BG61090B2 - 3,4-dihydro-2h-benzopyrane derivatives - Google Patents

Abstract

The compounds are used in the treatment of allergic diseases and have the formulas and in which r 1 is hydrogen or lower alkyl; r 2 is hydrogen or halogen; r 3 , r 4 and r 5 are hydrogen, acyl or lower alkyl; r 6 and r 7 are independently hydrogen or lower alkyl; x is alkylene containing 3 to 7 carbon atoms and n is an integer from 1 to 4, provided that only one of r 3 , r 4 or r 5 can be acyl. The invention also relates to an enantiomer thereof and, when r 7 is hydrogen, to salts thereof with pharmaceutically acceptable bases. 15 claims

Description

RELATED PATENT APPLICATIONS

This application is a partial continuation of application Serial No. 06/758 256, registered on July 24, 1985, abandoned, which is separate from the related unresolved application Serial No. 06/614 368, registered May 29, 1984, which is partial continuation of application Serial No 06/507 383, registered June 24, 1983, abandoned.

Brief description of the invention

The invention relates to compounds of formula

wherein R 1 is hydrogen or lower alkyl; R ₂ is hydrogen or halogen; R ₃ , R ₄ and R ₃ denote hydrogen, acyl or lower alkyl; R ₆ and R ₆ , independently of one another, denote hydrogen or lower alkyl; X is alkylene of 3 to 7 carbon atoms and η is an integer of 0 to 4, provided that only one of the substituents R ₃ , R ₄ or R ₅ can be acyl, their enantiomers, and when R ₇ is hydrogen, salts thereof with pharmaceutically acceptable bases.

The compounds of formulas I and II are useful as agents for the treatment of allergic conditions.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" means a straight or branched chain saturated hydrocarbon containing from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, pentyl, heptyl and similar. The term "halogen" means all halogens, i. E. chlorine, bromine, fluorine and iodine. The term "acyl" means an "alkanoyl" group derived from an aliphatic carboxylic acid containing from 1 to 7 carbon atoms, such as formyl, acetyl, propionyl and the like, and "aroyl" group means a radical derived from an aromatic carboxylic acid such as benzoyl and similar. The term "alkylene" means a straight chain radical containing from 3 to 7 carbon atoms, for example propylene, 25 methylpropylene, butylene, pentamethylene, hexamethylene, heptamethylene and the like. The term "aryl" means a phenyl radical or a phenyl radical having one or more substituents selected from halogen, 10 trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and di-lower alkylamino. The term "aralkyl" means a straight or branched chain lower alkyl group in which one or more hydrogen atoms are substituted with an aryl group such as benzyl or the like.

The invention relates to compounds of formula

wherein R ₁ is hydrogen or lower alkyl; R ₂ is hydrogen or halogen; R ₃ , R ₄ and R ₃ are hydrogen, acyl or lower alkyl, X is alkylene containing from 3 to 7 carbon atoms, and η is an integer from 0 to 4, provided that only one of the substituents R ₃ , R ₄ or R ₃ may be acyl;

to their enantiomers and when R ₇ is 35 hydrogen to their salts with pharmaceutically acceptable bases.

A preferred group of compounds of the invention are those represented by the formula:

wherein R 1 is lower alkyl, R ₂ is hydrogen, R ₃ is an acyl radical, R ₆ is hydrogen and R 1 is hydrogen.

A more preferred group of compounds of the invention are those of formula I wherein R 1 is lower alkyl, R ₂ is hydrogen, R ₃ is acyl; R ₄ , R ₃ , R ₆ and R ₇ are hydrogen, X is alkylene containing 3 to 5 carbon atoms.

An even more preferred group of compounds of the invention are those of formula I, wherein R 1 is propyl, R ₂ is hydrogen, R ₃ is acetyl; R ₄ , R ₅ , R ₆ and R 1 are hydrogen, X is an alkyd containing 3 to 5 carbon atoms.

Preferred compounds of formulas I and II are:

racemic-6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(S) - (+) - 6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

racemic-6-acetyl-7- (3, (4-acetyl-hydroxy-2-propylphenoxy) propoxy) -2-methyl-8-propyl-2H-1-benzopyran-2-propanoic acid and racemic-7- / 3 - (4-acetyl-3-hydroxy2-propylphenoxy) -propoxy / -3,4-dihydro2H-1-benzopyran-2-carboxylic acid.

Examples of compounds of formula I and II are:

m) -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

(S) -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

racemic-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy] -3,4-dihydro-2H-1-benzopyran-2-butyric acid;

racemic-8- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy] -3,4-dihydro-7-acetyl-2H-1-benzopyran-2-carboxylic acid;

racemic-5-acetyl-6- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-propanoic acid;

racemic-6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H -1-benzopyran-2-butyric acid;

racemic-6-propanoyl-7- [7- (4-acetyl-3-hydroxy-2-propylphenoxy) heptyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2 butyric acid;

(R) - (-) -6-acetyl-7- [5, (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and similar ones.

The compounds of formula I of the invention can be prepared as described below in Schemes I and II as follows:

Scheme I:

111

in which R 1, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , X un have the meanings described above, R 1 is lower alkyl, R 1 is hydrogen and HAL is halogen.

In Scheme I, the reaction of a compound of formula A, which are known compounds or may be prepared by known methods, with a compound of formula III to give a compound of formula 1a, is carried out under anhydrous conditions in an inert solvent, for example acetone , methyl ethyl ketone, diethyl ketone, dimethylformamide or the like, at the reflux temperature of the reaction mixture. When dimethylformamide is used, the temperature is in the range of about 70 ° C to about 100 ° C, in the presence of an acid acceptor, for example potassium carbonate or the like. A preferred solvent is a mixture of acetone and dimethylformamide. The compound obtained can be isolated by known methods such as crystallization, chromatography, etc.

The compound of formula Ia can be converted to the compound of formula Ib by hydrolysis, which is carried out with alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide or the like, in a mixture of water and a water miscible solvent, for example methanol, e.g. ethanol, tetrahydrofuran or the like, at a temperature in the order of about room temperature to that of reflux. The resulting compound of formula Ib can be isolated using conventional methods, for example crystallization, chromatography and the like.

moieties of formula 1 can be synthesized according to the following Schemes 111, IV, V, VI, VII, VIII,

IX or X as follows:

Scheme III:

i '

HAL-alkylene HAL +

3-7 JL> <aww

Scheme II

Ο

in which R 1, R ₂ , R ₆ , R ₇ , R ₇ , HAL un have the meanings described above and R ₃ ', R ₄ ' and R ₅ 'are hydrogen or lower alkyl.

In Scheme II, the reaction of the compounds of formula IV, which are known or can be prepared by known methods, with a compound of formula V to give a compound of formula 1a is carried out under anhydrous conditions in an inert solvent such as acetone, methyl ethyl ketone , diethylketone, dimethylformamide and the like, at the boiling point of the reaction mixture. When working with dimethylformamide, it is then preferred that the temperature be in the range of about 70 ° C to about 100 ° C in the presence of an acid acceptor, for example potassium carbonate or the like. A preferred solvent is a mixture of acetone and dimethylformamide. The compound of formula Ia 'obtained can be isolated using conventional methods such as crystallization, chromatography, etc.

The resultant compound of formula Ia 'can be converted to a compound of formula 16' by hydrolysis using alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like, in a mixture of water and a water miscible alcohol such as methanol, ethanol or the like , at a temperature in the order of about room temperature to that of the mixture boiling. The resulting compound of formula 16 'can be isolated by conventional methods such as crystallization, chromatography, etc.

The starting compounds of formulas 111 and V used to prepare compounds

in which R ₃ , R ₄ , R _s , R ₆ , R ₇ , X, HAL un have the above meanings.

In Scheme III, the reaction of the compound of formula VI, which are known compounds or can be prepared by known methods, with a compound of formula V to give a compound of formula III, is carried out in an inert organic solvent such as dimethylformamide, acetone , methyl ethyl ketone, and the like, preferably dimethylformamide, in the presence of an alkaline substance such as alkali metal carbonate or the like or alkali metal hydride such as sodium hydride or the like, at a temperature in the range of about 20 ° C to about 150 ° C. Room temperature is preferred. The resulting compound of formula III can be isolated in known ways such as crystallization, extraction, chromatography and the like.

Scheme IV:

R, '

VIQ.

wherein R ₆ , R, 'and η have the meanings described above, R ₃ ', R / u R ₃ 'are hydrogen or lower alkyl and R ₍ is lower alkyl or aryl.

In Scheme IV, the allyl halide, which is a known compound or can be prepared by known methods, is reacted with a compound of formula V to obtain a compound of formula VII, the reaction being carried out in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone and the like, preferably dimethylformamide, in the presence of an alkaline substance such as alkali metal carbonate, for example potassium or sodium carbonate, or the like, or alkali metal hydride, for example sodium hydride or the like, at a temperature in the range of o m about 20 ° C to about 150 ° C, preferably at room temperature. The resulting compound of formula VII can be isolated by conventional means such as crystallization, extraction, chromatography and the like.

The compound of formula VII is converted to the compound of formula VIII using conventional olefin hydroboration conditions. For example, using a hydride of formula (Q) ₂ BH, in which Q is hydrogen, lower alkyl or lower cycloalkyl, preferably borohydride (BH ₃ ), dicyclohexylboro hydride or boron hydride-dimethyl sulfide complex, in an inert ether solvent, for preferably tetrahydrofuran, at a temperature in the range of 0 ° C to about 100 ° C, preferably at room temperature. The resulting organoboric intermediate is oxidized, preferably using alkali hydrogen peroxides or the like. The resulting compound of formula VIII can be isolated by conventional means.

A compound of formula VIII is reacted with a sulfonyl chloride of the formula R _g SO ₂ Cl in which R ₈ is an alkyl or aryl radical, for example phenyl, to give a compound of the formula Villa under conditions commonly used for the conversion of alcohol into a sulfonate ester , preferably a methanesulfonate ester. For example, the sulfonation may be carried out in an inert solvent, such as dichloromethane, using as the sulfonating agent alkylsulfonyl chloride, preferably methanesulfonyl chloride, in the presence of an alkaline substance, for example three lower alkylamine, pyridine or the like, preferably three, or more, preferably at a temperature, preferably at 0 ° C to about 25 ° C, preferably 0 ° C. The resulting compound of formula Villa can be isolated in the usual way.

The compound of formula Villa is converted to the compound of formula IIIa under the conditions commonly used to transform a sulfonate ester into iodide. For example, a compound of formula Villa is treated with alkali metal iodide, for example sodium iodide, lithium iodide, potassium iodide, and the like, preferably sodium iodide, in a solvent, for example dialkylketone, such as ethylmethylketone, acetone and the like, preferably at acetone from about 20 ° C to about 100 ° C, preferably at 20 ° C. The resulting compound of formula IIIa can be isolated by conventional methods.

Alternatively, a compound of formula VII is converted to a compound of formula II 1a under conditions commonly used to convert a terminal olefin into primary iodide by hydroboration and iodination. For example, the reaction may be carried out using iodine and hydride of formula (Q) ₂ BH, in which Q is hydrogen, lower alkyl or lower cycloalkyl, preferably dicyclohexylboro hydride, in the presence of an inert ether solvent such as tetrahydrofuran and an alkaline substance, for example an alkali metal carboxylate, preferably sodium acetate, and at a temperature in the range of 0 ° C to about 20 ° C. The resulting compound of formula IIIa can be isolated by conventional methods.

Scheme V:

f '

XI

V wherein R ₃ ', R 1, R ₁ , R ₆ and R ₇ ' have the description 5

Scheme VII:

and R represents aralkyl.

In Scheme V, the compound of formula IX is reacted with a compound of formula (C ₆ H ₅ ) ₃ P = CHCO ₂ R ₇ 'in which R 1' is lower alkyl, preferably ethyl, which are known compounds or can be prepared by known methods to give a compound of formula XI. The reaction is carried out in an inert aromatic hydrocarbon solvent, preferably toluene, at a temperature in the range of from about 20 ° C to about 150 ° C, preferably about 110 ° C. The resulting compound of formula XI is isolated by known methods.

A compound of formula XI can be converted to a compound of formula Va by any of the known methods of catalytic hydrogenation. For example, by action with hydrogen in the presence of a catalyst such as palladium on carbon, in a solvent, for example alkanol such as ethanol, preferably at room temperature and under one atmosphere. The resulting compound of formula Va can be isolated by conventional means.

Scheme VI:

in which R ₃ ', R ₄ ', Rj * and R ₇ have the meanings described.

In Scheme VI, compounds of formula XII, which are known or can be prepared by known methods, are hydrogenated to give a compound of formula V6. In particular, the reaction is carried out using a catalyst such as palladium on carbon, in a solvent such as a lower carboxylic acid, preferably acetic acid, at a temperature in the range of about 20 ° C to about 150 ° C, preferably at 25 ° C and at elevated pressure, preferably at 50 pounds / inch ^2. The resulting compound of formula V6 is isolated by conventional means.

xv

VcfXVI) in which R ₃ ', R ₄ ', Rj ', R ₆ and R 1' have the meanings described above and η 'stands for 2, 3 or 4.

