JPH0250113B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to formula A (In the formula, R represents a hydrogen atom or a methyl group, and when R represents a hydrogen atom, the compound is in the form of a monohydrate) and pharmacologically acceptable additions thereof. Regarding salt. Compounds of formula A of the invention are leukotriene D ₄
Novel compounds of the _{formula below} and their pharmacological properties which are inhibitors of Useful in the production of acceptable addition salts: [In the formula, Z is a)-( _CH2 ) _o- ;b)-( _CH2 ) _p-
CH=CH−( _CH2 ) _q− ; or d) -CO-(CH ₂ ) _w - (in each formula, n is an integer from 1 to 3; p is an integer from 0 to 4; q is an integer from 0 to 4;
is an integer of 4; p+q is equal to or less than 6; r is an integer of 1 to 5; s is an integer of 0 to 4; t is an integer of 0 to 4;
and w is an integer from 1 to 6); m is an integer from 2 to 6; Y is a) - H; b) = H ₂ ; or c) ^-H _-OH ; with the proviso that A double bond at the 3-4 position can only exist if Y is H; R ₁ and R ₂ are each the same or different and 1
is alkyl having ~6 carbon atoms; _R3 is a) hydrogen or alkyl having 1 to 6 carbon atoms; b) -COOH; or c) ( _CH2 )
_l COOR ₅ (where l is an integer from 0 to 2, and
R ₅ is alkyl having 1 to 6 carbon atoms); and R ₄ is a) hydrogen; b) -CO ₂ H; c) -CO ₂ R ₆ where R ₆ is 1 to 6 or d) -OH]. LTD ₄ is a product of the 5-lipoxygenase pathway and is the main active component of the slow-reacting substance of anaphylaxis (SRS-A) in humans and guinea pigs [Lewis et al., Nature USA, 293 :103
~108 pages (1981)]. It is a powerful bronchoconstrictor released during allergic reactions. Because antihistamines are ineffective in managing asthma, SRS-
A is believed to mediate bronchoconstriction resulting from allergic challenge. SRS-A is also a potent inducer of vascular permeability and may also be involved in other inflammatory conditions such as rheumatoid arthritis [Gellar J. et al., J. Clin. Endocrinol.
Metab., 43 :686-688 (1976)]. General Information Appleton et al., J.Med.Chem. 20 , pp. 371-379 (1977) describes a group of chromone-2-carboxylic acid compounds that are agonists of SRS-A. In particular, sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate ( EPL55712) is considered to be the first reported specific agonist of SRS-A and LTD ₄ . Acid form salts of these compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, trialkylamines, dialkylamines, monoalkylamines, dibasic amino acids, sodium acetate, potassium benzoate, It can be produced by neutralization with appropriate amounts of inorganic or organic bases such as triethanolamine and similar bases. When LTD ₄ is administered to humans and guinea pigs,
Causes bronchoconstriction. This bronchoconstriction has two components: a) direct stimulation of respiratory smooth muscle by LTD ₄ and b) an indirect component due to the release of thromboxane A ₂ and subsequent production of contraction of respiratory smooth muscle. The compounds of the invention antagonize this direct factor. Compounds of the invention are tested in vivo as follows. Adult male fasted Hartly guinea pigs weighing 300-350 g are pretreated with pyrilamine and indomethacin to inhibit the bronchoconstrictor effects of endogenous histamine and the synthesis of thromboxane _A2 , respectively. The compounds of the invention are administered intravascularly or intragastrically prior to intravascular administration of 2000 units of LTD ₄ . Intratracheal pressure is monitored before and after administration of LTD ₄ in animals anesthetized with pentobarbital and connected to a rodent respirator. Compounds that antagonize the direct component of LTD ₄ to respiratory smooth muscle inhibit the increase in intratracheal inspiratory pressure caused by LTD ₄ (P or = 0.05).
FPL55712 is used as a control. Compounds of the invention can be administered in a number of dosage forms.
The preferred method of administration is oral or such that the action of the inhibitor is localized. For example, for asthma, the compounds can be inhaled using an aerosol or other suitable spray. For inflammatory conditions such as rheumatoid arthritis, compounds can be injected directly into the affected joint. The compounds can also be administered in oral unit dosage forms such as tablets, capsules, pills, powders or granules. These compounds can also be administered rectally or vaginally in the form of suppositories. These compounds can also be administered in intraperitoneal, subcutaneous or intramuscular forms well known in the pharmaceutical arts, as well as in the form of eye drops. For the treatment of allergic skin conditions, the compounds of this invention can also be administered topically in the form of ointments, creams, gels, and the like. Regardless of the route of administration chosen, the compounds of the invention can be formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical arts. An effective, non-toxic amount of the compound is used for treatment. Dosage regimens for inhibiting LTD ₄ with compounds of the invention include the species, age, weight, sex and medical condition of the mammal, the particular disease and its severity, the route of administration and the particular compound used. The choice depends on various factors. A skilled physician or veterinarian will readily determine and predict the amount of the compound that will be effective in preventing or arresting the progression of the condition. At the beginning of administration, the physician or veterinarian may initially use a relatively low dose and then increase the dose until maximal response is obtained. The compounds of this invention are prepared by the general methods illustrated in Reaction Schemes A-E. A variety of compounds and intermediates can be readily transformed by methods known to those skilled in the art. For example, ester compounds can be hydrolyzed to the corresponding carboxylic acid compounds (and their respective addition salts), converted to the corresponding amide compounds by appropriate reaction with amines, and alcohols by reducing agents such as lithium borohydride. Can be reduced to compounds. Of course, such products and intermediates can be interconverted as well. As illustrated in Figure A, the 2-hydroxyacetophenone of formula XI readily reacts with the ketone of formula XII to provide a fused ring compound of formula. Formula XII
The ketones include ketoesters where Z is alkylene or alkenylene and R ₄ is alkoxycarbonyl. An example of such a ketoester is ethyl levulinate. Suitable condensation and cyclization conditions include heating a compound of formula XI and a compound of formula XII to reflux in toluene in the presence of a base such as pyrrolidine with removal of water in an apparatus such as a Dean-Stark trap. includes. The intermediates of formula thus produced can be used in the reactions of Figure B without further purification or may be converted to related intermediates of formula by methods known to those skilled in the art. For example, hydrogenation over palladium on carbon converts the keto function of the formula into a dihydrobenzopyran of the corresponding formula (Y=H ₂ ).
will be reduced to Partial hydrogenation provides the corresponding hydroxyl compound (Y=H,OH). As illustrated in Figure B, compounds of formula can be alkylated under basic conditions to produce compounds of formula XI. Suitable reactants include dihaloalkanes such as 1,3-dibromopropane and the like. Preferred conditions include reaction in anhydrous dimethylformamide in the presence of anhydrous potassium carbonate. Intermediate XI is typically purified by column chromatography on silica gel. Reaction of these intermediates with 2-hydroxyacetophenone of formula XII provides the object compound of the present invention, formula. Preferred conditions include reaction in dry dimethylformamide in the presence of anhydrous potassium carbonate. Alternatively, the reaction can be carried out under phase transition conditions. Figure C illustrates the preparation of the compound using a variation of the method of Figure B. A 2-hydroxyacetophenone of Formula XI is reacted with a dihaloalkane as described above to form an intermediate of Formula XI. By the same general methods used to convert formula to XI, a compound of formula XI is reacted with a compound of formula to produce the object compound of the invention, formula. Figure D illustrates another route for making some of the compounds of the invention. Benzopyrones of formula XL known from the literature can be reduced to compounds of formula XL by catalytic hydrogenation; in this case Y
can range from =O to (H,OH) to _H2 , which can be further transformed by methods known to those skilled in the art. For example, hydroxyl compound (Y
=H,OH) can be dehydrated to form a benzopyran of formula XL. This method involves conversion to a mesylate derivative followed by elimination under basic conditions to produce formula XL. As another example,
The ester compound [R ₄ =COO(alkyl)] can be reduced with an active metal hydride such as lithium boron hydride to produce the corresponding alcohol compound of formula XL. Figure E also illustrates another route for making some of the compounds of the invention. Formula L
(wherein R ₁₁ can be a protecting group that is removed in a post-treatment, or can be the final aromatic side chain already formed as generally described above) is first Treatment with a strong base in a reactive solvent. Preferred reactants include n-butyllithium in tetrahydrofuran. Alkylation gives compounds of formula L. Examples of alkylating agents include simple alkyl halides or substituted alkyl halides such as iodoalkyl carboxylic esters, beta-unsaturated carboxylic esters (subject to conjugate addition), and many other reagents known to those skilled in the art. include. Further transformations of the compound of L can produce other derivatives such as the free carboxylic acid of formula L. That is, this carboxylic acid can be produced by hydrolysis of compound L. Acylation of compound L under similar conditions provides compounds of formula L. Acylating agents include acyl halides or other activated acyl derivatives. Suitable reactants include substituted N-alkanoylimidazole derivatives. Compounds of formula L can also be converted into other derivatives. For example, basic hydrolysis leads to decarboxylated compounds of formula L. The invention will become more fully apparent from the following examples. These examples are for illustrative purposes only and are not to be construed as limiting the invention in either spirit or scope. Many modifications, both to materials and methods, will be apparent to those skilled in the art from this description. In these examples, unless otherwise indicated, temperatures are given in degrees Celsius (° C.) and amounts of materials are given in grams and milliliters. Example 1 Ethyl 3-(3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-
2H-1-benzopyran-2-yl)propanoate 2,4-dihydroxy-3 in 250 ml of toluene
-Propylacetophenone 58.0g (0.299mol)
A solution of 29.5 ml (0.36 mol) of pyrrolidine and pyrrolidine is heated to reflux for 3 hours using a Dean-Stark trap. After the mixture has cooled, 68.2 ml (0.48 mol) of ethyl levulinate are added and the mixture is refluxed for 2 hours. Additional pyrrolidine 10ml (0.12mol)
is added and the mixture is refluxed under a Dean-Stark trap overnight. The reaction mixture is diluted with ethyl acetate and washed sequentially with water, 2M hydrochloric acid, water and brine. Then,
Dry over _MgSO4 , filter and evaporate to dryness.
