from 7.2</td><td> to 8</td><td> .7 (m), 1 H at</td>

<td> 12.9 (exchangeable).</td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td> H%</td><td> N% 0%</td>

<td> calculated:</td><td> 68.88</td><td> 3.77</td><td> 3.49 23.92</td>

<td> found:</td><td> 68.72</td><td> 3.66</td><td> 3.35</td>

2-(4-TRIFLUOROMETHYLPHENYL)-4-OXO-4H-[1]-BENZOPYRAN-8ACETIC ACID ^C18^H11^F3°4 ^MW ’ 348.268 [Formula 128]

<img file="IL89840A_D0113.tif" />

PF_g = 216-218’C; IR vC - 0 (acid) 1720 ־ cm¹; vC =0 ־ (pyrone) = 1640 cm¹; NMR (DMSO) $ in ppm relative to

<td> TMS: 2 H at 4 (3), 8</td><td> H from 7.1</td><td> to 8.4</td><td> (m), 1</td><td> H at 12.8</td>

<td> (exchangeable).</td><td></td><td></td><td></td><td></td>

<td> Elemental analysis</td><td> C%</td><td></td><td> F%</td><td> 0%</td>

<td> calculated:</td><td> 63.07</td><td> 3.18</td><td> 16.37</td><td> 18.38</td>

<td> found:</td><td> 63.02 ’</td><td> .3.32</td><td> 16.37</td><td></td>

- ( 4-DIMETHYLTRIAZENYLPHENYL)-4-0XQ-4H-[1]-BENZOPYRAN8-ACETIC ACID ^C19^H17^N3°4 ^{MW = 351135} [Formula 129]

<img file="IL89840A_D0114.tif" />

/^CH3

-ch₃

PF_p = 209-211^eC; IR vV 0 ־ (acid) = 1720 cm ¹j vC =0 (pyrone) = 1620 cm¹; NMR (DMSO) s in ppm relativeto

TMS: 6 H at 3.3 (m), 2 H at 4 (s), 1 H at 7 (s), 8H from 7.2 to 8.1 (m), 1 H at 12.8 (exchangeable).

<td> Elemental analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> 64.95</td><td> 4.88</td><td> 11.96</td><td> 18.22</td>

<td> found:</td><td> 64.75</td><td> 4.95</td><td> 12.25</td><td></td>

2-(3-NITRO-4-METHOXYPHENYL)4־-OXOt4H-[1]-BENZOPYRAN-8־ ACETIC ACID ^C18^H13^NO7

MW = 355.292

[Formula 130]

<img file="IL89840A_D0115.tif" />

PF254-256° = ״C; IR vC = 0 (acid) = 1720 cm“¹; vC = 0 G (pyrone) ⁼ 1620 cm ¹; NMR (CF^COOD): 3 H at 4.1 (s),

H at 4.3 (s), 7 H from 7.1 to 9 (m).

<td> Elemental analysis</td><td> C%</td><td></td><td> N%</td><td> 0%</td>

<td> calculated:</td><td> 60.85</td><td> 3.69</td><td> 3.94</td><td> 31.52</td>

<td> found:</td><td> 61.07</td><td> 3.68</td><td> 4.16</td><td></td>

2-(4-TERBUTYLPHENYL)-4-QXQ-4H-[1]-BENZOPYRAN-8-ACETIC ACID ^C21^H20°4

MW = 336.37 [Formula 131]

<img file="IL89840A_D0116.tif" />

PF240-242° = ״C; IR vC = 0 (acid) = 1720 cm; vC = 0 b (pyrone) = 1610 cm“¹; NMR (DMSO) δ in ppm relative to

<td> TMS: 6 H at 1.2 (3),</td><td> 2 H at 4.5</td><td> (s), 8 H from 7.1 to</td>

<td> 8.3 (m), 1 H at 12.9</td><td colspan="2"> (exchangeable).</td>

<td> Elemental analysis</td><td> C%</td><td> H% 0%</td>

<td> calculated:</td><td> 74.98</td><td> 5.99 19.03</td>

<td> found:</td><td> 74.76</td><td> 5.85</td>

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

Passages of the description which are not within the scope of the claims do not constitute part of the invention.