In Scheme VII, a compound of formula XIII, which are known compounds and can be prepared by known methods, is reacted with a compound of formula XIV, which are also known compounds, and can be prepared by known methods, to obtain a compound of formula XV . The reaction is carried out in the presence of a catalyst, such as a cyclic secondary amine, for example pyrrolidine, in an inert aromatic hydrocarbon, preferably toluene, and at a temperature in the range of about 25 ° C to about 150 ° C, preferably at 110 ° C. The resulting compound of formula XV can be isolated by known methods.

The compound of formula XV is reduced to a compound of formula Vc by using, for example, borohydride in the presence of Lewis acid such as boron trifluoride, boron trichloride, aluminum trichloride and the like, but preferably boron trifluoride etherate in inert ether tether, e.g. a temperature in the range of about 0 ° C to about 25 ° C, preferably 0 ° C.

The resulting compound of formula Vc is isolated by conventional means.

Scheme VIII:

(CH1VCO, ·

V4 (XV11) wherein R ₄ ', R _6, R,' un have the meanings given above, and R _{| 0} is hydrogen or lower alkyl.

In Scheme VIII, the phenolic compound of formula XVIII is converted to its acyl derivative of formula XIX using a suitable acylating reagent, for example lower alkyl halide or anhydride, preferably acetic anhydride, in a suitable alkaline medium such as pyridine, lower alkylamine or the like , preferably pyridine, at a temperature in the range of about 0 ° C to about 150 ° C, preferably 25 ° C. The resultant compound of formula XIX can be isolated by conventional methods.

A compound of formula XIX can be converted to a compound of formula Xl using the usual reaction conditions to induce a freeze rearrangement of phenyl acetylate. For example, it may be carried out in the presence of tin chloride, a Lewis acid catalyst such as aluminum chloride, boron trifluoride and the like, preferably boron trifluoride etherate in a solvent, for example halogenated hydrocarbons, lower alkanoic acid, and the like, preferably acid. , at a temperature in the range of about 20 ° C to about 150 ° C, preferably 120 ° C. The resultant compound of formula IIc can be isolated by conventional means.

Alternatively, a compound of formula XVIII can be converted to a compound of formula IIc under the usual conditions for conducting Friedel-Crafts acylation of phenol. For example, acylation may be carried out using a Lewis acid catalyst such as aluminum chloride, tin chloride, boron trifluoride and the like. Preferably gaseous boron trifluoride and an acylating agent, for example, lower acyl halide, lower acid anhydride, lower alkanoic acid and the like, preferably acetic acid, at a temperature in the range of about 20 ° C to about 150 ° C, preferably 80 ° C a compound of formula Va can be isolated in the usual way.

Scheme IX:

wherein R ₃ ', R ₄ ' and R ₃ 'have the meanings previously described, R _n is hydrogen or aryl-lower alkyl, preferably benzyl, and R ₁₂ is lower alkyl.

In Scheme IX, a compound of formula XXI is known or can be prepared by known methods, reacted with acrolein to obtain a compound of formula XXII, using, for example, a strong mineral acid, for example hydrochloric, sulfuric, aryl or alkylsulfonic an acid such as paratoluenesulfonic acid and the like, preferably concentrated sulfuric acid, in a solvent such as lower alkanol, e.g. ethanol, methanol or the like, preferably methanol, at a temperature in the range of about 20 ° C to about 200 ° C, reading at 150 ° C. The resulting compound of formula XXII can be isolated in known ways.

A compound of formula XXII is converted to a compound of formula IXa when used as a catalyst for a strong mineral acid, such as, for example, dilute hydrochloric acid, sulfuric acid or arylalkylsulfonic acid such as para-lUlsulfonic acid, or the like, preferably dilute aqueous hydrochloric acid, hydrochloric acid a solvent which is miscible with water such as acetone, methanol, ethanol, tetrahydrofuran, acetic acid and the like, preferably acetone, at a temperature in the range of 20 ° C to about 150 ° C, preferably mp 60 ° C.

Scheme X:

xxv XXVI IX »in which R ₃ ', R ₄ ', R ₅ ', R ₇ ' and R ₈ have the meanings described above.

In Scheme X, a compound of formula XXIII, which are known compounds or may be prepared by known methods, is reacted with a compound of formula X, which are also known or may be prepared by known methods, to obtain a compound of formula XXIV. The reaction is carried out in an inert organic ether solvent or in an aromatic hydrocarbon environment such as tetrahydrofuran, dioxane, glyme, benzene, toluene, xylene or the like, preferably toluene, at a temperature in the range of about 20 ° C to about 200 ° C. , preferably 110 ° C. The resulting compound of formula

XXIV can be isolated by conventional methods.

The compound of formula XXIV may be hydrogenated to give a compound of formula

XXV by the use of conventional hydrogenation catalysts, for example palladium on carbon, platinum oxide, nickel or the like. Preferably platinum oxide in the presence of a solvent, for example, lower alkanoic acid, ethyl acetate or the like, preferably ethyl acetate at a temperature in the range of about 20 ° C to about 100 ° C, preferably 20 ° C and at normal atmospheric pressure. The resulting compound of formula XXV can be isolated by conventional methods.

A compound of formula XXV can be converted to a compound of formula XXVI by saponification and then lactonization. The saponification may be carried out using alkali metal hydroxide, preferably potassium hydroxide, in a solvent medium, such as lower alcohol, preferably methanol, at a temperature in the range of about 20 ° C to about 100 ° C, preferably 65 ° C. . Lactonization can be carried out, for example, with a lower alkane anhydride, such as acetic anhydride, which may also be used as a solvent, at a temperature in the range of about 20 ° C to about 200 ° C, preferably at the boiling point of acetic anhydride. The resulting compound of formula XXVI can be isolated in known ways.

A compound of formula XXVI can be converted to a compound of formula 1Xb using conventional reducing agents, for example, dinisobutylaluminum hydride, preferably diisobutylaluminum hydride, at a temperature in the range of about -50 ° C to about -100 ° C, preferably 75 ° C, in an inert solvent medium, for example aromatic hydrocarbon, chlorinated alkane or lower alkane, preferably dichloromethane. The resulting compound of formula 1Xb can be isolated using conventional methods.

The compounds of formula II of the present invention can be prepared by the reactions shown in Schemes XI and XII.

Scheme XI.

About 11 i * ν * »

A XXX

wherein R _p R ₂ , R ₃ , R ₄ , RjU X have the meanings described, R ₇ 'is lower alkyl, R ₇ ' is hydrogen, and HAL is halogen.

In Scheme XI, the reaction of a compound of formula A, which are known compounds or can be prepared by known methods, with a compound of formula XXX to give a compound of formula Pa, is carried out under anhydrous conditions in inert and XXXIa which used in Schemes XI and

XII for the preparation of compounds of formula

II, may be obtained by schemes XIII, XIV and

XV:

a solvent, for example acetone, methyl ethyl ketone, diethyl ketone, dimethylformamide or the like, at a reflux temperature of the reaction mixture when working with dimethylformamide, preferably a temperature of about 70 ° C to about 100 ° C, in the presence of an acid acceptor, for example potassium carbonate or the like. A preferred solvent is a mixture of acetone and dimethylformamide. The resulting compound of Formula IIa can be isolated using known methods, for example crystallization, chromatography or the like.

A compound of formula Pa may be converted to a compound of formula IIb by hydrolysis, which is carried out with alkali metal hydroxide, potassium hydroxide or the like, in a mixture of water and a water miscible solvent, for example methanol, ethanol, tet-20 hydrofuran or the like, at a temperature in the order of about room temperature to that of reflux. The resulting compound of formula IIb can be isolated using conventional methods, for example crystallization, chromatography and the like.

Scheme XII.

in which R _p R 1, R ₃ ', R ₄ ', R _s ', R ₇ ', R ₇ ', HAL and X are as defined above. 45

In Scheme XII, a compound of Formula IV is reacted with a compound of Formula XXXIa to produce a compound of Formula Pa ', which is then converted to a compound of Formula IIb' as previously described 50 in connection with Scheme II.

The starting compounds of formulas XXX

Scheme XIII.

HA-alkylene _{3 7} -HAL

VI

XXX in which R ₃ , R ₄ , R ₅ , R ₇ ', X and HAL have the meanings already described.

In Scheme XIII, the reaction of the compounds of formula VI, which are known compounds or can be prepared by known methods, with a compound of formula XXXI to give a compound of formula XXX, is carried out in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone or the like, preferably dimethylformamide, in the presence of an alkaline substance such as alkali metal carbonate such as potassium carbonate, sodium carbonate or the like, or in the presence of alkali metal hydride such as sodium hydride or the like, n and a temperature in the range of about 20 ° C to about 150 ° C, preferably at room temperature. The resulting compound of formula XXX can be isolated using conventional methods such as extraction, crystallization, chromatography or the like.

Scheme XIV.

xxx

in which R ₃ ', R ₄ ', Rj ', R,' and R ₈ have the meanings described.

In Scheme XIV, a compound of formula XXIII is reacted with acrylonitrile to give a compound of formula XXVII. The reaction is carried out in the presence of a catalyst such as an aromatic amine, such as triethylamine, diazabicycloundecane, diazabicyclo (2,2,2) octane, which is preferably at a temperature in the range of about 20 ° C to about 100 ° C, preferably 80 ° With, without solvent. The resulting compound of formula XXVII can be isolated in known ways.

The compound of formula XXVII is converted to a compound of formula XXVIII by saponification, for example with an alkali metal hydroxide such as potassium, in a solvent, 10 as a water-miscible organic solvent, for example tetrahydrofuran, methanol, ethanol or the like, preferably ethanol or tetrahydrofuran from about 20 ° C to about 100 ° C, preferably 15 to 60 ° C. The resulting compound of formula XXVIII can be isolated by known methods.

The conversion of a compound of formula XXVIII to a compound of formula XXIX can be accomplished by esterification using a lower alkanol as a reagent and solvent, for example ethanol, at a temperature in the range of about 20 ° C to about 100 ° C, preferably 78 ° C, in the presence of a 25 catalyst, for example a strong acid such as sulfuric, para-toluenesulfonic or the like, preferably paratoluenesulfonic acid. The resulting compound of formula XXIX can be isolated in known ways. 30 A compound of formula XXIX can be converted to a compound of formula XXX 1a by catalytic hydrogenation, for example using palladium on a carrier, nickel, platinum, preferably palladium on 35 carbon, in the presence of a solvent, for example lower alkanol, acetic acid. ethyl acetate or the like, preferably ethanol, at a temperature in the range of about 20 ° C to -200 ° C, preferably at 20 ° C and at a pressure of 40 atmosphere.

The resulting compound of formula XXXIa is isolated by known methods.

Scheme XV.

wherein R ₄ ', R _7' u R _1o have the abovementioned meanings.

In Scheme XV, a compound of formula XXXI6 may be converted to a compound of formula XXXlc directly or by compound XXXII, as described above in Scheme VIII for the conversion of a compound of formula XVIII to Bp.

Scheme XVI.

OQ about D? CO11G + ^ halide

R ⁴ Q

XVIII I

ΧΧΧΠΙ

XXXIV in which R ₄ ', R ₆ , and R ₉ have the meanings described.

In Scheme XVI, the reaction of the compound of formula XVIIIa with a compound of formula a to give a compound of formula XXXIII is carried out under anhydrous conditions in an inert solvent, e.g.

You ·· ^ • Λ * '- · * ·. ·. ·. Acetone, methyl ethyl ketone, diethyl ketone, dimethylformamide or the like, at the reflux temperature of the reaction mixture, preferably at a temperature in the order of about 40 ° C to about 100 ° C and in the presence of 5 acid acceptor, for example potassium carbonate or the like, acetone is preferred as the solvent The resulting compound of formula XXXIII can be isolated using conventional methods such as crystallization , chromatography or the like.

The compound of formula XXXIII can be converted to a compound of formula XXXIV using conventional reducing agents, for example, dinisyl alkyl aluminum hydride, preferably diisobutylaluminum hydride, at a temperature in the range of about -50 ° C to about -100 ° C, preferably -75 ° C, in an inert solvent, for example aromatic hydrocarbon, chlorinated alkanes or lower alkanes, preferably toluene. The resulting compound of formula XXXIV can be isolated in the usual way.

Scheme XVII. 25

pit ♦ < ^C 6 ^H 5> 3 ^? - Ci '· OS - CH. ly

UT

steps in which m is 0 or 1, and R ₄ ', R ₆ , R ₇ ' and R have the meanings described.

In Scheme XVII, the reaction of a compound of formula XXXIV with a compound of formula (C ₆ H ₅ ) ₅ P = CH (CH = CH) _m CO ^ ₇ 'is lower alkyl, preferably ethyl and m is 0 or 1, which are known compounds, or may be prepared by known methods, to give 45 a compound of formula XXXVI is carried out in an inert aromatic hydrocarbon solvent, preferably toluene, at a temperature in the range of about 20 ° C to about 150 ° C, preferably about 110 ° C. The resulting compound can be isolated using conventional methods.

A compound of formula XXXVI can be converted to a compound of formula XVIII6 by any of the known catalytic hydrogenation methods. For example, when exposed to hydrogen in the presence of a catalyst such as palladium on charcoal, in a solvent, for example alkanol such as ethanol or in ethyl acetate, preferably at room temperature and under one atmosphere. The resulting compound of formula XVIII6 can be isolated in known ways.