Chromatography of the residue on silica gel using 30% ethyl acetate/hexane as eluent gives 35.5 g of the title ester; mp: 92~
94°. The estimated structure was confirmed by nmr and infrared spectra. IR ( _CHCl3 ): 1665, 1730 cm ^-1 . Example 2 1-[3-(3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-
2H-1-benzopyran-2-yl)-1-oxopropyl]pyrrolidine From another chromatographic fraction of Example 1, 30 g of the title amide are obtained; melting point: 182-184°. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (KBr): 1615, 1675cm ^-1 . Elemental analysis: Regarding C ₂₀ H ₂₇ NO ₄ , Calculated value: C69.54; H7.88; N4.05 Actual value: C69.22; H7.93; N3.97 Example 3 3-(3,4-dihydro- 7-hydroxy-2
-Methyl-4-oxo-8-propyl-2H-
1-benzopyran-2-yl)propanoic acid To a mixture of 20.0 g (103 mmol) of 2,4-dihydroxy-3-propylacetophenone and 15.5 g (134 mmol) of methyl levulinate in 100 ml of dry toluene are added 21.5 ml (approximately 260 mmol) of pyrrolidine by syringe. After stirring for 1 hour, the solution is heated on a steam bath for 4 hours and then cooled. Wash the toluene solution with water and 2N NaOH. The basic solution is acidified and extracted with diethyl ether followed by saturated sodium bicarbonate. Neutralize the basic aqueous extract with dilute hydrochloric acid,
Extract again with diethyl ether. After drying, the solution is concentrated under reduced pressure and the resulting oil crystallizes to give the title compound; mp: 152-153°. Elemental analysis: For _C16H20O5 , calculated value: C65.74; H6.90 Actual value: C65.24; _H6.86 Example 4 Methyl 3-(3,4-dihydro _- 7-hydroxy-2-methyl -4-oxo-8-propyl-
2H-1-benzopyran-2-yl)propanoate The title compound of Example 3 (4.3 g; 14.7 mmol),
6 ml of trimethyl orthoformate, and sulfuric acid
Stir 1.4 ml of the mixture at room temperature for 2 hours. The reaction mixture is poured onto stirred ice/water and then extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and concentrated to an oil. Purify the oil by chromatography on silica gel to obtain 3.7 g of the title compound as a crystalline solid;
Melting point: 101.5~102.5°. The estimated structure was confirmed by nmr and infrared spectra. Example 5 4-(3-bromopropoxy)-2-hydroxy-3-propylacetophenone 50.0 g (257 mmol) of 2,4-dihydroxy-3-propylacetophenone in 250 ml of dichloromethane, tetrabutylammonium hydrogen sulfate
87.4 g (257 mmol) and dibromopropane
52.2 ml (approximately 514 mmol) of the mixture
Add 225 ml (450 mmol) of 2NNaOH. The mixture is then heated to reflux for about 30 minutes and cooled. After concentrating the reaction mixture under reduced pressure, the residue is triturated with diethyl ether, the ether solution is filtered and then concentrated to dryness. After purification by column chromatography on silica gel, the title compound is isolated and used in the next reaction without further confirmation. Example 6 Methyl 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H- 1-benzopyran-2-yl)propanoate A mixture of 1.9 g (6.2 mmol) of the ester product of Example 4, 2.2 g (6.8 mmol) of the title product of Example 5 and 1.8 g (13 mmol) of anhydrous potassium carbonate in 30 ml of dry dimethylformamide is stirred at room temperature for 16 hours. do. The inorganic salts are filtered off and the dimethylformamide is evaporated under reduced pressure. Dissolve the residue in ethyl acetate and filter off additional inorganic salts. The filtrate is evaporated and the residue is chromatographed on silica gel using 7% ethyl acetate/toluene as eluent to give 2.5 g of the title compound; mp: 73~
74.5°. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.89 (t, J = 7.5Hz,
6H, propyl CH ₃ ′s); 1.24 (t, J=7Hz, 3H,
Ester CH ₃ ); 1.35 (s, 3H, 2-methyl proton); 2.55 (s, 3H, acetyl CH ₃ ); 4.22 (t,
J=6Hz, 4H, OCH ₂ 's); 6.42, 6.53, 7.54,
7.71 (set of d, aromatic) IR (CHCl ₃ ): 1625, 1675, 1730 cm ^-1 Elemental analysis: For C ₃₁ H ₄₀ O ₈ , Calculated value: C68.87; H7.46 Actual value: C69.12 ;H7.44 Example 7 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-4-oxo-
8-propyl-2H-1-benzopyran-2-
yl}propanoic acid A solution of 0.5 g (19.5 mmol) of lithium hydroxide in 10 ml of water is added to a solution of 2.2 g (3.9 mmol) of the title compound of Example 6 in 25 ml of tetrahydrofuran and 20 ml of methanol. The reaction mixture was heated at room temperature for 3
After stirring for an hour, the solvent is evaporated and water is added to the residue. After extraction with a little diethyl ether, the aqueous phase is acidified with dilute hydrochloric acid and left overnight in the cold. The solid is filtered off, washed with water and recrystallized from ethyl acetate/hexane to yield 1.83 g of the title compound; mp 80-83°. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): Disappearance of ester CH ₃ (compare with Example 6) IR (KBr): 1625, 1675, 1710, 1730 cm ^-1 Elemental analysis: For C ₃₁ H ₃₈ O ₈・H ₂ O, calculated value: C66 .16; H7.40 Actual value: C66.15; H7.44 Example 8 1-{3-[7-(3-bromopropoxy)-3,
4-dihydro-2-methyl-4-oxo-8-
Propyl-2H-1-benzopyran-2-yl]
-1-oxopropyl}pyrrolidine The title compound (melting point: 103-104°) is prepared by the method of Example 6 using the amidopyrrolidone product of Example 2 and 1,3-dibromopropane as starting materials. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1625, 1675 cm ^-1 Elemental analysis: For C ₂₃ H ₃₂ BrNO ₄ , calculated value: C59.23; H6.92; N3.00 Actual value: C59.44; H6.96; N2.84 Example 9 1-[3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl- 2H-1-benzopyran-2-yl}-1-oxopropyl]pyrrolidine The title compound (melting point: 93-94.5°) is prepared by the method of Example 6 using the title compound of Example 8 and 2,4-dihydroxy-3-propylacetophenone as starting materials. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1625, 1675 cm ^-1 Elemental analysis: Regarding C ₃₄ H ₄₅ NO ₇ , calculated value: C70.44; H7.82; N2.42 Actual value: C70.32; H7.78; N2.35 Example 10 Methyl 3-(3,4-dihydro-7-hydroxy-2-methyl-8-propyl-2H-1-benzopyran-2-yl)propanoate A solution of 4.1 g (13.4 mmol) of the ester product of Example 4 in 100 ml of acetic acid and 50 ml of methanol was heated to 4 psi.
and hydrogenation for 21 h using palladium on carbon as catalyst at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.8 g of the title compound as an oil. The estimated structure was confirmed by nmr and infrared spectra. nmr (CKCl ₃ ): δ (ppm) 0.94 (t, J=7Hz,
3H, propyl CH ₃ ); 1.23 (s, 3H, 2-methyl proton); 3.67 (s, 3H, ester CH ₃ ); 6.28
(d, J=8Hz, 1H, aromatic); 6.71 (d, J=8
Hz, 1H, aromatic) IR (CHCl ₃ ): 1730 cm ^-1 Example 11 Methyl 3-[7-(3-bromopropoxy)-3,
4-dihydro-2-methyl-8-propyl-
2H-1-benzopyran-2-yl]propanoate Title compound from Example 10 in 12 ml of methylene chloride
To a solution of 1.7 g (5.51 mmol), 1.1 ml (11 mmol) of 1,3-dibromopropane and 1.9 g (11 mmol) of tetrabutylammonium hydrogen sulfate are added 5.5 ml of 2M sodium hydroxide solution. The reaction mixture is heated to reflux for 15 minutes, then cooled.
The organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give the title compound as 1.8 g of an oil. The estimated structure was confirmed by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 4.02 (t, J = 6Hz)
Addition of CH ₂ Br signal to (compare with example 10) IR (CHCl ₃ ): 1735 cm ^-1 Example 12 Methyl 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy ]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-2-yl}
Propanote The title compound (melting point: 53-55°) is prepared by the method of Example 6 using the product of Example 11 and 2,4-dihydroxy-3-propylacetophenone as starting materials. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1625, 1730 cm ^-1 Elemental analysis: Regarding C ₃₁ H ₄₂ O ₇ , Calculated value: C70.70; H8.04 Actual value: C70.59; H8.10 Example 13 3-{7-[ 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-2-yl}propanoic acid The title compound is prepared by the method of Example 7 using the product of Example 12 as starting material, but by extracting the acidified aqueous layer with ethyl acetate. The organic layer is then washed with water and brine, dried over _MgSO4 , filtered and then evaporated to dryness to give the title compound as an oil. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (KBr): 1620, 1705, 1735 cm ^-1 Elemental analysis: Regarding C ₃₀ H ₄₀ O ₇ , Calculated value: C70.29; H7.87 Actual value: C69.93; H7.77 Example 14 3-(2- Carboxy-3,4-dihydro-7
-Hydroxy-4-oxo-8-propyl-
2H-1-benzopyran-2-yl)propanoic acid The title compound is prepared by the method of Example 1 using α-ketoglutaric acid as starting material. The crude product is used without further purification. α−
Instead of ketoglutarate, congeners such as 4-
4-ketopinslicacid can be used to generate homologues of the title compound. Example 15 Methyl 3-(3,4-dihydro-7-hydroxy-2-methoxycarbonyl-4-oxo-8
-Propyl-2H-1-benzopyran-2-yl)propanoate To a solution of 13 g of the crude product of Example 14 in 250 ml of methanol and 25 ml of trimethyl orthoformate are added 5 ml of sulfuric acid. The reaction mixture is stirred at room temperature for 12 hours, poured onto an ice/water mixture and then extracted with ethyl acetate. The organic layer was washed sequentially with water, 5% sodium bicarbonate solution, water and brine;
Dry over _MgSO4 , filter and then evaporate to dryness. The residue was eluted on silica gel for 13
Chromatography using % ethyl acetate/hexane gives 6.1 g of the title compound. The estimated structure was confirmed by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 0.99 (t, J=6Hz,
3H, propyl CH ₃ ); 3.64, 3.71 (a pair of s, 6H,
Ester CH ₃ ′s): 6.45, 7.56 (1 pair of d′s, aromatic) IR (CHCl ₃ ): 1685, 1740 cm ^-1 Example 16 Methyl 3-{7-[3-(4-acetyl-3- Hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methoxycarbonyl-4-oxo-8-propyl-2H-1-
Benzopyran-2-yl}propanoate The title compound is prepared by the method of Example 2 using the product of Example 11 as starting material. The estimated structure is
Confirmed by nmr and infrared spectroscopy and by elemental analysis; homologs of the corresponding compounds in which l is 1 or 2 can be used instead. nmr (CDCl ₃ ): δ (ppm) 0.88, 0.93 (one pair of t,
6H, propyl CH ₃ ′s); 2.56(s, 3H, acetyl
CH ₃ ); 3.61, 3.68 (a pair of s, 6H, ester
CH ₃ ′s); 4.21 (t, J=7Hz, 4H, OCH ₂ ′s);
6.39, 6.55, 7.53, 7.66 (1 set of d's, aromatic) IR (CHCl ₃ ): 1630, 1685, 1740 cm ^-1 Elemental analysis: For C ₃₂ H ₄₀ O ₁₀ , calculated value: C65.74; H6 .90 Actual value: C65.89; H6.87 Example 17 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
2-Carboxy-3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-
2-yl}propanoic acid The title compound (melting point: 76-79°) is prepared by the method of Example 7 using the product of Example 16 as starting material, but with 10 equivalents of lithium hydroxide. The acidified aqueous layer was extracted with ethyl acetate, then washed with water and brine, then _MgSO4
Dry, filter and then evaporate to dryness to give the title compound. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): Disappearance of ester CH ₃ ′s (compare with Example 16) IR (KBr): 1620, 1680, 1710 ~ 1740 cm ^-1 Elemental analysis: For C ₃₀ H ₃₆ O ₁₀・H ₂ O, calculated value : C62.71; H6.67 Actual value: C62.85; H6.64 Example 18 3-(3,4-dihydro-7-hydroxy-2
-Methyl-4-oxo-8-propyl-2H-
1-benzopyran-2-yl)propanamide To a solution of the title product of Example 3 (1.0 g; 3.4 mmol) in 50 ml of dry tetrahydrofuran, cooled to 0°, are added 2.1 g (10.2 mmol) of phosphorus pentachloride.
After the mixture has been stirred for 30 minutes, about 2 ml of liquid ammonia are added, the solution is warmed to room temperature and stirred for a further 30 minutes. The solvent is evaporated and the residue is dissolved in ethyl acetate. Saturate the organic layer with sodium bicarbonate solution,
Wash successively with water and brine, dry over MgSO ₄ , filter, and then concentrate to dryness. The crude product (melting point: 108-115°) is not purified further. The predicted structure was supported by nmr and infrared spectra. IR (KBr): 1680cm ^-1 example 19 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-4-oxo-
8-propyl-2H-1-benzopyran-2-
il}propanamide The title compound (melting point: 77-79°) was prepared by the method of Example 6 using the amide product of Example 18 as starting material, except that the reaction mixture was stirred at room temperature for 16 hours.
Produced by further heating at 50° for 3 hours.
The estimated structure was determined by nmR and infrared spectra.
and confirmed by elemental analysis. IR (KBr): 1630, 1675 cm ^-1 Elemental analysis: For C ₃₀ H ₃₉ O ₇ , calculated value: C68.55; H7.48; N2.66 Actual value: C68.62; H7.81; N2.49 Example 20 3-(3,4-dihydro-7-hydroxy-N,
N,2-trimethyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)propanamide Dry dimethylformamide 40 cooled to -20°
Title product of Example 3 (1.0 g; 3.4 mmol) in ml
0.37 ml (3.4 mmol) of N-methylmorpholine and then a solution of 0.45 ml (3.4 mmol) of isobutyl chloroformate in 3 ml of dimethylformamide are added to the solution. The reaction mixture was heated at -30° for about 20 minutes.
Stir for 2 min, then add 2 ml of gaseous dimethylamine.