The invention also relates to pharmaceutically acceptable salts of 3,4-dihydro-2H-1-benzopyran derivatives of formulas I and II and their enantiomers when R ₇ is hydrogen. These salts may be prepared by reacting an acid of formula I or II or an enantiomer thereof with a base having a non-toxic, pharmacologically and pharmaceutically acceptable cation. In general, any base which may form a carboxylic acid salt and whose pharmacological properties will not reverse its physiological effect upon its administration to warm-blooded animals is considered to be within the scope of the invention. Suitable bases are, for example, alkali metal or alkaline earth hydroxides or carbonates such as sodium, potassium or calcium bases, potassium carbonate and the like, ammonia, primary, secondary or tertiary amines, such as monoalkylamine, dialkylamines, trialkylamine amines, bases amino acids such as lysine and the like. The pharmaceutically acceptable salts thus obtained are functionally equivalent to the corresponding 3,4-dihydro-2H-1-benzopyranic acids of formulas I and II and their enantiomers. The salts of the invention are useful as medicaments and their diversity within the scope of the invention will be limited only by the criterion that the bases from which they are derived are non-toxic and physiologically acceptable.

The anti-allergic activity of the compounds of formulas I and II and their enantiomers is demonstrated "in vitro" in warm-blooded animals using standard pharmacological techniques. Examples of such methodologies are:

(a) Guinea pig in vitro test for ileum (second part of small intestine).

The guinea pig ileum bioassay is described by Orange Austen, Adv. Immunol. 10: 105144 (1969).

A 1.5 cm segment was removed from animals weighing 300-400 g and suspended in an organ bath containing 10 ml of Tyrodes solution with ΙΟ ⁶ M atropine sulfate and ΙΟ ^{6 6} M pyrilamine maleate. The bath was maintained at 37 ° C and aerated with a mixture of 95% oxygen and 5% carbon dioxide. The SRS-A used in this test was obtained by inoculating the lungs from actively sensitized guinea pig with egg albumin, in vitro. The corresponding response curve to the SRS-A challenge is determined for the ileum. The SRS-A dosage giving 50% of the maximum contraction (EU ₅₀ ) is then used for challenge. Determine the concentration of the drug substance that retains 50% SRS-A contraction in the guinea pig ileum. In this biotest, the standard SRS-A antagonist, 7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) 2-hydroxypropoxy] -4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid has IC _J0 3.5 χ ΙΟ ⁸ M.

(b) Guinea pigs, in vivo (aerosol):

Male guinea pigs (Hartley type) weighing 300 to 500 g are anesthetized with urethane (2g / kg) intraperitoneally and a polyethylene cannula is inserted into the neck (jugular) to administer the drug. The tracheal pressure is recorded by a cannula inserted into the trachea and connected to a Statham pressure reading apparatus. After the animals are surgically prepared, a period of time is waiting to stabilize the lung function. The test compound was administered as follows: Propanolol (0.1 mg / kg) was administered intravenously while the animal was breathing spontaneously. After five minutes, the animals are exposed to a 5% 1% (w / v) aerosol solution of the test compound (where the pH of the medium is made alkaline to dissolve the drug) or distilled water with the appropriate pH (to serves for control). Monaghan (model 750) ultrasonic mist generator was used to administer the test compounds by inhalation. The ultrasonic frequency is adjusted to obtain particles with a diameter of the order of 1-8μ (average 3µ). The aqueous solutions are prepared immediately and placed in the mist formation chamber. The outlet of the mist generator is connected by a diverted stream of aerosol via a Y-tube directly to the cannula in the trachea. At the end of the exposure period, the animals were paralyzed with succinylcholine (1.2 mg / kg in a vein) and mechanically breathed (with a Harvard rodent respirator) with 40 breaths per minute and 2.5 cm ³ of air per breath and exhale. The animals were then challenged with the maximum constructive dose of leukotrine E ₄ administered intravenously 30 s after the administration of succinylcholine.

The change (cm H ₂ O) between pre and peak ventilation pressure, taking into account and averaging the values of three control animals and five animals to which the test compound was placed, gives the retention percentage calculated by the following formula: control - Compound treated ------------------------------------- x 100 controls

When testing different concentrations of the active ingredient, then the percent retention of each concentration is plotted as log concentration (abscissa) with respect to percent inhibition (ordinate) and IC _J0 is determined by linear regression analysis.

Testing the compounds of formulas I and II listed in Table I in the above test gave the following results:

Table 1

SRS-A antagonism

Test compound

Guinea pig in vitro ileum • With ₅₀ (M)

In vivo bronchodilator in guinea pig aerosol-IC ₅₀ (%) rac-6- / 3- (4-acetyl-3-hydroxy-2-propylenephenoxy) propoxy / -3,4-dihydro-2,5,7,8 tetramethyl- 2H-1-benzopyran-2-carboxyl

acid 1 x 10 ' 1.0 rac-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2-methyl-2H- 1-Benzopyran-2-propanoic acid 1 X 10 ⁷ more than 1.0 rac-6- (3,4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2,5,7,8tetramethyl-2H-1-benzopyran-2-acetic acid 2 X 10 ⁷ 1.0 rac-7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2-methyl-8-propyl-3H-1-benzopyran-2-propanoic acid 5 X 10 ⁷ 0.71 rac-6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl2H -1-benzopyran-2-carboxylic acid 1 X 10 ⁷ 0.20 rac-6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H1-benzopyran-2-propionic acid 5 X 10 ⁷ more than 1 rac-6-acetyl-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy-2-methyl-8-propyl-2H-1-benzopyran-2-propanoic acid 8 X 10 0.12 rac-6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylic acid 1 X ⁷ 1.0 rac-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2H-1-benzopyran-2-acetic acid 1 X ⁷ 0.67 rac-6- / 3- (4-acetide-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2H-1-benzopyran-2-acetic acid 4 X 10 ' 1.0 rac-6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 5 X 10 ⁷ 0.50 rac-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-8-propyl-2H-benzopyran-2-carboxylic acid 1 X 10- ⁷ 0.20 rac-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 6 X 10 0.14

rac-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2H-1-benzo-

pyran-3-carboxylic acid rac-6-acetyl-7- / 3- (4-acetyl-3-hydroxy-2- 1 χ 10 ⁷ more than 1.0 propylphenoxy) propoxy / -3,4-dihydro-2H-1 benzopyran-2-carboxylic acid rac-6-acetyl-7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro -8-propyl-2H-1-benzopyran-2-carboxyl 1 x 10 ⁷ 0.20 acid 1 x 10 ⁷ 0.38 rac-7-acetyl-6- [3- (4-acetyl-3-hydroxy-2-propyl phenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid rac-6-acetyl-7- / 5 - (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H- 2 χ ΙΟ ' ⁷ 0.34 1-Benzopyran-2-carboxylic acid 6 x 10 ⁸ 0,052 rac-6-acetyl-7 - // 7- (4-acetyl-3-hydroxy-2-propylphenoxy) heptyl (oxy) -3,4-dihydro-2H- 1-Benzopyran-2-carboxylic acid rac-8-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1 - 1 χ ΙΟ ⁶ 1.0 benzopyran-2-carboxylic acid rac-7-acetyl-6- / 3- (4-acetyl-3-hydroxy-2- 3 x 10 ⁷ 0.59 propylphenoxy) propoxy / -3,4-dihydro-2-methyl- 2H-1-benzopyran-2-carboxylic acid 5 x 10- ⁷ 1.0

e

When leucotriene E ₄ was used in the above aerosol test instead of leukotriene N ₄ , racemic-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3 was found to be used. 4-Dihydro-2H-1-benzopyran-2-carboxylic acid exhibits an IC ₅₀ value of 0.0056% upon inhibition of bronchospasm; (R - (-) - 6-acetyl-7/5, (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4dihidro-2H-1-benzopyran-2-carboxylic acid exhibit IC _J0 0,018 % in bronchospasm inhibition and (5) - (+) - 6-acetyl-7- / 5, (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H-1-benzopyran -2-carboxylic acid exhibits IC ₅₀ 0.0018% by inhibition of bronchospasm.

Table 1 - continued rac-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid rac-6-acetyl-7 - / 6- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid rac-6-acetyl-7- / 5- (4- acetyl-3-hydroxyphenoxy) pentyloxy / -

3.4-Dihydro-2H-1-benzopyran-2-carboxylic acid rac-6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-8-propyl -2H-1-Benzopyran-2-carboxylic acid rac-6- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -

3.4-Dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2carboxylic acid rac-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy / -3.4 x 10 ⁶ x 10 ⁶ χ ΙΟ ' ⁷ χ ΙΟ' ⁷ Dihydro-2H-1-benzopyran-2-carboxylic acid rac-6-acetyl-7- / 6- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyloxy / -3,4 -Dihydro-2H-1-benzopyran-2-carboxylic acid rac-6-acetyl-7- (4-acetyl-3-hydroxy-2-propylphenoxy) butoxy) -3,4-dihydro-2H-1-benzopyran-2 -carboxylic acid rac-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid rac-7- / 5- (4- acetyl-3-hydroxy-2-propylphenoxy) pent cyclohexyloxy / -

3,4-Dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid (+) - (D) -6- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyloxy) - 3,4-Dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid (-) - (S) -6- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2carboxylic acid (S) -6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2 -propylphenoxy) pentyloxy (-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (S-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) - 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid x 10 ⁶ x 10 ⁶ x 10 ⁶ x 10 ⁷ x 10 ⁷ x ΙΟ ⁷ x 10 ⁸ x 10 '(c) Oral test for leukotrine antagonists

Male guinea pigs (Hartley type) weighing 400 to 600 g are anesthetized with urethane (2 g / kg) intraperitoneally and a cannula is inserted into the neck vein for intravenous administration of the drug. Tracheal pressure (cm water) from a Statham pressure measuring apparatus is recorded. After the animals are surgically prepared, it will take some time to stabilize spontaneous breathing. Since previous studies found that propanolol (0.1 mg / kg intravenously) had a potentiating effect on bronchial spasm when administered with synthetic leukotrin, propanolol was administered five minutes before the leukotrine challenge. After two minutes, spontaneous breathing was stopped with succinylcholine chloride (1.2 mg / kg intravenously) and the animals were inhaled with a Harvard respirator (model 680) for small animals at 40 breaths per minute and 4.0 cm ³ inhalation volume. Animals were given a maximum spasmodic dose of leukotrine C ₄ or leukotrin D ₄ or leukotrin E ₄ (25 µg / kg intravenously) for 5 min. Controls administered solely by the test compound carrier or test animals given by the test compound (when alkaline pH is required to dissolve the compound) are treated (with 10 mg / kg by mouth). ) 2 h before leukotrine exposure. To determine ID _J0 for the test compound, doses ranged from 10 mg / kg by mouth to 100, 50, 30, 20, 5, 3 and 1 mg / kg by mouth.

To determine the duration of activity, the time between administration of the test compound and leukotrine exposure is also determined.

In test (c) of the compounds tested orally, racemic-6-acetyl-7- (5, (4acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-dihydro-2H-

1-Benzopyran-2-pentanoic acid exhibits 46 ± 14% inhibition of leukotrine D ₄ pre-induced bronchospasm when administered orally at a dose of 10 mg / kg.

The compounds of formula I and II, or their enantiomers or salts, when R 1 is hydrogen, or compositions containing therapeutically effective amounts of a compound of formula I or II, of its salt or enantiomer, when R ₇ is hydrogen, may be administered by ways well known in the art. Thus, a compound of formula I or II, its enantiomer or salt, when R ₇ is hydrogen, can be administered either alone or with other pharmaceutical agents, such as antihistamines, mediator releasing inhibitors, methylxanthines, beta-agonists or anti-asthmatic steroids such as prednisone and prednisolone , orally, parenterally, rectally or by inhalation, for example in the form of an aerosol, a micro-atomized powder or a mist solution. Currently, the most preferred route of administration of the compounds of formula I or II is by inhalation, for example as an aerosol and in particular for administration as an anti-asthmatic agent. For oral administration, they may be in the form of tablets, capsules, for example in mixtures with talc, starch, milk sugar or other inert ingredients, e.g. with pharmaceutically acceptable carriers. They may be in the form of aqueous solutions, suspensions, elixirs or, for example, in admixture with sugar or other sweetening agents, flavoring agents, colorants, sealants and other conventional pharmaceutical excipients. For parenteral administration, they may be in the form of solutions or suspensions, for example as a solution in water or in peanut oil or suspension, using conventional excipients and carriers. For administration as aerosols, they can be dissolved in a suitable pharmaceutically acceptable solvent, for example ethyl alcohol or a combination of miscible solvents, and mixed with a pharmaceutically acceptable volatile substance. These aerosol formulations are packed in pressurized containers provided with an aerosol valve (valve) capable of releasing the pressurized composition. Preferably, the valve is metered, i.e. one that, upon activation, will release a predetermined amount of the aerosol composition.

According to the invention, the dosage of a compound of formula I or II, of its enantiomer or salt thereof, when R ₇ is hydrogen to be administered and the frequency of administration will depend on the effectiveness and duration of activity of the corresponding compound of formula 1 or II, its enantiomer or salt, the route of administration, and the severity of the disease, the condition of the patient, the age of the warm-blooded animal to be treated, and the like. The doses of a compound of formula I or 11, of its enantiomer or salt, when R ₇ is hydrogen, are practically administered in the range of about 25 to about 1000 mg per day, preferably about 25 to 250 mg, either as a single dose or in divided doses. a few for the day.