Whisk for a minute. After stirring for 20 minutes, the mixture is warmed to room temperature and stirred for a further 30 minutes. The solvent is evaporated and the residue is dissolved in ethyl acetate, washed successively with saturated sodium bicarbonate solution, water and brine, then dried over _MgSO4 . filter,
Removal of solvent yields 0.84 g of the title compound; melting point
108~110°. The estimated structure was confirmed by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 0.97 (t, J = 7Hz,
3H, propyl CH ₃ ); 1.39 (s, 3H, 2-methyl proton); 2.89, 3.06 (a pair of s, 6H, N
(CH ₃ ) ₂ ); 6.55, 7.52 (1 set of d's, aromatic) IR (KBr): 1625, 1985 cm ^-1 example 21 3-{7-[3-(4-acetyl-3-hydroxy- 2-propylphenoxy)-propoxy]-
3,4-dihydro-N,N,2-trimethyl-
4-oxo-8-propyl-2H-1-benzopyran-2-yl}-propanamide The title compound (melting point: 126-128°) is prepared by the method of Example 6 using the amide product of Example 20 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): Additional signal for aryloxypropoxy proton (compare with example 20) IR (KBr): 1635, 1685 cm ^-1 Elemental analysis: For C ₃₂ H ₄₃ NO ₇ , calculated value: C69.41; H7 .83; N2.63 Actual value: C69.06; H7.87; N2.51 Example 22 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-4-oxo-
8-propyl-2H-1-benzopyran-2-
yl}propanoic acid monopotassium salt 0.13g of 85% potassium hydroxide in 25ml of methanol
Example 7 A solution of (1.9 mmol) in 25 ml of methanol
Add to a solution of 1.0 g (1.8 mmol) of the title compound. The solution is neutralized with a sulfonic acid type cation exchange resin, filtered and then evaporated to dryness. Triturate the residue with diethyl ether to give the title compound 0.7
get g. The predicted structure was confirmed by elemental analysis. Elemental analysis: For C ₃₀ H ₃₇ O ₈ K・^3/2 H ₂ O, calculated value _: C60.89; H6.81; K6.61 Actual value: C61.08; H6.71; K6.69 Example 23 3 -{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-4-oxo-
8-propyl-2H-1-benzopyran-2-
yl}propanoic acid tris(hydroxyethyl) ammonium salt 0.8 g of the title compound of Example 7 in 25 ml of methanol
(1.5 mmol) of triethanolamine in a solution
Add 0.2 ml (1.5 mmol). Evaporate the solvent and triturate the residue with ether to obtain a solid. Recrystallization from ether/hexane gives 0.6 g of the title compound. ; Melting point: 84-85°. The estimated structure is
Confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1620, 1670, 1700, 1740 cm ^-1 Elemental analysis: For C ₃₆ H ₅₃ O ₁₁ N, calculated value: C63.98; H7.91; N2.07 Actual value: C63.86; H8. 01; N1.98 Example 24 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-4-oxo-
8-propyl-2H-1-benzopyran-2-
yl}propanoic acid 5-amino-5-carboxypentanammonium salt The title compound (melting point: 125-127°) is prepared by the method of Example 23 using 0.98 g (1.8 mmol) of the title compound of Example 7 and 0.24 g (1.6 mmol) of DL-lysine as starting materials. The estimated structure is
Confirmed by nmr and infrared spectra and by elemental analysis. IR (KBr): 1635, 1685 cm ^-1 Elemental analysis: C ₃₆ H ₅₂ O ₁₀・^1/2 Regarding H ₂ O, calculated value: C66.42; H7.84; N4.11 Actual value: C63.43 _; H7 .79; N4.09 Example 25 Methyl 4-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy)-3,4-dihydro-2-methyl-4-oxo- 8-Propyl-2H-1-benzopyran-2-yl}butanoate The title compound is prepared by the method of Examples 1 and 6 using methyl 5-oxohexanoate as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1625, 1675, 1730 cm ^-1 Elemental analysis: Regarding C ₃₂ H ₄₂ O ₈ , Calculated value: C69.29; H7.63 Actual value: C68.80; H7.72 Example 26 4-{7 -[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-methyl-4-oxo-
8-propyl-2H-1-benzopyran-2-
yl}butanoic acid The title compound (melting point: 106-108°) is prepared by the method of Example 7 using the title compound of Example 25 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1625, 1675, 1710, 1750 cm ^-1 Elemental analysis: For C ₃₁ H ₄₀ O ₈ , calculated value: C68.87; H7.46 Actual value: C68.68; H7.79 Example 27 Ethyl 3 -[3,4-dihydro-7-hydroxy-8-propyl-2H-1-benzopyran-
2-yl)propanoate 2.0 g of ethyl 3-(4-oxo-7-phenylmethoxy-8-propyl-4H-1-benzopyran-2-yl)-2-propanoate in 40 ml of acetic acid.
(5.1 mmol) solution at 50 psi and 70°, 5%
Hydrogenation over palladium on carbon catalyst. The catalyst was filtered off and the filtrate was evaporated to dryness to yield the title compound 1.3.
g as an oil. The predicted structure was supported by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 0.95 (t, J = 7Hz,
3H, propyl CH ₃ ); 1.27 (t, J = 7Hz, 3H,
Ester CH ₃ ); 3.9 (m, 1H, 2-proton);
4.13 (q, J=7Hz, 2H, ester CH ₂ ); 6.29,
6.69 (1 pair of d, aromatic) IR (CHCl ₃ ): 1725 cm ^-1 Example 28 Ethyl 3-[7-(3-bromopropoxy)-3,
4-dihydro-8-propyl-2H-1-benzopyran-2-yl]propanoate The title compound is prepared by the method of Example 11 using the product of Example 27 as starting material. The estimated structure is
Supported by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 3.59 (t, J = 7Hz,
2H, CH ₂ Br) (compare with Example 27) IR (CHCl ₃ ): 1725 cm ^-1 Example 29 Ethyl 3-{7-(3-(4-acetyl-3-hydroxy-2-propylph) enoxy)propoxy]-3,4-dihydro-8-propyl-2H-
1-benzopyran-2-yl}propanoate The title compound (melting point: 68-70°) is prepared by the method of Example 6 using the product of Example 28 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.89 (t, J = 7Hz,
6H, propyl CH ₃ ′s); 1.25 (t, J=7Hz, 3H,
Ester CH ₃ ); 2.27 (t, J=6H, 2H, CH ₂ C
H ₂ CH ₂ ); 2.54 (s, 3H, acetyl CH ₃ ); 3.9
(m, 1H, 2-proton); 6.39, 6.42, 6.78,
7.54 (1 set of d's, aromatic) IR (CHCl ₃ ): 1625, 1725 cm ^-1 Elemental analysis: For C ₃₁ H ₄₂ O ₇ , Calculated value: C 70.70; H8.04 Actual value: C 70.57; H 8.09 Example 30 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-8-propyl-2H-1-
Benzopyran-2-yl}propanoic acid The title compound (melting point: 109-110°) is prepared by the method of Example 7 using the product of Example 29 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): Disappearance of ester proton (compare with Example 29) IR (KBr): 1635, 1705 cm ^-1 Elemental analysis: For C ₂₉ H ₃₈ O ₇ , calculated value: C69.86; H7.68 Actual value: C69.83; H7.68 Example 31 Ethyl 3-[3,4-dihydro-7-(2-oxiranylmethoxy)-8-propyl-2H-1-
Benzopyran-2-yl]propanoate The title compound was converted to the product of Example 27 by the method of Example 11.
It is produced using 3.0 g (10.3 mmol) and 1.3 ml (15 mmol) of epibromohydrin as starting materials. The predicted structure was supported by nmr and infrared spectra. IR (CHCl ₃ ): 1725 cm ^-1 Example 32 Ethyl 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-3,4-dihydro-8
-Propyl-2H-1-benzopyran-2-yl}-propanoate 2.9 g (8.3 mmol) of the title compound of Example 31 and 2.4 g of 2,4-dihydroxy-3-propylacetophenone in 30 ml of dry dimethylformamide.
Add 2 drops of Triton B to the solution of (12.5 mmol). The reaction mixture is heated to 110-120° for 48 hours, then cooled and evaporated to dryness. The crude product is chromatographed on silica gel using 20% acetone/hexane as eluent to obtain 1.6 g of product as an oil. The predicted structure was supported by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 0.91, 0.93 (one pair of t,
6H, propyl CH ₃ ′s); 1.25 (t, J=7Hz, 3H,
ester CH ₃ ); 2.56 (s, 3Hz, acetyl
CH ₃ ); 3.90 (m, 1H, C H OH); 4.12 (d, J=
7Hz, 4H, OCH ₂ ′s); 6.40, 6.43, 6.80, 7.56 (1
d′s, aromatic) IR (CHCl ₃ ): 1625, 1725 cm ^-1 Example 33 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-yl}propanoic acid The title compound is prepared by the method of Example 7 using the ester product of Example 32 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): loss of ester proton (Example 32
IR (CHCl ₃ ): 1625, 1705 cm ^-1 Elemental analysis: Regarding C ₂₉ H ₃₈ O ₈ , Calculated value: C67.68; H7.44 Actual value: C67.03; H7.39 Example 34 Methyl 7- Hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-oate 99.7 g of 2,4-dihydroxy-3-propylacetophenone in 1 part dry dimethylformamide
(0.513 mol) and dimethyl oxalate 72.7 g
(0.77 mol) of sodium methoxide in a solution of 97 g
(1.8 mmol) little by little. After stirring for 4 hours, 1.8 of acetic acid is added and stirring is continued for 4 days.
The reaction mixture is heated in a steam bath for 4 hours and evaporated to dryness. Add water to the residue and heat the mixture to boiling. The solid is filtered and recrystallized from ethanol to yield 89.8 g of the title compound; melting point: 222
~224°. The predicted structure was supported by nmr and infrared spectra. IR (KBr): 1650, 1745cm ^-1 example 35 Methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
4-oxo-8-propyl-4H-1-benzopyran-2-oate The title compound is prepared by the method of Example 6 using the product of Example 34 as starting material. The estimated structure is
Confirmed by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 0.89, 0.93 (one pair of t,
6H, propyl CH ₃ ′s); 2.55(s, 3H, acetyl
CH ₃ ); 2.62, 2.88 (a pair of t, 4, OCH ₂ 's);
6.98 (s, 1H C=CH); 6.42, 7.00, 7.54, 8.00
(1 set of d′s, aromatic) IR (CHCl ₃ ): 1650, 1745 cm
^-1 example 36 Methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-8-propyl-2H-1-
Benzopyran-2-oate The title compound was converted to the product of Example 35 by the method of Example 27.
Produced using 30.7 g (61.9 mmol) as raw material. The putative structure is supported by nmr and infrared spectra. nmr (CDCl ₃ ): loss of alkenyl proton; δ
Addition of 2-proton to (ppm) 4.41 (t, J = 5Hz) (compare with example 35) IR (CHCl ₃ ): 1610, 1620, 1730, 1750 cm ^-1 example 37 7-{3-[3-hydroxy- 4-(1-hydroxyethyl)-2-propylphenoxy]propoxy}-3,4-dihydro-8-propyl-
2H-1-benzopyran-2-ylmethanol A solution of 2.8 g (0.13 mol) of lithium boron hydride in 500 ml of tetrahydrofuran was added to 25.0 g of the title compound of Example 36 in 200 ml of tetrahydrofuran.
(51.6 mmol). The reaction mixture is stirred at room temperature for 2 hours and then heated to reflux for 1 hour. After the mixture has cooled, excess borohydride reagent is added with water and then decomposed by adding a small amount of dilute hydrochloric acid. The reaction mixture is diluted with ethyl acetate, washed successively with sodium bicarbonate solution, water and brine, dried over _MgSO4 , filtered and then evaporated to dryness. The residue is chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 16.5 g of the title compound as an oil. The predicted structure was supported by nmr and infrared spectra. nmr( _CDCl3 ): disappearance of ester _CH3 ; acetyl
Change of CH ₃ to δ (ppm) 1.55 (d, J = 7Hz);
Additional signal at 4.96 (q, J = 6 Hz, 1H, methyl-CHO-) (compare with example 36) IR ( _CHCl3 ): no carbonyl band appears between 1600 and 1800 cm ^-1 . Example 38 7-{3-[4-(1-hydroxyethyl)-3-
(Phenylmethoxy)-2-propylphenoxy]propoxy}-3,4-dihydro-8-propyl-2H-1-benzopyran-2-ylmethanol The title compound is prepared by the general method of Example 11 using the product of Example 37 and benzyl chloride as starting materials. The predicted structure was supported by nmr and infrared spectra. IR (CHCl ₃ ): No carbonyl band appears between 1600 and 1800 cm ^-1 nmr (CDCl ₃ ): Additional aromatic proton (compare with Example 37) Example 39 7-{3-[4-acetyl-3 -(phenylmethoxy)-2-propylphenoxy]propoxy}
-3,4-dihydro-8-propyl-2H-1
-benzopyran-2-ylmethanol 8.9 g of the title compound of Example 38 in 150 ml of methylene chloride
(16.2 mmol) in a solution of manganese dioxide 18 g
(162 mmol) is added. The reaction mixture was incubated at room temperature for 12
Stir for an hour and then filter. Removal of the solvent gives 6.9 g of the title compound; mp 83~
85°. The predicted structure was supported by nmr and infrared spectra. Acetyl CH ₃ reappears at IR (CHCl ₃ ): 1665 cm ^-1 nmr (CDCl ₃ ): δ (ppm) 2.55 (s, 3H) (compare with Examples 36, 37, and 38) Example 40 7-{3-[ 4-acetyl-3-(phenylmethoxy)-2-propylphenoxy]propoxy}
-3,4-dihydro-8-propyl-2H-1
-benzopyran-2-carboxaldehyde Oxalyl chloride 1.2 in 30ml methylene chloride
ml (13.3 mmol) of dimethyl sulfoxide in 9 ml of methylene chloride was cooled to -70°.
(26.6 mmol) solution. The mixture is stirred for 5 minutes and then a solution of 6.6 g (12.1 mmol) of the title compound of Example 39 in 20 ml of methylene chloride is added. After stirring for a further 15 minutes, triethylamine
8.5 ml (60.5 mmol) are added and the mixture is stirred at -70° for 5 minutes and warmed to room temperature. Add water;
Separate the layers. The organic layer was washed sequentially with dilute hydrochloric acid, 5% sodium bicarbonate solution, water and brine;
Dry over MgSO ₄ and then filter. Removal of the solvent gives 6.44 g of the title compound as a yellow oil. The predicted structure was supported by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 9.76 (s, 1H, CHO) IR (CHCl ₃ ): 1665, 1735 cm ^-1 example 41 3-[7-{3-[4-acetyl-3-(phenylmethoxy) )-2-propylphenoxy]propoxy}-3,4-dihydro-8-propyl-2H
-1-Benzopyran-2-yl]-2(E and Z)-propenenitrile 6.35 g of the title compound of Example 40 in 150 ml of benzene
Add 4.04 g (13.5 mmol) of cyanomethylenetriphenylphosphorane to a solution of (11.7 mmol). The reaction mixture is stirred for 12 hours at room temperature and then evaporated to dryness. The residue was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent, yielding 1.3 g of the cis isomer, 0.8 g of the trans isomer and a 53:47 cis/trans mixture.
Obtain 1.1g. The predicted structure was supported by nmr and infrared spectra. nmr (CDCl ₃ ) (cis isomer): δ (ppm) 5.44 (dd,
J ₁ = 11Hz, J ₂ = 1.5Hz, 1H, CHCN) (trans isomer): δ (ppm) 5.69 (dd, J ₁ = 16Hz, J ₂ = 3
Hz1H, CHCN); 6.77 (dd, J ₁ = 16Hz, J ₃ = 4Hz,
1H, HC=C-CN) IR (CHCl ₃ ) (cis isomer): 1665, 2210 cm ^-1 (trans isomer): 1665, 2230 cm ^-1 Example 42 3-{7-[3-(4-acetyl- 3-Hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-8-propyl-2H-1-
Benzopyran-2-yl}-2(Z)-propenenitrile To 1.4 g (2.4 mmol) of the cis isomer product of Example 41 in 70 ml of methylene chloride cooled to -78° are added 9.7 ml (9.6 mmol) of a 1M solution of boron trichloride in methylene chloride. After the addition is complete, pour the reaction mixture onto an ice/water mixture and then add additional methylene chloride. The organic layer is washed with water and brine, dried over MgSO ₄ and then filtered. Removal of the solvent gives 1.13 g of the title compound as an oil. The predicted structure was supported by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 5.46 (dd, J ₁ = 11Hz,
1H, CHCN); 6.67 (dd, J ₁ = 11Hz, J ₃ = 3.5Hz,
1H, HC=C-CN); disappearance of ester proton (compare with example 41) IR (CHCl ₃ ): 1625, 2230 cm ^-1 example 43 3-{7-[3-(4-acetyl-3-hydroxy-2 -Propylphenoxy)propoxy]-
3,4-dihydro-8-propyl-2H-1-
Benzopyran-2-yl}propanenitrile A solution of 1.6 g (3.4 mmol) of the title compound of Example 42 in 27 ml of ethyl acetate and 3 ml of acetic acid is hydrogenated at atmospheric pressure and room temperature using a 10% palladium on carbon catalyst. The catalyst is filtered off and the filtrate is evaporated to dryness. 20% residue as eluent on silica gel
Chromatography using ethyl acetate/hexane gives 1.3 g of the title compound; mp 89
~89.5°. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): loss of alkenyl proton (Example 41
IR (CHCl ₃ ): 1625, 2250 cm ^-1 Elemental analysis: Regarding C ₂₉ H ₃₇ O ₅ N, calculated value: C72.62; H7.78; N2.92 Actual value: C72.92; H7.79 ;N2.85 Example 44 Methyl 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy]propoxy]-3,4-dihydro-4-oxo-8-propyl-2H- 1-benzopyran-2-yl}
propanoate 20ml ethanol and 20ml tetrahydrofuran
Methyl 3-{7-[3-[4-acetyl-3-
1.9 g (3.6
(mmol) solution is hydrogenated using a Raney-nickel catalyst at room temperature and 2 psi. The reaction mixture is filtered and evaporated to dryness. The crude product was chromatographed on silica gel using 4% acetone/toluene as eluent to yield the title compound 0.9
g; melting point: 101-101.5°. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1625, 1675, 1730 cm ^-1 Elemental analysis: For C ₃₀ H ₃₈ O ₈ , Calculated value: C68.42; H7.27 Actual value: C68.30; H7.22 Example 45 Methyl 3-{ 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-4-hydroxy-8
-Propyl-2H-1-benzopyran-2-yl}propanoate Another chromatographic fraction of Example 44 yields 1.0 g of the title alcohol compound; mp 125-125.5°.