Because the compounds of formulas I and II according to the invention have an asymmetric carbon atom, they are generally obtained as racemic mixtures. The separation of these racemates into optically active isomers can be accomplished by known methods. Some racemic mixtures may precipitate as eutectics and then separate. Chemical separation is preferred. In this method, diastereomers are formed from the racemic mixture of a compound of formula I or II when It is hydrogen, with an optically active separating agent, for example, an optically active base such as d - (+) - a methylbenzylamine, which can react with carboxyl group. The diastereomers formed are separated by selective crystallization and converted to the corresponding optical isomers. Thus, the invention encompasses the racemates of the compounds of formulas 1 and II as well as their optically active isomers (enantiomers).

Alternative separation can be achieved by treating the corresponding acid of an ester of formula V or XXX with an optically active amine used as a resolving agent such as (R) - or (S) - a methylbenzylamine, (R) - or (S) -a -naphthylethylamine, quinine, quinidine, ephedrine and the like, preferably (R) - or (S) -a-methylbenzylamine. After separation of the diastereomeric salts in the manner described above, the obtained optically active acid is separated by acid treatment, and after conversion to the corresponding ect, the corresponding optically active compound of formula I or II is obtained as described in the preparation of racemic forms.

In addition, separation can be achieved by treating the corresponding acid ester of formulas III, V, XXX or XXXI with optically active alcohol to obtain a mixture of diastereomeric esters, which may be obtained by recrystallization or chromatography. Representatives of such optically active alcohols used as release agents are methanol, borneol, 2octanol, 2,3-butanediol and the like. The preferred separation method is using the monoester of 2I, 3I-butanediol and acids derived from esters of formulas III, V, XXX or XXXI. These esters may be obtained by conventional methods. The preferred method is Fischer esterification using a strong acid catalyst. A preferred such catalyst is paratoluene sulfonic acid. The diastereomeric esters of the acids of formulas III or XXX can be prepared by alkylation of the corresponding diastereomeric esters of formulas V or XXXI with the dihaloalkane of formula VI, using the usual techniques described above. The preferred chromatographic technique for achieving separation is high performance liquid chromatography (HPLC). After separation, the separated diastereomeric esters of the acids of formulas III and XXX are converted to the corresponding separated acids of formulas 16 'and IIb' using the conventional methods described above for the racemic compounds.

In the following examples, all reactions are carried out in an inert atmosphere (argon). "Normal refinement" or "routine operation" includes three solvent-specific extractions. The organic extracts were then combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo created by a water pump. The residue is dried to constant weight at 40-50 ° C under high vacuum. Column chromatography on silica gel 0,0630,2 mm is used.

The following examples further describe the invention. All temperatures are given in Celsius degrees unless otherwise indicated.

Example 1. A mixture of 30.4 g of 2 ', 4'dihydroxyacetophenone, 28.8 g of ethylevulinate, 21.3 g of pyrrolidine and 400 ml of toluene was stirred and refluxed for 3 h while removing the water using Dean and Stark the catcher. The resulting mixture was cooled with an ice bath and treated with 300 ml of 1.2 N aqueous hydrochloric acid. After stirring at room temperature for 45 min, the mixture was treated with ether and the aqueous layer was separated. The organic solution was washed with 1.2 N hydrochloric acid. The combined aqueous acidic solutions were combined and extracted twice with ether. The organic solutions were combined, washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous brine, then dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resulting red oil (42 g) was chromatographed on 400 g of silica gel. Elution with 9: 1 toluene-ethyl acetate afforded 32.3 g (58.1%) of the racemic ethyl ester of 3,4-dihydro-7-hydroxy-2-methyl4-oxo-2H-1-benzopyran-2- propanoic acid in the form of orange viscous oil.

Example 2. To a solution of 1.5 g of racemic-3,4-dihydro-7-hydroxy-ethyl ester

2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid in 8 ml of dry tetrahydrofuran, while stirring and cooling with an ice bath, 1.4 ml of boron TFA is added over 2 min. The mixture was stirred at 0 ° -5 ° C for 5 min, then 5.4 ml of 1M boron hydride 1M in tetrahydrofuran was added. Stirring was continued at 0 ° -5 ° C for another 2.5 hours and then the mixture was decomposed by the addition of glacial acetic acid. The solvents were removed in vacuo and the residue was dissolved in methylene chloride. The solution was washed with sodium bicarbonate solution and with sodium chloride solution and then dried, filtered and concentrated under reduced pressure. The residue in the form of an orange oil (1.4g) was chromatographed on 50 g of silica gel. Elution with 4.1 hexane: ethyl acetate afforded 0.9 g (63.1%) of racemic 3,4-dihydro-7-hydroxy-2-methyl2H-1-benzopyran-2-propanoic acid ethyl ester as a colorless oil.

Analysis: Calculated for C ₅ H ₂₀ O ₄ : C 68.16; H, 7.63;

Found C, 67.86; H, 7.60;

Example 3. To a mixture of 120 mg of a suspension of 50% sodium hydride in mineral oil in 0.5 ml of dry N, N-dimethylformamide was added a solution of 292 mg of ethyl racemic 3,4-dihydro-7-hydroxy-2- methyl-2H-

1- Benzopyran-2-propanoic acid in 3 ml of dry N, N-dimethylformamide. The mixture was stirred at room temperature for 25 min, at which point a solution of 364 mg of 4 '- (3bromopropoxy) -2'-hydroxy-3'-n-propylacetophenone in 3 ml of dry N, N-dimethylformamide was added. After stirring at room temperature for 21 h, the mixture was treated with ether and dilute hydrochloric acid and treated with ether in the usual way to give 523 mg of an orange oil. This product was chromatographed on 50 g of silica gel. Elution with 19: 1 toluene-ethyl acetate afforded 257 mg (46.55%) of racemic 7- (3) hydroxy-

2- Propylphenoxy) -propoxy] -3,4-dihydro-2methyl-2H-1-benzopyran-2-propanoic acid as a pale yellow oil.

Analysis: Calculated for C ₂₉ H _3g O _? ; C, 69.86; H, 7.68;

Found: C, 69.65; H, 7.73.

Example 4. To a mixture of 1.55 g of the ester obtained in example 3 and 35 ml of 1: 1 tetrahydrofuran-water were added 2.3 g of lithium hydroxide monohydrate under stirring. The mixture was stirred at room temperature for 22 h and then diluted with water and extracted 3 times with ether (ether extracts discarded). The aqueous solution was acidified to pH 1 by the addition of a saturated aqueous solution of oxalic acid and treated with ether in the usual way. 1.4 g (95.8%) of racemic-7/3 (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy- / 3,4-dihydro-2-methyl-2H-1-benzopyran2-propane are obtained acid as a viscous yellow oil.

Analysis: Calculated for C ₂₇ H ₃₄ O ₇ : C 68.92; H, 7.28 Found: C, 68.62; H, 7.23.

Example 5. A mixture of 3.88 g of 2 ', 4'-dihydroxy-3'-n-propylacetophenone, 3.17 g of ethylevulinate, 0.83 ml of pyrrolidine and 20 ml of toluene was stirred at room temperature for 1 h and then stirred heated to reflux when the water was removed using a Dean and Stark trap. The resulting dark red mixture was cooled, treated with 25 ml of 1 N-hydrochloric acid and stirred at room temperature for 30 min. Water was added and the mixture was triturated with ether as usual to give 5.1 g of a dark red oil. This product was chromatographed on 100 g of silica gel. Elution with 9: 1 and 4: 1 toluene-ethyl acetate afforded 2.9 g (45.3%) of racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-3n-propyl ethyl ester -2H1-benzopyran-2-propanoic acid as a yellow oil.

Analysis: Calculated for C _{| g} H ₂₄ O _5: C, 67.48; H, 7.55;

Found: C, 67.31; H, 7.54.

Example 6. Using the method of Example 2, 257 mg of racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester is reduced with boron hydride, tetrahydrofuran and boron hydride trifluoride etherate. 195 mg of racemic 3,4-dihydro-7-hydroxy-2-methyl-8-propyl-2H-1-benzopyran-2-propanoic acid are obtained as a pale yellow oil after chromatographic purification on silica gel.

Analysis: Calculated for C _lg H ₂₆ O _4: C, 70.56; H, 8.55;

Found: C, 70.01; H, 8.28.

Example 7. To a mixture of 108 mg of a 50% suspension of sodium hydride in mineral oil (pre-washed with hexane) in 1 ml of anhydrous N, N-dimethylformamide was added with stirring a solution of 268 mg of ethyl racemic 3,4- dihydro-7-hydroxy-2-methyl-

3-n-propyl-2H-1-benzopyran-2-propanoic acid in 3 ml of dry N, N-dimethylformamide at room temperature for 1 min. After stirring at room temperature for 30 minutes, a solution of 313 mg of 4 '- (3-bromopropoxy) -2'-hydroxy-3'-n-propylacetophenone in 3 ml of dry dimethylformamide was added dropwise to the mixture. Sodium iodide (0.3 g) was added and the mixture was stirred at room temperature for 2.5 h before quenching with 1 ml of water. After 30 min, 0.3 g of lithium hydroxide monohydrate and 1 ml of water were added and stirring continued for 3 h. The mixture was acidified to pH 1 with 1 N hydrochloric acid and treated with ether as usual. The resulting orange oil (0.7 g) was chromatographed on 50 g of silica gel. Elution of 4: 1 toluene-ethyl acetate afforded 310 mg (69.1%) of racemic 7- / 3- (4-acetyl61090).

3-hydroxy-2-p-propylphenoxy) propoxy / -

3,4-Dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as a viscous yellow oil, after drying at 60 ° C in high vacuum.

Analysis: Calculated for C, HN: O: C, 70.29; H, 7.87;

Found C, 70.19; H, 7.99.

EXAMPLE 8 Using the method of Example 1, 15 g of 2 ', 5'-dihydroacetophenone were condensed with 14.2 g of ethylevulinate and 12.3 ml of pyrrolidine in 200 ml of toluene. The crude product (20.5 g) was purified by flash chromatography (silica gel; 2: 1 hexane-ethyl acetate) to give 17.6 g (64.1%) of racemic 3,4-dihydro-6 ethyl ester -hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid as a yellow oil.

Analysis: Calculated for C ₁₅ H ₁₈ O ₅ : C 64.74; H, 6.52;

Found: C, 64.28; H, 6.64.

Example 9. To a solution of 8.25 g of racemic 3,4-dihydro-6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester in 50 ml of dry glime was added 7 , 29 ml of boron trifluoride etherate dropwise while stirring and cooling in an ice bath. After stirring at 0 ° -5 ° C for 10 min, 1.75 g of boron hydride-dimethylamine complex were added to the mixture. Stirring was continued for 1 h at room temperature, after which 5 ml of glacial acetic acid were added and the solution was poured into cold water and treated with ether as usual (the combined and combined organic extracts were further washed with sodium bicarbonate solution). The crude product has been found to contain a significant amount of starting ketone and is subjected to the above reduction and refinement once again. 8.1 g of a yellow oil are obtained, which is purified by preparative high pressure liquid chromatography (silica gel, 2: 1 hexane-ethyl acetate) to give 5.8 g (74.1%) of racemic ethyl ester 3, 4-Dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid as a yellow oil.

Example 10. Using the method of Example 7, 0.695 g of racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester was alkylated with 0.939 g of 4 '- (3- bromopropoxy) -2'-hydroxy

3'-n-propylacetophenone using sodium hydride and sodium iodide in dry, dimethylformamide. After saponification (1.25 g of lithium hydroxide monohydrate) 1.4 g of crude acid are obtained. Column chromatography on silica gel (50 g) afforded 0.837 g (67%) of racemic 6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H -1-Benzopyran-2-propanoic acid as a colorless oil (eluting with 9: 1 and 4: 1 toluene-ethyl acetate). Analysis Calcd for C ₁₇ H ₃₄ O ₇ : C 68.92; H, 7.28;

Found: C, 68.36; H, 7.20.

Example 11. The method of Example 7 was used to alkylate 0.9 g of racemic 3,4-dihydro-6-hydroxy-2-methyl2H-1-benzopyran-2-carboxylic acid ethyl ester with 4 '(3- bromopropoxy) -2'-hydroxy-3'-n-propylacetophenone (1.5 g) using sodium hydride (12.16 mmol) and sodium iodide (10 mmol) in N, N-dimethylformamide. After saponification with lithium hydroxide monohydrate (1.5 g), the crude product was purified by chromatography on silica gel. 1.16 g (68.9%) of racemic-6- [3- (4-acetyl-3-hydroxy-2-propyl phenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1-benzopyran are obtained 2-carboxylic acid as a white solid, m.p. 108-110.5 ° C. Analysis-Calculated for C _2J H ₃₀ O _7: C, 67.86;; H, 6.83;

Found: C, 67.92; H, 6.97.

Example 12. 365 mg of a dispersion of 50% sodium hydride in mineral oil was washed with hexane and suspended in 32 ml of anhydrous N, N-dimethylformamide. To the mixture was added 1 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester. After stirring at room temperature for 45 minutes, 3.2 ml of allyl bromide (4.47 g) was added dropwise to the mixture. Stirring was continued for another 90 h at room temperature, followed by the addition of 3 ml of methanol. The mixture was poured into water and treated with ether as usual. An amber oil was obtained, which was purified by silica gel column chromatography and then by high pressure preparative liquid chromatography (silica gel, 19: 1 hexanethyl acetate). 772 mg (67.2%) of racemic-3,4-dihydro- methyl ester are obtained.