The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCl ₃ ): 1630, 1735 cm ^-1 Elemental analysis: Regarding C ₃₀ H ₄₀ O ₈ , Calculated value: C68.16; H7.63 Actual value: C68.21; H7.60 Example 46 3-{7-[ 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-2-yl}propanoic acid The title compound (melting point: 149-150°) is prepared by the method of Example 7 using the ketone product of Example 44 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (KBr): 1635, 1665, 1725 cm ^-1 Elemental analysis: Regarding C ₂₉ H ₃₆ O ₈ , Calculated value: C67.95; H7.07 Actual value: C67.73; H7.05 Example 47 Methyl 3-{7 -[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-8-propyl-2H-1-benzopyran-
2-yl}propanoate A solution of 0.2 g (2.4 mmol) of methanesulfonyl chloride in 5 ml of methylene chloride was dissolved in 20 methylene chloride.
Add dropwise to a cooled (-20°) solution of 0.7 ml (5 mmol) of triethylamine and 1.0 g (2.0 mmol) of the hydroxy compound of Example 45 in ml.
The reaction mixture is cooled at -5° for 16 hours, then poured onto ice and extracted with diethyl ether. The organic layer is washed successively with 2M hydrochloric acid, 10% sodium bicarbonate solution and water, dried over MgSO ₄ and then filtered. Removal of the solvent gives 0.6 g of the title compound as an oil. The estimated structure was confirmed by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 3.64 (s, 3H, ester
CH ₃ ); 4.8 (m, 1H, 2-proton); 5.5 (dd, J ₁
= 10Hz, 1H, 3-proton); 6.75 (dd, J ₁ = 10
Hz, 1H, 4-proton) IR (CHCl ₃ ): 1605, 1625, 1745 cm ^-1 example 48 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
8-propyl-2H-1-benzopyran-2-
yl}propanoic acid The title compound (melting point: 60-62°) is prepared by the method of Example 7 using the product of Example 47 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 5.58 (dd, J ₁ = 10Hz, J ₂
=3Hz, 1H, 3-proton); 6,37(dd, J ₁ =
10Hz, J ₃ = 1.5Hz, 1H, 4-proton); disappearance of ester CH ₃ IR (KBr): 1605, 1625, 1725, 1730 cm ^-1 Elemental analysis: For C ₂₉ H ₃₆ O ₇ , calculated value: C70. 14; H7.31 Actual value: C69.94; H7.11 Example 49 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-2H-2-benzopyran-2-carboxaldehyde A solution of 30.0 g of 2,4-dihydroxy-3-propyl-acetophenone in 125 ml of toluene containing 15.5 ml of pyrrolidine is heated to reflux with water removed in a Dean-Stark trap. After adding 29.2 ml of bilbaldehyde dimethyl acetal to the cooled (approximately 0°) solution, the mixture is heated to reflux with further removal of water. After 5 hours, a further 5.2 ml of pyrrolidine are added and the mixture is refluxed for a further 18 hours. The reaction mixture is cooled, concentrated and then taken up in ethyl acetate. The resulting solution is water,
Wash sequentially with 1N hydrochloric acid and brine, dry over magnesium sulfate, filter, and then concentrate to dryness. Dissolve the residue in ethyl acetate/hexane and
After filtration through silica gel and concentration, the resulting oil is purified by column chromatography on silica gel. The intermediate acetal derivative of the title compound is obtained as a yellow solid (13.7 g). This product is used to prepare the title compound without further purification. [Analytically pure samples (melting point:
146-148°) is recrystallized from ethyl acetate/hexane. A solution of 2.0 g of the intermediate acetal compound in 20 ml of acetic acid containing 10 ml of 10% sulfuric acid is heated at 80° for 3 hours. The mixture was taken up in ethyl acetate and washed with water, aqueous sodium bicarbonate and brine,
then dried over magnesium sulfate, filtered,
Then concentrate. Obtained as an oil (1.7g)
The title compound is used in the next reaction without further purification. The predicted structure was supported by nmr and infrared spectra. nmr (CDCl ₃ ): δ (ppm) 0.99, 1.55, 2.70 (t,
m, t, 7H, propyl proton); 1.53 (s,
3H, methyl); 2.88 (q, 2H, ring CH ₂ ); 6.52,
7.62 (1 pair of d, aromatic); 9.60 (s, 1H, CHO) IR (CHCl ₃ ): 1740, 1675 cm ^-1 example 50 2R-(3,4S-dimethyl-5R-phenyl-2S
-oxazolidinyl)-3,4-dihydro-7
-Hydroxy-2-methyl-8-propyl-
2H-1-benzopyran-4-one A solution of 20.0 g of the title compound of Example 49 and excess 1-ephedrin in 150 ml of benzene is heated to reflux with water removed by a Dean-Stark trap. After refluxing for 4 hours, the solution is filtered through silica gel, washed with 50% by volume ethyl acetate/hexane and concentrated to dryness under reduced pressure. After column chromatography on silica gel using ethyl acetate/hexane and recycling to obtain the least polar compound, 1.1 g of the title compound are obtained; melting point: 196-197°. Structure determination was confirmed by X-ray crystallography. [α] _D = −2.1° (1.029% in acetone). Example 51 2S-(3,4R-dimethyl-5S-phenyl-2R
-oxazolidinyl)-3,4-dihydro-7
-Hydroxy-2-methyl-8-propyl-
2H-1-benzopyran-4-one The title compound [4.85 g; melting point: 196-198°] is prepared by the method of Example 50 using 17 g of the title compound of Example 49 and an excess of d-ephedrin. The optical rotation of the title compound was opposite to that of the title compound of Example 50. [α] _D = +1.6° (1.014% in acetone). Example 52 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2R-carboxaldehyde Dowex-50 (H ⁺ form) 12 to 4.1 g of the title compound of Example 50 dissolved in 150 ml of methanol.
g and 50 ml of water. After 2.5 hours at 50°, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound.
Obtain 1.2g. A second crop of product is obtained by suspending the recovered exchange resin in 100 ml of 90% aqueous methanol, adding an additional 4 g of Dovex-50, heating at 60° for 3 hours, filtering, and then concentrating to dryness. A total of 2.4 g of aldehyde product is obtained. This (R)-aldehyde is used in the next reaction without further purification. Example 53 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2S-carboxaldehyde The title compound (3.05 g) was prepared by the method of Example 52.
51 using 5.0 g of the title compound. This (S)-aldehyde is used in the next reaction without further purification. Example 54 Ethyl 3-(3,4-dihydro-7-hydroxy-2R-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)-2(Z)
-propenoate A solution of 1.2 g of the (R)-aldehyde product of Example 52 and 1.8 g of (carboethoxymethylene)triphenylphosphorane is allowed to stand for about 7 hours. The solution is filtered through silica gel and the filtrate is concentrated to dryness.
The residue was then eluted on silica gel with 18%
Chromatograph using ethyl acetate/hexanes. The title compound (i.e. the cis isomer) is obtained from the initial chromatographic fraction; melting point: 104-106°. Example 55 Ethyl 3-(3,4-dihydro-7-hydroxy-2R-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)-2(E)
-propenoate The trans isomer is obtained from the late chromatographic fraction of Example 54; melting point 111.5-112.5°. The estimated structure is
Supported by nmr spectrum, optical rotation and elemental analysis. nmr (CDCl ₃ ): δ (ppm) 6.00 (d, J = 16Hz),
Alkenyl proton [α] at 6.93 (d, J = 16Hz)
_D = +129.0゜ (0.903% in CHCl ₃ ) Elemental analysis: C ₁₈ H ₂₂ O ₅・^1/2 Regarding H ₂ O, _calculated value: C66.96; H7.02 Actual value: C67.08; H6. 95 Example 56 Ethyl 3-(3,4-dihydro-7-hydroxy-2S-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)-2(Z)
-propenoate The title compound (i.e. cis isomer; melting point:
109-110°) by the method of Example 54 and 3.05 g of the (S)-aldehyde product of Example 53 and the phospholane reactant.
Manufactured using 4.7g. The predicted structure was supported by optical rotation and elemental analysis. [α] _D = -185.8° (0.771% in _CHCl3 ) Example 57 Ethyl 3-(3,4-dihydro-7-hydroxy-2S-methyl-4-oxo-8-propyl-2H-1-benzopyran-2 -il)-2(E)
-propenoate The trans isomer is obtained from the late chromatographic fraction of Example 56; melting point: 110.5-111.5°. The predicted structure was supported by optical rotation and elemental analysis. [α] _D = -125.7゜ (1.015% in CHCl ₃ ) Elemental analysis: For C ₁₈ H ₂₂ O ₅ , Calculated value: C67.91; H6.97 Actual value: C67.67; H6.98 Example 58 Ethyl 3 -{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2R-methyl-4-oxo-8-propyl-2H-1-benzopyran- 2-yl}-2(E)-propenoate A mixture of 1.1 g of the title compound of Example 55, 1.0 g of the title compound of Example 5 and 0.91 g of powdered potassium carbonate in 30 ml of dimethylformamide is stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate,
Filter, wash the filtrate sequentially with ammonium chloride solution and brine, filter, and then concentrate under reduced pressure to give an oil. Column chromatography on silica gel with 7% ethyl acetate/toluene gives 1.2 g of the title compound; melting point: 135.5~
136.5°. The predicted structure was supported by optical rotation and elemental analysis. [α] _D = +91.8゜ (1.000% in CHCl ₃ ) Elemental analysis: Regarding C ₃₂ H ₄₀ O ₈ , Calculated value: C69.54; H7.30 Actual value: C69.32; H7.25 Example 59 Ethyl 3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2S-methyl-4-oxo-8-propyl-2H-1- Benzopyran-2-yl}-2(E)-propenoate The title compound (melting point: 134-135°) is prepared by the method of Example 58 using the title compound of Example 57. The predicted structure was supported by optical rotation and elemental analysis. [α] _D = -87.3゜ (1.002% in CHCl ₃ ) Elemental analysis: Regarding C ₃₂ H ₄₀ O ₈ , Calculated value: C69.54; H7.30 Actual value: C69.37; H6.96 Example 60 3- {7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2R-methyl-4-oxo-8-propyl-2H-1-benzopyran-2
-yl}-2(E)-propenoic acid The title compound (melting point: 179.5-181°) was prepared by column chromatography on silica gel using the general method of Example 7, but the initially formed solid was column chromatographed on silica gel (85:15:1 toluene/ethyl acetate/acetic acid as eluent). ) to give the ester product of Example 58
Produced from 1.05 g, yielding 0.67 g of pure solid.
The predicted structure was supported by optical rotation and elemental analysis. [α] _D = +93.3゜ (1.001% in CHCl ₃ ) Elemental analysis: Regarding C ₃₀ H ₃₆ O ₈ , Calculated value: C68.68; H6.92 Actual value: C68.62; H6.76 Example 61 3 -{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2S-methyl-4-oxo-8-propyl-2H-1-benzopyran-2
-yl}-2(E)-propenoic acid The title compound (melting point: 179-181°) is prepared by the method of Example 60 using 1.1 g of the ester product of Example 59. The predicted structure was supported by optical rotation and elemental analysis. [α] _D = -90.8゜ (1.002% in CHCl ₃ ) Elemental analysis: For C ₃₀ H ₃₆ O ₈ , Calculated value: C68.68; H6.92 Actual value: C68.60; H6.79 Example 62 Ethyl 3 -{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2S-methyl-4-oxo-8-propyl-2H-1-benzopyran- 2-yl}-2(Z)-propenoate The title compound (melting point: 98-99°) is prepared by the method of Example 58 using the title compound of Example 56. The predicted structure was supported by optical rotation and elemental analysis. [α] _D = -118.8゜ (1.013% in CHCl ₃ ) Elemental analysis: Regarding C ₃₂ H ₄₀ O ₈ , Calculated value: C69.54; H7.30 Actual value: C69.63; H7.30 Example 63 N- [3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1- Benzopyran-2-yl}-propanoyl-L-proline methyl ester The title compound is prepared by the method of Examples 20 and 21 using L-proline methyl ester in place of dimethylamine. The predicted structure was confirmed by nmr spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 1.35 (s, 3H, 2-methyl proton); 2.55 (s, 3H, acetyl CH ₃ );
3.71 (s, 3H, ester CH ₃ ); 6.42, 6.55, 7.56,
7.72 (1 set of d, aromatic) Elemental analysis: For C ₃₆ H ₄₇ NO ₉ , Calculated value: C67.80; H7.43; N2.20 Actual value: C67.68; H7.70; N2.15 Example 64 N-[3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H -1-benzopyran-2-yl}-propanoyl]-L-proline The title compound is prepared according to the method of Example 7, but using sodium hydroxide in place of lithium hydroxide and using the title compound of Example 63. The predicted structure was confirmed by elemental analysis. Elemental analysis: Regarding C ₃₅ H ₄₅ NO ₉・H ₂ O, calculated value: C65.55; H7.38; N2.18 Actual value: C65.76; H7.44; N1.89 Example 65 N-[3- {7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2 -yl}propanoyl]sarcosine ethyl ester The title compound (melting point: 101-102°) is prepared by the method of Examples 20 and 21 using sarcosine ethyl ester in place of dimethylamine. The predicted structure was confirmed by nmr spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 2.15 (s, 3H, N-
CH ₃ ); 2.55 (s, 3H, acetyl CH ₃ ); 3.07 (s,
2H, N-CH ₂ -CO); 6.50 (repeated d, aromatic); 7.57, 7.72 (a pair of d, aromatic) Elemental analysis: For C ₃₄ H ₄₇ NO ₉ , calculated value: C67.18; H7.57; N2.24 Actual value: C67.12; H7.55; N2.19 Example 66 N-[3-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl}propanoyl]sarcosine The title compound is prepared by the method of Example 7 using the title product of Example 65. The predicted structure is supported by elemental analysis. Elemental analysis: C ₃₃ H ₄₃ NO ₉・^1/2 For H ₂ O, calculated value _: C65.33; H7.31; N2.31 Actual value: C65.10; H7.40; N1.98 Example 67 Methyl 7 -hydroxy-3,4-dihydro-8
-Propyl-2H-1-benzopyran-2-oate The title compound (melting point: 51-53°) was prepared from Example 34 from the title product (6.6 g; 25 mmol) using the general method of Example 27 but as a chromatographic eluent of 15
% ethyl acetate-hexane. The estimated structure was determined by nmr, infrared and ultraviolet spectra.
and supported by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.95 (t, 3H, propyl
CH ₃ ); 3.77 (s, 3H, ester CH ₃ ); 4.75 (t,
1H, 2-proton); 6.33, 6.72 (1 pair of d's, aromatic) IR (CHCl ₃ ): 1740, 1760 cm ^-1 UV (methanol): λ _nax 284 nm (ε1830) Elemental analysis: C ₁₄ H ₁₈ For O ₄ , calculated value: C67.18; H7.25 Actual value: C67.10; H7.42 Example 68 Methyl 7-phenylmethoxy-3,4-dihydro-8-propyl-2H-1-benzopyran-
2-Oate The title compound is prepared as an oil from the title product of Example 67 (5.25 g; 21 mmol) and benzyl bromide by the general procedure of Example 6. The deduced structure was supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 5.03, 7.38 with additional signal for benzyl proton (compare with example 67) IR (CHCl ₃ ): 1735, 1755 cm ^-1 UV (methanol): λ _nax 276 nm (ε 1862), 284 nm
(ε1933) Elemental analysis: Regarding C ₂₁ H ₂₄ O ₄ , Calculated value: C74.09; H7.11 Actual value: C74.11; H7.06 Example 69 Methyl 2-(7-phenylmethoxy-3,4-
dihydro-2-methoxycarbonyl-8-propyl-2H-1-benzopyran-2-yl)-1
-cyclopropyl carboxylate Cooled (-10°) anhydrous tetrahydrofuran 300
To a solution of 0.77 ml (approximately 5.5 mmol) of diisopropylamine in 100 ml, 2.1 ml of 2.5 M n-butyllithium in tetrahydrofuran are added under an argon atmosphere. The solution was further cooled to -70° and 1.7 g (5 ml) of the title product of Example 68 in 10 ml dry tetrahydrofuran was added.