2,5,7,8-tetramethyl-6-) (2-propenyloxy) -2H-1-benzopyran-2-carboxylic acid as a pale yellow oil. This oil, after evaporating at 1O5 ° -1O7 ° C at a bath temperature (0.02 mm), gives an oil which, when left to stand, solidifies and has a m.p. 68-7 ° C.

Analysis-Calculated for C _lg H ₂₄ O _4: C, 71.03; H, 7.95;

Found: C, 71.37; H, 7.90.

Example 13. To a solution of 1.8 g of racemic 3,4-dihydro-2,5,7,8tetramethyl-6- (2-propenyloxy) -2H-1-benzopyran-2-carboxylic acid methyl ester in 36 ml of anhydrous 1.98 ml of boron hydride-dimethyl sulfide are added to the tetrahydrofuran while stirring and cooling with an ice bath. The reaction mixture was stirred for 1.5 h at 0 ° -5 ° C, then decomposed by the addition of 9 ml of water dropwise. After stirring at 0 ° -5 ° C for 6.8 min, 6.84 ml of 3N sodium hydroxide and then 2.2 ml of 30% hydrogen peroxide are added dropwise to the mixture. The mixture was stirred at 5 ° -10 ° C for 1 h and acidified with 7 ml of 3N hydrochloric acid. It was triturated with ether in the usual way to give 2 g of oil, which was purified by preparative HPLC (silica gel, 1: 1 hexane-ethyl acetate). 1.22 g (64%) of the racemic 3,4-dihydro-2,5,7,8-tetramethyl-6- (3-hydroxypropoxy) -2H-1-benzopyran2-carboxylic acid methyl ester are obtained as a colorless oil . Analysis-Calculated for C _lg H ₂₆ O _5: C, 67.06; H, 8.13;

Found: C, 67.39; H, 8.19.

Example 14. To a solution of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6- (3-hydroxypropoxy) -2H-1-benzopyran-2-carboxylic acid methyl ester (0.3 g ) 0.17 ml of methanesulfonyl chloride are added in 5 ml of anhydrous methylene chloride. The mixture was stirred at room temperature for 45 min, added with 1 N sulfuric acid and treated with methylene chloride in the usual way. 0.461 g of racemic-3,4-dihydro- methyl ester is obtained

2,5,7,8-Tetramethyl-6- (3-methanesulfonyloxypropoxy-2H-1-benzopyran-2-carboxylic acid as an oil, which is used without further purification.

EXAMPLE 15 A mixture of the crude methanesulfonate of Example 14 (about 0.932 mmol), 595 mg of sodium iodide and 5 ml of acetone was stirred at room temperature for 43.5 h and then water was added and worked up in the usual way (ether extracts were further added. washed with dilute sodium bisulfite solution). The oily product (390 mg) was chromatographed on 20 g of silica gel. Elution with 19: 1 and 9: 1 hexane-ethyl acetate gave 306 mg of racemic methyl ester.

3,4-Dihydro-2,5,7,8-tetramethyl-6- (3-iodo-propoxy) -2H-1-benzopyran-2-carboxylic acid as a colorless oil. In another experiment, the iodide thus obtained is crystallized in solid with m.p. 73-75.5 ° C.

Example 16. A mixture of 0.137 g of 2 ', 4'-dihydro-3-n-propylacetophenone, 0.195 g of anhydrous potassium carbonate and 3 ml of anhydrous N, N-dimethylformamide were stirred for 1 h at room temperature. A solution of iodide of Example 15 (0.306 g) in 5 ml of N, N-dimethylformamide was added and the mixture was stirred for 30 min at room temperature and for 31 h at 60 ° C. After cooling, the reaction mixture was treated with 1 N hydrochloric acid and treated with ether as usual. The oily product (0.406 g) was chromatographed on 20 g of silica gel. Elution with 4: 1 hexane-ethyl acetate afforded 0.291 g (82.5%) of racemic 6- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / 3,4-dihydro-2 methyl ester , 5,7,8-tetramethyl-2H-1-benzopyran-2 carboxylic acid as a pale yellow oil. In another experiment a crystalline product, colorless, m.p. 121 ⁰ -123 ° C (from ethanol). Calcd for C ₂₉ H ₃ G O ₇ : C 69.86; H, 7.68;

Found: C, 69.31; H, 7.67.

Example 17. A solution of 0.246 g of the methyl ester of Example 16 and 0.227 g of sodium hydroxide in 8 ml of methanol and 2 ml of water was stirred at room temperature for 1.5 h and then 1 N hydrochloric acid was added and treated with ether. the usual way. The crude product was redissolved in ether and the solution was washed with dilute sodium bicarbonate solution. The aqueous alkaline phase was acidified with 2N hydrochloric acid and treated with ether in the usual way to give 0.161 g (67.3%) of the acid as a yellow oil which crystallized on standing. Recrystallization from benzohexane gave racemic-6- [3- (4acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2 -carboxylic acid as a colorless solid, m.p. Mp 137 ° 139 ° C.

Analysis - Calculated for C ₂ H ₃₆ O ₇ : C 69.40; H, 7.49;

Found: C, 69.28; H, 7.58.

Example 18. Using the method of Example 12 1.42 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2 H -1-benzopyran-2-acetic acid methyl ester is alkylated with allyl bromide (2.79 g) and sodium hydride (5.58 mmol) in anhydrous Ν, dimethylformamide. 1.35 g (83.1%) of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6- (2-propenyloxy) -2H1-benzopyran-2-acetic acid methyl ester are obtained as yellow oil, after purification by column chromatography (silica gel, 9: 1 hexanethyl acetate).

Analysis - Calculated for C, H, O, C 71.67; H, 8.23;

Found: C, 71.54; H, 8.25.

Example 19 To a solution of 1 M boron hydride in tetrahydrofuran (10 ml) was added dropwise, with stirring and ice-cooling, a solution of 2 ml (1.64 g) of cyclohexane in 6 ml of dry tetrahydrofuran. The mixture was allowed to stir at 0 ° - 5 ° C for 1.5 h. To the resulting suspension of dicyclohexylboro hydride was added dropwise a solution of 1.59 g of the allyl ether of Example 18 in 4 ml of tetrahydrofuran. The mixture was stirred at 0 ° - 5 ° C for one hour and at room temperature for 18 h. 20 ml of a 1 M solution of sodium acetate in methanol were added dropwise and then 23.8 ml of 0.4 M iodine in methanol. The resulting mixture was stirred at room temperature for 4 h and then 3.1 ml of aqueous sodium thiosulphate was added. The reaction mixture was poured into water and treated with ether as usual. The crude product (4.4 g) was chromatographed on 100 g silica gel to give 1.71 g (76.7%) of racemic-3,4-dihydro-6- (3-iodopropoxy) -2 methyl ester. 5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid as an oil eluting with 19: 1 and 9: 1 hexane-ethyl acetate.

Example 20. Using the method of Example 16, 328 mg of 2 ', 4'-dihydroxy-3'-n-propylacetophenone was alkylated with 756 mg of Example 19 iodide and anhydrous potassium carbonate (467 mg) in anhydrous N, N-dimethylformamide . Racemic-6 / 3- (4-acetyl-3-hydroxy-2-propyl phenoxy) propoxy / -3,4-dihydro-2,5,7,8-tetramethyl methyl ester is obtained

2H-1-benzopyran-2-acetic acid as a yellow oil after column chromatography (silica gel, 4: 1 hexane-ether).

Example 21. 0.669 g of the sample of the methyl ester of Example 20 was saponified with sodium hydroxide using the method described in Example 17. The crude acid was chromatographed on 30 g of silica gel. Elution with 2: 1 hexane-ethyl acetate gave 0.386 g (59.6%) of racemic-6- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2,5 , 7,8-tetramethyl-2H-1-benzopyran-2acetic acid as a yellow glassy mass.

Analysis - Calculated for C _M H ₃₈ O ₇ : C 69.86; H, 7.68;

Found: C, 69.63; H, 7.89.

EXAMPLE 22 To a solution of racemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of pyridine was added 0.37 ml of acetic anhydride. The solution was stirred at room temperature for 5 h and then poured into ice water and treated with ether in the usual way (the combined ether extracts were further washed with 1 N hydrochloric acid and saturated sodium bicarbonate solution). The oily product (1.0 g) was chromatographed on 50 g silica gel and eluted with 19: 1 toluene-ethyl acetate to give 0.575 g (63.3%) of racemic-7-acetoxy-3,4-dihydro ethyl ester -2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as a pale yellow oil.

Analysis calculated for C 68.94;

H, 8.10;

Found: C, 68.73; H, 8.06.

Example 23. To a solution of 276 mg of racemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran2-propanoic acid ethyl ester in 2 ml of glacial acetic acid and stirring 0.21 ml of boron TFA is added at room temperature. The mixture was stirred at 105 ° C for 24 h, then cooled and diluted with ether. The ether solution was washed with water and brine and treated in the usual way to give 298 mg of a yellow-brown oil. This product was chromatographed on 30 g of silica gel and eluted with 4: 1 toluene-ethyl acetate to give 183 mg (72.1%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8- propyl-2H-1-benzopyran-2-propanoic acid as a white solid, m.p. 154 ° - 156 ° C. Analysis calculated for C ₁₈ H ₂₄ O ₅ : C 67.48; H, 7.55;

Found: C, 67.17; H, 7.72.

Example 24. A solution of 692 mg of racemic-6-acetyl-3, 4-dihydro-7-hydroxy-2-methyl8-n-propyl-2H-1-benzopyran-2-propanoic acid and 100 mg of paratoluenesulfonic acid monohydrate in 10 ml absolute ethanol was stirred and refluxed for 17 h. The resulting solution was cooled and treated with a small amount of saturated sodium bicarbonate solution and then concentrated in vacuo to remove ethanol. The residue was dissolved in ether and the ether solution was treated as usual to give 752 mg of a yellow oil. This product was chromatographed on 50 g of silica gel and eluted with 4: 1 toluene-ethyl acetate to give 706 mg (93.9%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2- methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as a yellow oil.

Analysis - Calculated for C _M H _M O ₃ : C 68.94; H, 8.10;

Found: C, 68.86; H, 7.85.

Example 25. A mixture of 263 mg of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester, 222 mg of anhydrous potassium carbonate , 0.39 ml of 1,3-dibromopropane, 6 ml of anhydrous acetone and 3 ml of anhydrous N, N-dimethylformamide were stirred and refluxed for 16 h. An additional 0.25 g of anhydrous potassium carbonate was added and stirring and boiling continued for another 25 h. The mixture was cooled and the volatiles removed first by a water pump and then under high vacuum. The residue was treated with ether and acetone and the undissolved particles were removed by filtration. Concentration of the filtrate in vacuo gave 359 mg of racemic-6-acetyl-7- (3-bromopropoxy) ethyl ester -

3,4-Dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as an orange oil.

Example 26. A mixture of 335 mg of racemic-6-acetyl-7- (3-bromopropoxy) ethyl ester -

3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid, 143 mg 2 ', 4'-dihydroxy-3'-p-propylacetophenone, 217 mg anhydrous potassium carbonate, 6 ml of anhydrous acetone and ml of anhydrous N, N-dimethylformamide were stirred and refluxed for 17 h. An additional 100 mg of potassium carbonate was added and stirring was continued for 4 hours. After cooling to room temperature, the mixture was carefully acidified to pH 1 by the addition of 1 N hydrochloric acid. Water was added and the mixture was treated with ether as usual. The residue was chromatographed on 50 g of silica gel and eluted with 9: 1 toluene-ethyl acetate to give 219 mg (52.6%) of the racemic-6-acetyl-7- / 3- (4-acetyl-3 ethyl ester) -hydroxy-2-propyl-phenoxy) propoxy / -3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as a yellow oil.

Example 27. 191 mg of the product of Example 26 was saponified with lithium hydroxide monohydrate (273 mg) in 5 ml of a 3: 2 mixture of tetrahydrofuran-water according to the method described in example 4. After column chromatography on silica gel, racemic-6- acetyl 7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid in the form of yellow viscous oil.

Assays - Calculated for C ₃₂ H ₄₂ O _g: C 69.29; H, 7.63;

Found: C, 69.07; H, 7.79.

Example 28. A sample of 809 mg of racemic-3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylic acid ethyl ester was alkylated with 1.2 g 4 ' - (3bromopropoxy) -2'-hydroxy-3'-propylacetophenone, 448 mg of a 50% dispersion of sodium hydride in mineral oil and 1.2 g of sodium iodide in anhydrous dimethylformamide using the method of Example 7. After saponification (1 (2 g of lithium hydroxide monohydrate) to give 1.6 g of crude crystalline acid. It was chromatographed on 50 g of silica gel, eluting with 4: 1, 2: 1 and 1: 1 toluene-ethyl acetate to give 1.2 g (83.2%) of racemic-6- / 3- (4- acetyl-3-hydroxy-2-propylphenoxy) propoxy-3,4-dihydro-

5,7,8-trimethyl-2H-1-benzopyran-2-carboxylic acid as a white solid, m.p. 144 ° - 147 ° C.

Analysis calculated for C ₂₇ H ₃₄ O ₇ : C 68.92; H, 7.28;

Found: C, 68.68; H, 7.02.

Example 29 A mixture of 25 g of benzyloxyphenol, 20 ml of freshly distilled acrolein 70 ml of methanol and 0.5 ml of concentrated sulfuric acid were heated at 150 ° C in an autoclave vessel with stirring for 2 h. The mixture was cooled and diluted with ether. The ether solution is treated as usual. The brown oily residue (47.9 g) was chromatographed on 250 g of silica gel. It was eluted with toluene to give 23.1 g of an orange oil, which was again chromatographed on 300 g of silica gel. Eluted with 9: 1 hexane: ethyl acetate to give 12.8 g (37.9%) of racemic-3,4-dihydro-2-methoxy-6- (phenylmethoxy) -2H-1-benzopyran as yellow butter. This product was dissolved in 200 ml of acetone and 120 ml of 2 N aqueous hydrochloric acid were added. The mixture was stirred and refluxed for 2h, kept at room temperature overnight, and refluxed for another 2 h. After cooling, the mixture was concentrated in a water pump to remove most of the acetone. The aqueous residue was treated with ether in the usual manner (the combined extracts were further washed with saturated sodium bicarbonate solution) to give 12.1 g of a pale yellow solid. This product was chromatographed on 250 g of silica gel and eluted with 9: 1 and 4: 1 toluene ethyl acetate to give 9.8 g (80.7%) of racemic-3,4-dihydro-6- (phenylmethoxy) 2H- 1-benzopyran-2-ol as a pale yellow solid, m.p. 92.5 ° - 95 ° C.

Analysis calculated for C ₁₆ H ₁₆ O ₃ : C 74.98; H, 6.29;

Found: C, 74.78; H, 6.41.

Example 30. A solution of 1.8 g of racemic-3,4-dihydro-6- (phenylmethoxy) -2H-1-benzopyran-2-ol and 2.6 g (carbethoxymethylene) triphenylphosphorane in 20 ml of toluene were stirred and refluxed. reflux 22 h. The solution was cooled and placed in a column of silica gel and toluene. It was eluted with toluene and 19: 1 toluol ethyl acetate to afford 1.7 g (74.2%) of racemic-3,4-dihydro-6 (phenylmethoxy) -2H-1-benzopyran-2-acetic acid ethyl ester like pale yellow oil. This product was dissolved in 25 ml of absolute ethanol and the solution was stirred in the presence of 0.2 g of 10% palladium on charcoal at room temperature under a hydrogen atmosphere. After 1.5 h, hydrogen absorption ceases and the catalyst is removed by filtration. The filtrate was concentrated in vacuo to yield

1.2 g (97.6%) of racemic 3,4,4-dihydro-6-hydroxy-2H-1-benzopyran-2 acetic acid ethyl ester as a pale yellow oil.

Example 31. A mixture of 1.2 g of racemic-3,4-dihydro-6-hydroxy-2H- ethyl ester

1-benzopyran-2-acetic acid, 1.8 g of 4 '- (3bromophenoxy) -2'-hydroxy-3'-propylacetophenone, 1.6 g of anhydrous potassium carbonate, 30 ml of dry acetone and 15 ml of dry dimethylformamide are stirred and reflux 23 h. An additional 1.6 g of potassium carbonate was added and the mixture was stirred and refluxed for an additional 2.5 h. After cooling, the mixture was carefully poured into 1 N aqueous hydrochloric acid. It is further worked up with ether in the usual way (the combined ether extracts are washed further with saturated aqueous sodium bicarbonate solution) to give 3.7 g of a brown oil which is chromatographed on 50 g of silica gel. It was eluted with 19.1 toluene ethyl acetate to give 1.6 g of a pale yellow oil. A solution of this ester and 3.0 g of lithium hydroxide monohydrate in 40 ml of 1: 1 tetrahydrofuran-water mixture was stirred at room temperature for 23 h. The resulting solution was diluted with water and acidified to pH 1 with 2 N hydrochloric acid. Further elaboration in the usual manner with ether gave an oil which was chromatographed on 50 g of silica gel. Eluted with 4: 1, 2: 1 and 1: 1 toluene-ethyl acetate to give 831 mg (37%) of racemic-6- / 4- (3-acetyl-3-hydroxy-2-propylphenoxy) -propoxy [-3,4-Dihydro-2H-1-benzopyran-2-acetic acid as a pale yellow solid, m.p. 102.5 ° - 105 ° C. Analysis Calcd for C 24 H 25 O 3: C, 67.86; H, 6.83;

Found: C, 68.03; H, 6.75.

Example 32 A mixture of 17.5 g (carbethoxymethylene) triphenylphosphorane and 11.4 g 4-benzyloxy-2-hydroxybenzaldehyde in 200 ml of toluene was stirred and refluxed for 1 h. After evaporation of the solvent in vacuo, the residue of 28.2 g contains (4'benzyloxy-2'-hydroxy) benzpropionic acid ethyl ester and triphenylphosphine oxide. This product was dissolved in 300 ml of ethyl acetate and hydrogenated at atmospheric pressure and room temperature in the presence of 0.35 g of platinum oxide.

The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 28.1 g of product containing (4'-benzyloxy-2'-hydroxy) benzpropanoic acid ethyl ester. To this was added 100 ml of 5% potassium hydroxide solution in methanol and the mixture was refluxed for 2 h. Most of the methanol was removed by concentration in vacuo and the residue partitioned between ether and water. The ether layer is discarded. The aqueous phase was acidified with 2 N hydrochloric acid and treated with 1: 1 ether-tetrahydrofuran in the usual way to give 9.8 g (4'-benzyloxy) 2'-hydroxy) benzpropionic acid. It was dissolved in 98 ml of acetic anhydride and the solution was refluxed for 2 h. After cooling, 100 ml of methanol are added to the solution and the solvents are removed by concentration in vacuo. The addition of methanol and evaporation was repeated two more times and the residue was purified by flash chromatography on silica gel eluting with 4: 1 hexanethyl acetate. 6.2 g (48.8%) of 3,4-dihydro-7- (phenylmethoxy) -1-benzopyran-2-one are obtained as a solid.

Example 33 To a solution of 6.2 g of 3,4-dihydro-7- (phenylmethoxy) -1-benzopyran-2-one in 80 ml of dichloromethane was added dropwise 20 ml of a solution of 25% diisobutylaluminum hydride in toluene at -76 ° C, with stirring. The reaction mixture was stirred at this temperature for 1 h then carefully added 5 ml of methanol. The solution was poured into 25 ml of 1 N sulfuric acid and the mixture was treated with ether as usual (the combined organic extracts were further washed with saturated sodium bicarbonate solution). The residue (5.9 g) was purified by flash chromatography on silica gel (eluting with a solvent system 3: 1 hexanethyl acetate). 4.8 g (76.8%) of racemic-3,4-dihydro-7- (phenylmethoxy) 2H-1-benzopyran-2-ol are obtained as a colorless solid, m.p. 64 ° - 65.5 ° C.

Analysis - Calculated for C, .H, .O · C, 74.98; H, 6.29;

Found: C, 74.44; H, 6.38.

Example 34 A sample of 2.2 g of racemic-3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-ol was condensed with (carboxymethylene) triphenylphosphorane (3.2 g) by the method of Example 30. 2.6 g (92.8%) of racemic-3,4-dihydro-7 (phenylmethoxy) -2H-1-benzopyran-2-acetic acid ethyl ester were obtained as a yellow oil after purification by column chromatography. This product is hydrogenated over 0.2 g of 10% palladium on carbon as described in Example 30. 1.9 g of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2- are obtained acetic acid as a pale yellow oil.

Example 35. A sample of 0.9 g of racemic-3,4-dihydro-7-hydroxy-2H1-benzopyran-2-acetic acid ethyl ester was alkylated with 3 g of 4 '- (3-bromopropoxy) -2'-hydroxy -3'-propylacetophenone by the method described in Example 31. The crude product was chromatographed on silica gel 50 g to give the desired ester as a pale yellow oil (19: 1 toluene-ethyl acetate was used as eluent). This product was saponified with 2.0 g of lithium hydroxide monohydrate by the method described in Example 31. The crude acid (1.1 g) was chromatographed on 50 g of silica gel and eluted with 2: 1 and 1: 1 toluene-ethyl acetate to afford to obtain 682 mg (40.5%) of racemic-7- / 3- (4-acetyl3-hydroxy-2-propylphenoxy) -propoxy / -3,4-dihydro-2H-1-benzopyran-2-acetic acid as a pale yellow solid mass, m.p. 107 ° 109.5 ° C.

Analysis - Calculated for C _and H ₃₀ O _? : C, 67.86; H, 6.83;

Found: C, 68.07; H, 6.87.

Example 36 A solution of 8.75 g of ethyl 6-hydroxychromone-2-carboxylate in 200 ml of acetic acid was hydrogenated in the presence of 2 g of 10% palladium on charcoal at 50 lb / in ² and room temperature by shaking the suspension over at 17 h. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 7.85 g of crude product. Purification by HPLC (solvent system 3: 1 hexane-ethyl acetate) yields 4.9 g (59%) of racemic-3,4-dihydro-6-hydroxy-2H1-benzopyran-2 pure ethyl ester -carboxylic acid. Recrystallization from ethyl acetate-hexane gave a colorless solid, m.p. 72 ° 74 ° C.

Analysis - Calculated for C, H, O: C, 64.85; H, 6.35;

Found: C, 64.57; H, 6.45.

-.44 - · ίν * Μ:

Example 37. A solution of boron trifluoride gas at 20 ° - 25 ° C was passed into a solution of 2.23 g of racemic-ethyl-6-hydroxychroman-2-carboxylate in 30 ml of acetic acid. During the gas leak (30 - 45 min) 5 a cold water bath is used to control the exothermic reaction. The cold water bath was removed and the reaction mixture was heated to 80 ° C for 5 h. The reaction mixture was then cooled and carefully poured into a mixture of saturated sodium bicarbonate and ice and the product extracted with 1: 1 tetrahydrofuran-ether. Evaporation of the crude product was chromatographed on a silica gel column to give 1.6 g (60%) of racemic-7-acetyl-6-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester as viscous oil.

Example 38. Using the method described in Example 42, 1.0 g of racemic ethyl 6-hydroxychroman-2-carboxylate was converted to racemic-6- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy). -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 27% yield as white crystals, m.p. 125 ° - 127 ° C. Analysis - Calculated for C ₂₄ H ₂ G O ₇ : C 67.28; H, 6.59;

Found: C, 67.27; H, 6.67.

Example 39. A mixture of racemic-7-acetyl-6-hydroxychroman-2-carboxylic acid ethyl ester (1.6 g), 3.0 g of potassium carbonate, 5 ml of 1,3-dibromopropane, 60 ml of dry acetone and 30 ml of dry dimethylformamide was stirred and refluxed for 20 h. After 35 most of the solvents were removed in vacuo, the residue was diluted with ether and 1 N hydrochloric acid was carefully added. The organic phase was separated, washed with saturated sodium bicarbonate solution and water, dried and concentrated in vacuo. The crude bromopropyl product (2.1 g) was dissolved in 30 ml of acetone and added to a mixture of 1.2 g of 2 ', 4'-dihydroxy-3'propylacetophenone, 2.5 g of anhydrous potassium carbonate, 30 ml of dry acetone and 30 ml of dimethylformamide. The reaction mixture was refluxed for 25 h. After most of the solvent was removed, the product was extracted with ether, the ether extracts washed with saturated sodium chloride solution and dried. The crude product (3,1

g) obtained after evaporation of the solvent is chromatographed on silica gel to give 1.3 g (43%) of the desired ester. It is hydrolyzed by the action of the ester (1.3 g in 18 ml of tetrahydrofuran) with aqueous lithium hydroxide solution (2.2 g of lithium hydroxide monohydrate in 18 ml of water). The turbid reaction mixture was stirred for 21 h at room temperature, poured into 1 N hydrochloric acid and 10 extracted with ether. The organic phase was washed with saturated brine, dried and evaporated to give 1.2 g of a viscous yellow oil. Purification by chromatography on a silica gel column afforded 0.778 g (27.3%) of racemic 7-acetyl-6- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2H -1 Benzopyran-2-carboxylic acid as a white crystalline product, m.p. 140.5 ° - 142.5 ° C (from 20 ethyl acetate).

Analysis - Calculated for C ₂₆ H ₃₀ O _g : C 66.37; N.

6.43;

Found: C, 66.44; H, 6.51.

Example 40. Using the hydrogenation conditions of Example 36, 1.09 g of ethyl-7-hydroxychroman-2-carboxylate was converted to racemic-ethyl 7-hydroxychroman-2-carboxylate in 53% yield, yielding as of crystals of m.p. 81 ° C - 82.5 ° C (from ethyl 30 cetate-hexane).

Analysis Calculated for C 10 H 10 O / C 64.85; N.

14 4 ⁷⁷

6.35;

Found: C, 64.60; H, 6.26.