(mmol) slowly while stirring. After 1 hour, methyl 4-
Slowly add a solution of 0.87 ml (approximately 6.3 mmol) of bromocrotonate. The reaction mixture is warmed to about 0° and then cooled with dilute hydrochloric acid. The mixture is poured into 150 ml of diethyl ether, washed successively with water, saturated sodium bicarbonate and brine, then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. Purification by high performance liquid chromatography affords the title compound as an oil. Product slowly crystallizes; melting point: 82
~84°. The putative structure is supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.94 (t, 3H, propyl
CH ₃ ); 3.66, 3.68 (a pair of s, 6H, ester
CH ₃ ′S); 5.02 (s, 2H, benzyl CH ₂ ); 6.3−7.4
(Aromatic) IR (CHCl ₃ ): 1720cm ^-1 UV (methanol): λ _nax 276nm (sh; ε1875),
284nm (ε1964) Elemental analysis: For C ₂₆ H ₃₀ O ₆ Calculated value: C71.21; H6.90 Actual value: C70.41; H6.88 Example 70 Methyl 2-(7-hydroxy-3,4-dihydro -2-methoxycarbonyl-8-propyl-
2H-1-benzopyran-2-yl)-1-cyclopropylcarboxylate The title compound (530 mg) was converted to the title product of Example 69 699
mg (1.6 mmol) using the general method of Example 27 but using ethanol as the hydrogenolysis solvent. The putative structure is supported by nmr spectra. nmr (CDCl ₃ ): Disappearance of benzyl signal (compare with Example 69) Example 71 Methyl 2-[7-(3-bromopropoxy-3,
4-dihydro-2-methoxycarbonyl-8-
Propyl-2H-1-benzopyran-2-yl]
-1-cyclopropylcarboxylate 658 mg (1.7 mmol) of the title product of Example 70, 1.
5.18 g (25.7 mmol) of 3-dibromopropane,
A mixture of 112 mg (0.75 mmol) of sodium iodide and 480 mg (3.5 mmol) of anhydrous potassium carbonate is heated to reflux in 15 ml of methyl ethyl ketone in the presence of 3A molecular sieves for 3 days. After filtering off the insoluble materials, the mixture is concentrated under reduced pressure to obtain an oil. Purification by centrifugal thick layer chromatography gives 470 mg of the title compound as an oil. This product is used in the next reaction without further purification. Example 72 Methyl 2-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methoxycarbonyl-8-propyl-2H-1-benzopyran -2-yl}-1-cyclopropylcarboxylate The title compound (209 mg) was converted to the title product of Example 71 (470 mg; 0.90 mmol) using the general method of Example 6.
and 2,4-dihydroxy-3-propylacetophenone. The predicted structure is supported by elemental analysis. Elemental analysis: Regarding C ₃₃ H ₄₂ O ₉ , Calculated value: C68.02; H7.26 Actual value: C67.44; H7.18 Example 73 2-{7-[3-(4-acetyl-3-hydroxy- 2-propylphenoxy)propoxy]-
3,4-dihydro-2-carboxy-8-propyl-2H-1-benzopyran-2-yl}-1
-cyclopropylcarboxylic acid The title compound (melting point: 138-140°) was obtained from the title product of Example 72 using the method of Example 7, but without purification.
It is produced by centrifugal thick layer chromatography using 73:25:2 hexane-ethyl acetate-acetic acid as the eluent. The resulting oil crystallizes as a 1 1/2 hydrate on standing. The estimated structure is
Supported by nmr spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.88, 0.90 (one pair of t,
6H, propyl CH ₃ ′s); 1.14 (m, 1H, cyclopropyl-CH terminal to carbonyl); 2.00
(m, 1H, cyclopropyl-CH-COO-); 2.24
(t, 2H, cyclopropyl CH ₂ ); 2.53 (s, 3H,
Acetyl CH ₃ ); 6.3-7.3 (aromatic) Elemental analysis: C ₃₁ H ₃₈ O ₉・^3/2 Regarding H ₂ O, calculated value: C64.01; H7.11 Actual value: C64.26; _H6.71 Example 74 Ethyl 4-(7-phenylmethoxy-3,4-
dihydro-2-methoxycarbonyl-8-propyl-2H-1-benzopyran-2-yl)-4
-Oxobutanoate The title compound (3.0 g) was prepared using the general method of Example 69, but the reaction was quenched with 0.5N sodium bisulfate and extracted with ethyl acetate before chromatography to give N-(3-ethoxy Carbonylpropanoyl)-imidazole and the title compound of Example 68 above (5.1 g; 15 mmol). The deduced structure was supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.99 (t, 3H, propyl
CH ₃ ); 1.23 (t, 3H, ethyl CH ₃ ); 3.71 (s,
3H, methyl ester CH ₃ ); 4.10 (q, 2H, ethyl CH ₂ ); 5.01 (s, 2H, benzyl CH ₂ ); 6.3-
7.4 (Aromatic) IR (CHCl ₃ ): 1725, 1745cm ^-1 UV (methanol) λ _nax 279nm (sh; ε2027),
284nm (ε2085) Elemental analysis: For C ₂₇ H ₃₂ O ₇ , Calculated value: C69.21; H6.89 Actual value: C69.34; H6.94 Example 75 Ethyl 4-{7-[3-(4-acetyl -3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methoxycarbonyl-8-propyl-2H-1-benzopyran-2-yl}-4-oxobutanoate The title compound (1.6 g) was prepared from the title product of Example 74 in Examples 70 and 71 (but without chromatography).
and 72 (but add 3 molecular sieves to the reaction mixture)
Manufactured using the method of Purification is carried out by high performance liquid chromatography using 20% ethyl acetate-hexane followed by centrifugal thick layer chromatography using 20% dioxane-hexane. The deduced structure was supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl ₃ ): δ (ppm) 0.90, 0.95 (one pair of t,
6H, propyl CH ₃ ′s); 1.23 (t, 3H, ethyl
CH ₃ ); 2.55 (s, acetyl CH ₃ ); 3.69 (s, 3H,
Methyl ester CH ₃ ); 6.3-7.4 (aromatic) IR (CHCl ₃ ): 1625, 1730, 1750 cm ^-1 UV (methanol): λ _nax 283 nm (ε17690) Elemental analysis: Calculated value for C ₃₄ H ₄₄ O ₁₀ : C66.65; H7.24 Actual value: C66.62; H7.31 Example 76 4-{7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-
3,4-dihydro-2-carboxy-8-propyl-2H-1-benzopyran-2-yl}-4
-Oxobutanoic acid The title compound (melting point: 100-102°) was prepared from 1.1 g (1.8 mmol) of the title product of Example 75 using the method of Example 7 but allowing the reaction to proceed for 4 hours and using sodium bisulfate. The mixture is acidified and prepared. The solid obtained by concentrating the ethyl acetate extract to dryness (700 mg) is analytically pure. The deduced structure was supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl ₃ ): loss of methyl and ethyl ester protons; addition of 2-proton to δ (ppm) 4.46 (dd, 1H) (compare with example 75) IR (CHCl ₃ ): 1630, 1715, 1750 cm ^-1 UV (Methanol): λ _nax 284nm (ε18600) Elemental analysis: Regarding C ₃₀ H ₃₈ O ₈ , calculated value: C68.42; H7.27 Actual value: C68.12; H7.26

Claims (1)

[Claims] 1 formula (In the formula, R represents a hydrogen atom or a methyl group, but when R represents a hydrogen atom, the compound is in the form of a monohydrate) and pharmacologically acceptable additions thereof salt.