Example 41 A sample of 1.1 g of racemic ethyl 7-hydroxychroman-2-carboxylate was treated with 10 ml of 1: 1 acetic anhydride-pyridine and stirred for 17 h at room temperature. After removal of the solvents, the residue (1.2 g) was dissolved in 12 ml of glacial acetic acid 40 and treated with 1.26 ml of boron TFA. The reaction mixture was carefully refluxed for 17 hours, cooled, poured carefully onto a mixture of sodium bicarbonate and ice, and the product was extracted with 45: 1 tetrahydrofuran-ether. Evaporation of the solvent gave 1.1 g of crude racemic-7-hydroxy-6-acetylchroman-

2-carboxylic acid. Conversion of the acid to the corresponding ethyl ester is achieved 50 by refluxing 1.1 g of the crude acid in absolute ethanol in the presence of 10 mg of p-toluene25 sulfonic acid for 17 h. After most of the solvent was removed, the product was extracted with 1: 1 tetrahydrofuran-ether, washed with saturated sodium bicarbonate solution and water, dried and the solvent concentrated to give 1.2 g of crude ethyl ester as a mixture of the 6acetyl and 8-acetyl derivatives in a ratio of about 7: 1. This product was purified by silica gel column chromatography to give 0.7 g (53.5%) of the racemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester in the form of colorless crystals of m.p. 93.5 ° - 95.5 ° C (from ethyl acetate-hexane).

Example 42 A mixture of 1 g of racemic ethyl 7-hydroxychroman-2-carboxylate, 1.6 g of 4 '(3-bromopropoxy) -2'-hydroxy-3'propylacetophenone, 1.6 g of anhydrous potassium carbonate, 25 ml of acetone and 12 ml of dimethylformamide were stirred and refluxed for 23 h. After cooling, 1 N hydrochloric acid was carefully added and the product extracted with ether. The ether layers were washed with saturated sodium chloride solution, dried and evaporated in vacuo to give 3.6 g of an orange oil. After purification by chromatography on silica gel, 1.4 g of the alkyl ethyl ester are obtained. This product, dissolved in 20 ml of tetrahydrofuran, was treated with aqueous lithium hydroxide (2.6 g of lithium hydroxide monohydrate in 20 ml of water) and stirred for 23 h at room temperature. The reaction mixture was acidified and the product was extracted with ether, washed with saturated sodium chloride solution and dried. After removal of the solvent, 1.3 g of pale yellow acid are obtained, which is purified by chromatography on silica gel to give 0.554 g (28.7%) of racemic-7- / 3- (4-acetyl-3-hydroxy-2-propyl) ) phenoxy) propoxy / -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid as white crystals of m.p. 142.5 ° - 145 “S. Analysis calculated for C ₂₄ H ₂₈ O ₇ : C 67.28; H, 6.59;

Found: C, 67.34; H, 6.62.

Example 43. Using the method of Example 39 0.840 g of racemic-ethyl 6-acetyl-7-hydroxychroman-2-carboxylate was converted to racemic-6-acetyl-7- / 3- (4-acetyl-3-hydroxy-2- propylphenoxy) propoxy / -

3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 49.5% yield and as a colorless solid, m.p. 176 ° - 178.5 ° C (e) (from ethyl acetate).

Analysis - Calculated for C ₂₆ H ₃₀ O _g : C 66.37; N.

6.43;

Found: C, 66.27; H, 6.39.

Example 44. Using the hydrogenation conditions described in Example 36 5.52 g of ethyl 7-hydroxy-8-propylchromone-2-carboxylate was converted to racemic-ethyl 7-hydroxy-8-propylchroman-2-carboxylate with 43.5 % yield and is a viscous pale yellow oil.

Example 45. Using the method described in Example 41, 1.3 g of racemic-3,4-dihydro-7-hydroxy-8-propyl2H-1-benzopyran-2-carboxylic acid ethyl ester was converted to the corresponding 6-acetyl derived from 79.5% yield and is a viscous oil.

Example 46. Using the method described in Example 42 1.0 g of racemic-7-hydroxy-8-propylchroman-2-carboxylic acid ethyl ester was converted to racemic-7- / 3- (4-acetyl-3- hydroxy-2-propyl) phenoxy) propoxy / -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid as a pale yellow solid, m.p. 105 - - 107 ° C.

Analysis - Calculated for C ₂₇ H ₃₄ O _? : C, 68.92; H, 7.28;

Found: C, 69.06; H, 7.29.

Example 47. A mixture of 0.85 g of racemicenetethyl 6-acetyl-7-hydroxy-8-propylchroman-2carboxylate, 1.2 g of anhydrous potassium carbonate, 2.3 ml of 1,3-dibromopropane, 0.1 g of 18-crown- The ether and 20 ml of acetonitrile were refluxed for 23 h. After cooling, the reaction mixture was diluted with ether. The organic phase was washed with brine, dried and evaporated to give 1.2 g of the bromopropyl derivative as a yellow oil. Using the conditions described in Example 39, this bromide is converted by alkylation of 2 ', 4'-dihydroxy-3'-propylacetophenone and subsequent saponification into racemic-6-acetyl7- [3- (4-acetyl-3-hydroxy) -2-propylphenoxy) propoxy / -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid in about 40% average yield. The acid is obtained as a colorless solid, m.p. 108 DEG-110.5 DEG C. (from ethyl acetate-hexane).

t «•• l l. f ΜβΖΛΒ * ί-- ·. ' 'ST61090

Analysis - Calculated for C _{2 g} H ₃₆ O _g : C 67.95; H, 7.08;

Found: C, 68.16; H, 7.20.

EXAMPLE 48 Using the method described in Example 39 except that

1,5-dibromopentane is used instead of 1,3dibromopropane, racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester is converted to racemic-6-acetyl-7- (5- (4-acetyl3-hydroxy-2-propylphenoxy) pentyloxy) 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 32.8% yield and is a colorless solid, m.p. 113 DEG-115 DEG C. (from ethyl acetate-hexane). 15

Analysis - Calculated for C ₂ H ₃₄ O _g : C 67.45; H, 6.87; Found: C, 67.61; H, 6.80.

Example 49. Using the method described in Example 39 except that instead of 1,3-dibromopropane, 1,7dibromoheptane was used, racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H ethyl ester -1-Benzopyran-2-carboxylic acid is converted to racemic-6-acetyl-7- (7- (4-acetyl-3-hydroxy-2-propyl phenoxy) heptyloxy) 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid acid representing a colorless solid, m.p. 133 ° - 135 ° C (ethyl acetate-hexane), with an average yield of 39.1% total. Analysis - Calculated for C ₃₀ H _{3 G} O _g : C 68.42; H, 7.27; Found: C, 68.22; H, 7.18.

Example 50. Using the method described in Example 39 0.62 g of racemic-8-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester was converted to racemic- 8-acetyl-7- / 3- (4acetyl-3-hydroxy-2-propylphenoxy) propoxy / -3,4-dihydro-2H-1 benzopyran-2-carboxylic acid with a total average yield of 27.7% and representing a colorless solid with mp 146.5 ° - 148.5 ° C (from ethyl acetate-hexane).

Analysis - Calculated for C18 H14 OS 66.37; N.

2o 30 b

6.43; Found: C, 66.51; H, 6.47.

Example 51 A sample of racemic-3,4-dihydro-6-hydroxy-2-methyl2H-1-benzopyran-2-carboxylic acid ethyl ester (0.125 g) was converted to racemic-3,4-dihydro- 7-acetyl-6-hydroxy-2 methyl-2H-1-benzopyran-2-carboxylic acid in 65.5% yield, which is a viscous oil, using the method described in Example 37.

Example 52. Using the method described in Example 39, a sample of 96.5 mg of racemic-3,4-dihydro-7-acetyl6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester is converted to racemic 10 7-acetyl-6- [3- (4-acetyl-3-hydroxy-2-propyl phenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid by 65 , 7% yield and foam.

Example 53 A mixture of 1.14 g of 4-benzyloxy-2-hydroxybenzaldehyde, 0.125 g of 1,4-diazabicyclo / 2,2,2 / octane and 0.65 g of acrylonitrile was stirred and heated at 80 ° - 85 ° C in argon atmosphere for 2 h. After removal of the solvent, the residue was dissolved in tetra20 hydrofuran-ether (1: 1), washed with 1 N sodium hydroxide and water, dried and the solvent removed in vacuo. The crude product (1.10 g) was purified by silica gel column chromatography to give 0.6 g of 25 (45.7%) 7- (phenylmethoxy) -2H-1-benzopyran3-carbonitrile as a colorless solid with mp. t. 95 ° - 98 ° C (from ethyl acetate-hexane).

Analysis - Calculated for C ₁₇ H ₁₃ NO ₂ : C, 77.55; H, 4.98; N, 5.32;

Found: C, 77.41; H, 5.00; N, 4.80.

Example 54 A sample of 2.2 g of 7 (phenylmethoxy) -2H-1-benzopyran-3-carbonitrile was dissolved in 40 ml of a mixture of tetrahydrofuran-ethyl alcohol (1: 1) and treated with 20 ml of 2 35 N potassium base and the reaction mixture was heated to reflux for 21 h under argon. An additional 10 ml of 2 N potassium hydroxide was added and the mixture was again stirred and refluxed for another 27 h. 40 The reaction mixture was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried and the solvent removed in vacuo to give 2.2 g of an orange 45 solid. This product, dissolved in 30 ml of ethanol containing 0.3 g of p-toluenesulfonic acid monohydrate, was refluxed under reflux for 18 hours. After most of the solvent was removed, the residue was extracted with ether, the extracts were washed with saturated sodium bicarbonate solution, water, dried and the solvent was removed to give 2.3 g of the crude ester. The ethyl ester was purified by chromatography on silica gel, yielding 1.4 g of 7 (phenylmethoxy) -2H-1-benzopyran-3-carboxylic acid ethyl ester as crystals.

Example 55. The ester of Example 54 (1.4 g) was dissolved in 25 ml of absolute alcohol and hydrogenated at atmospheric pressure in the presence of 0.2 g of 10% palladium on carbon. The catalyst was removed by filtration through diatomaceous earth and, after removal of the solvent, 0.9 g of racemic-3,4-dihydro-7-hydroxy-2H-1 benzopyran-3-carboxylic acid ethyl ester was obtained as a white solid.

Example 56 The ethyl ester of Example 55 was converted to racemic-7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy) -3,4-dihydro-2H-1-benzopyran-3-carboxylic acid by a common mean yield 17.7% by operation of the method described in Example 42. The acid was obtained as a colorless solid, m.p. 153.5 ° - 155.5 ° C (from ethyl acetate-hexane).

Analysis - Calculated for C ₂₄ H ₂ G O ₇ : C 67.28; H, 6.59;

Found: C, 67.46; H, 6.66.

Example 57 A sample of 0.9 g of racemic-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester was dissolved in 5 ml of pyridine and treated with 1.2 ml of acetic anhydride. After stirring for 3 hours at room temperature, the reaction mixture was diluted with ether. The organic layer was washed with 2 N hydrochloric acid with sodium bicarbonate with brine, dried and the solvent evaporated. 1.2 g of crude acetate are obtained, which is dissolved in 10 ml of glacial acetic acid and treated with 1 ml of boron TFA. The reaction mixture was heated at 100 ° C under argon for 6 h. After cooling, ether was added. The organic layer was washed several times with water, dried and the solvent removed in vacuo to give 1.0 g of an orange oil. Esterification of this product with ethanol, which was carried out as described in Example 41, yields the racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester .

Example 58. Using the method described in Example 39, racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester was converted to racemic-6-acetyl- 7- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy propoxy / -3,4-dihydro-2H-1-benzopyran-3-carboxylic acid. The acid is a colorless solid with mp 127 ° - 129 ° C. decomposition (from ethyl acetate-hexane).

Analysis - Calculated for C ₂₆ H ₃₀ O _g : C 66.37; H, 6.43;

Found: C, 66.45; H, 6.43.

Example 59. Using the method of Example 41 11.3 g of racemic-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester was converted to crude racemic-7-hydroxy-6 -acetyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 93% yield (11 g). A sample of 1 g of this crude acid was treated with 3.8 g of (-) (2 H, 3 R) -butanediol in 30 ml of toluene in the presence of 0.2 g of p-toluenesulfonic acid monohydrate. After refluxing for 18 hours, the reaction mixture was cooled and poured into saturated sodium bicarbonate solution and the product extracted with ether. The ether extracts were washed twice with water, dried and concentrated. 1.8 g of crude product is obtained after removal of the solvents, which is a mixture of the 6-acetyl and 8-acetyl monobutanediol ester derivatives in a ratio of about 7: 1. Purification of this product by HPLC gave 0.8 g (61% yield) / 2R, S-2 - / (R ⁺ , 2R ⁺ ) // -

6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 1-methyl-2-hydroxypropyl ester as a viscous pale yellow oil.

Example 60. Using the method described in Example 25, the 1-methyl-2-hydroxypropyl ester of (2R, S-2 - / (1R ⁺ , 2R ⁺ ) N-6-anethyl-7-hydroxy-3, 4-Dihydro-2H-1-benzopyran-2-carboxylic acid (3.5 g), 12 ml of 1,5dibromopentane, 7.2 g of anhydrous potassium carbonate in 100 ml of acetone and 50 ml of N, N-dimethylformamide give 2.6 g (50%) 2-hydroxy-1-methylpropyl ester of (2R, S-2 - / (1R ⁺ , 2R ⁺ ) // 6-acetyl-7- / (5-bromopentyl) oxy / -3,4- dihydro-2H-1-benzopyran-2-carboxylic acid. This product is recovered by recycling by high performance liquid chromatography (toluene-ethyl acetate 2: 1). The less polar di

.. 'F> ......

the asteroisomer is recrystallized from ethyl ether to give 786 mg of (2S-) - (2-6eTa- (1R ⁺ , 2R ⁺ ) N- (6-auethyl-7 -) (5-bromopentyl) 2-hydroxy-1-methylpropyl ester. oxy / -3,4-dihydro-2H-

1-benzopyran-2-carboxylic acid as a colorless solid, m.p. 94.5 °

- 98 ° C; / a D ¹⁵ - 7.99 ° (Cl, CHCl ₃ ).

Analysis - Calculated for C _{2 |} H _M BrO ₆ : C 55.15; H, 6.39;

Found: C, 54.79; H, 6.20.

Recrystallization of the more polar diastereomer from ethyl ether giving 1,03 g 2-hydroxy-1-methylpropyl ester / 2R- / 2a - (1 ^{R +, 2R +) / /} - 6- acetyl-7 / (5brompentil) oxy / -3,4-Dihydro-2H-1-benzopyran-2-carboxylic acid, m.p. 80 ° - 83 ° C; / a / D ²⁵ - 21.49 ° (Cl, CHCl ₃ ) as a colorless solid.

Analysis - Calculated for C ₂₁ H ₂₉ BrO ₈ : C 55.15; H, 6.39;

Found: C, 55.06; H, 6.39.

Example 61. Using the method described in Example 26, 199.8 mg of (2S- (2-6eTa (2R ⁺ , 2R ⁺ ) 2H-7-aHe ^, nui-7-) 2-hydroxy-1-methylpropyl ester (5-Bromopentyl) oxy / -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is alkylated with 2 ', 4'-dihydroxy-3'-propylacetophenone After chromatographic purification on a silica gel column, 106 mg of (2S- (2-6eTa- (1R *, 2R ⁺ )) -6-ethyl-7- (2-hydroxy-1-methylpropyl ester).

5- (4-acetyl-3-hydroxy-2-propyl phenoxy) pentyloxy / -3,4-dihydro-2H1-benzopyran-2-carboxylic acid (42.8% yield) / a No. - 7.25 ° (Cl, CHCl 1 ₃ ); mp 124 »

127.5 ° C (recrystallized from ethyl acetate hexane).

Analysis - Calculated for C ₃₂ H ₄₂ O ,: C 67.35; H, 7.42;

Found: C, 67.14; H, 7.51.

Example 62. Using the method of Example 61, 554 mg of the 2R-6pOM ester of Example 60 was converted into the (3- (2A- (11A, 2K ⁺ ) -6-acetyl-7) 2-hydroxy-1-methylpropyl ester. - / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H1-benzopyran-2-carboxylic acid in 72.6% yield, mp 100 ° - 105 ° C; / a / D "15,75 ° ( C1, CHC1 ₃₎ (from ethyl acetate-hexane). Analysis - Calculated for C ₃₂ H ₄₂ O _9: C, 67.25; H, 7.42;

Found: C, 66.98; H, 7.39.

Example 63 A sample of 405 mg of the 2S-H3Omer ester of Example 61 was saponified with lithium hydroxide monohydrate (0.6 g) in 10 ml of a 1: 1 mixture of tetrahydrofuran-water using the method of Example 4. After recrystallization from ethyl acetate -hexane afforded 185 mg (52.2% yield) of (S) -6-acetyl-7- [5 (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H1- benzopyran-2-carboxylic acid, m.p. 94 ° - 97.5 ° C, / / D + + 1.25 ° (Cl, CHCl ₃ ).

Analysis - Calculated for C ₂₈ H ₃₄ O _g : C 67.45; H, 6.87;

Found: C, 66.60; H, 6.70.

Example 64. Using the method of Example 63, 502 mg of the 2E-isomer ester of Example 62 gave, after recrystallization from ethyl acetate-hexane, 185 mg (40.7%) of (R) -6-acetyl-7- / 5- ( 4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H1-benzopyran-2-carboxylic acid, m.p. 102.5 "- 108" C, / tz / D ²⁵ - 1.02 "(Cl, CHCH1 ₃ ). Analysis for C ₂₈ H ₃₄ O ₈ : Calculated: C 67.45; H, 6.87;

Found: C, 67.26; H, 6.78.

Example 65. A mixture of 1 g (4.5 mmol) of racemic-3,4-dihydro-7-hydroxy-2H-1-benzylated-2-carboxylic acid ethyl ester, 3.7 ml (27.2 mmol) 1,5-dibromopentane, 2 g (14.5 mmol) of anhydrous potassium carbonate, 30 ml of acetone and 15 ml of N, N-dimethylformamide were stirred and refluxed for 20 h. The mixture was cooled and diluted with ether. The ether solution was washed with water and with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 7.2 g of a yellow liquid. This product was chromatographed on 50 g of silica gel. It was eluted with 19: 1 and 9: 1 toluene-ethyl acetate to give 1.2 g of racemic ethyl ester.

7 - [(5-bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (72% yield) as a pale yellow oil.

Example 66. Using the method and the molar ratios of Example 65 and the corresponding starting materials, the following compounds were obtained. All compounds were purified by chromatography on silica gel and isolated as a pale yellow oil:

Racemic-6-acetyl7 - [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-6-acetyl-7hydroxy -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and 1,5dibromopentane;

Racemic-6-acetyl7- [(5-bromopentyl) oxy] -3,4-dihydro-2H-1 benzopyran-2-carboxylic acid ethyl ester of racemic-6-acetyl-3,4-dihydro-7hydroxy -2H-1-benzopyran-2-carboxylic acid and 1,5-dibromhexane;

Racemic-6-acetyl7 - [(6-bromohexyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-6-acetyl-3,4-dihydro-7- hydroxy-2H-1-benzopyran-2-carboxylic acid and 1,6-dibromopentane;

Racemic-6-acetyl7- [(4-bromobutyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-6-acetyl-3,4-dihydro- 7hydroxy-2H-1-benzopropane-2-carboxylic acid and 1,4-dibromobutane;

Racemic-7 - [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H1-benzopyran-2-carboxylic acid ethyl ester of racemic-3,4-dihydro-7-hydroxy-8- propyl-2H-1-benzopyran-2-carboxylic acid and 1,5-dibromopentane;

Racemic-8-acetyl7 - [(5-bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester of racemic-8-acetyl-3,4-dihydro-7- hydroxy-2H-1-benzopyran-2-carboxylic acid and 1,5-dibromopentane.

Example 67. A mixture of 1.2 g (3.23 mmol) of racemic-7 - [(5 bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester, 1.0 g (5.15 mmol) 2 ', 4'-dihydroxy-3'-propylacetophenone, 1.8 g (13.0 mmol) anhydrous potassium carbonate, 30 ml acetone and 15 ml N, N-dimethylformamide are stirred and heated at reflux. at reflux. After cooling, the mixture was diluted with ether. The ether phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (2.1 g) was chromatographed on 50 g of silica gel. After elution with 19: 1 toluene-ethyl acetate, 1.3 g (83%) of the racemic-7- / 5- (4-acetyl-3 ethyl ester) were obtained -hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H 1-benzopyran-2-carboxylic acid as a yellow oil.

Example 68. Using the method and molar ratios of Example 67 of the starting materials, the following compounds were obtained. All compounds were purified by chromatography on silica gel and isolated as a pale yellow oil:

Racemic-6-acetyl 7- (5- (4-acetyl-3-hydroxyphenoxy) pentyloxy) -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-6-acetyl- 7 - [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxyacetophenone;

Rac-6-acetyl-7- / 5- (4acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester of rac-6-acetyl- 7) (5-Bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 2 ', 4, dihydroxyacetophenone;

rac-6-acetyl-7- / 5- (4acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester -acetyl-7 - [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H1-benzopyran-2-carboxylic acid ethyl ester and 2 ', 4'-dihydroxy-3'propylacetophenone;

rac-7- (5- (4-acetyl-3-hydroxyphenoxy) pentyloxy) -3,4-dihydro2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-7 - ((5-bromopentyl) oxy) - 3,4-dihydro-2H -1-benzopyran-2-carboxylic acid and 2 ', 4'dihydroxyacetophenone;

Racemic-6-acetyl 7- (6- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyloxy) -3,4-dihydro-2H1-benzopyran-2-carboxylic acid ethyl ester of racemic-6-acetyl- 7 - [(6-bromohexyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone;

Racemic-7- / 4- (4-acetyl-3-hydroxy-2-propylphenoxy) butoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-

6- acetyl-7- (4-bromobutyl) oxy) -3,4-dihydro2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone;

Racemic-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester of racemic-7 - / (5- bromopentyl) oxy / -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-acetophenone;

Racemic-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydroxy-ethyl ester

8-Propyl-2H-1-benzopyran-2-carboxylic acid of racemic-7- ((5-bromopentyl) oxy) -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 2 ', 4'-dihydroxy-3'-propylacetophenone;

Racemic-8-acetyl- methyl ester

7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-dihydro-2H-

1-Benzopyran-2-carboxylic acid from racemic-8-acetyl-7- ((bromopentyl) oxy) -3,4-dihydro-2H-1-benzo-25 pyran-2-carboxylic acid methyl ester and 2 ', 4'-dihydroxy-3'-propylacetophenone.

Example 69. A mixture of 1.3 g (2.68 mmol) of the ester product of Example 67 60 ml of a mixture of 1: 1 tetrahydrofuran-water and 2.4 g (57.1 mmol) of lithium hydroxide monohydrate were stirred at 5 rooms temperature 5 h. The mixture was diluted with water and extracted three times with ether. The aqueous phase was acidified to pH 1 with 2 N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 0.725 g (59%) of racemic-7- [515 (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1 benzopyran-2-carboxylic acid as a colorless solid with m.p. 124 ° - 126.5 ° C.

Analysis calculated for C 24 H 25 N 3 O: C 68.40; H, 7.07; 20 Found: C, 68.34; H, 7.29.

Example 70. Using the method and the molar ratios of Example 69, the acids of the following table are obtained by saponification of the corresponding esters of Example 68:

Microanalysis mp ° C from Zekrist formula % Calculated% C H Found% C H 1 2 3 4 5 6 7 in rac-6-acetyl-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid 105-107 ethyl acetate hexane ^C 28 ^H 34 ° 8 67.45; 6.87 67.24 6.91 rac-6-acetyl-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2 carboxylic acid 183-185.5 ethyl- acetate ^C 25 ^H 28 ° 8 65.78 6.18 65.80 6.08 rac-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyloxy] -3,4-dihydro-8-propyl2H-1-benzopyran-2-carboxylic acid butter ^C 31 ^H 40 ° 8 68.87 7.46 68.76 7.70 rac-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 146.5-149 ethyl acetate: hexane ^ 29 ^ 3 ^ 8 67.95 7.08 67.99 7.14 p-6-acetyl-7- [4- (4-acetyl-3-hydroxy-2-propylphenoxy) butoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. 137-140 ethyl acetate (1H) hexane 66.93 6.66 67.21 6.77 rac-7- / 5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-parboxylic acid 120-123 ethyl acetate ^C 26 ^H 32 ° 7 68.40 7.07 '68 .70 7.14 rac-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy- si) pentyloxy / -3,4-dihydro-8-propyl-2H-1- butter ^C 29 ^H 38 ° 7 69.86 7.68 70.02 7.80

benzopyran-2-carboxylic acid rac-8-acetyl-7 - [5-4-acetyl-3-hydroxy-134-136 aceto-C 1 H H 2 O 67.45 6.87 67.20 6 ^ 84

2-propylphenoxy) pentyloxy / -3,4-dihydro-nitrile

2H-1-benzopyran-2-carboxylic acid

Example 71. A mixture of 6.5 g (24.6 mmol) of (N) - (+) - 6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran- 2-carboxylic acid methyl ester, 10.37 g (75.1 mmol) anhydrous potassium carbonate, 1.12 g 18-crown-6, 39.3 ml (0.2 mol) 1,5-dibromopentane and 150 ml acetonitrile was stirred and refluxed for 21 h. After cooling, the mixture was treated with ether and water. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (68 g) was first purified by column chromatography on silica gel (400 g, eluting with 49: 1 toluene-ethyl acetate) and then by high performance liquid chromatography on silica gel using 9: 1 hexane-ethyl acetate as the mobile phase. 9.71 g (95.6%) of (R) - (+) - 6- ((5-bromopentyl) oxy) -3,4-dihydro-2,5,7,8-tetramethyl- methyl- 2H-1-benzopyran-2-carboxylic acid as a solid. Recrystallization from ethanol gave a colorless solid, m.p. 64 ° - 65,5 ° C, / a / Ό ¹⁵ + 36,37 ° (c 2, CHC1 _3).

Analysis - Calculated for C ₂₀ H ₂ G BrO ₄ : C, 58.12; H, 7.07; Br 19.33;

Found: C, 58.01; H, 7.07; Br 19,20.

Example 72. Using the method and molar ratios of Example 71, the (8) - (-) - 6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran methyl ester -2-Carboxylic acid is alkylated with 1,3dibromopentane to give (S) - (-) -6- (5-bromopentyl) oxy / -3,4-dihydro- methyl ester

2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid / a / D "- 35,60 ° (c 2, CHC1 _3), with a 88.5% yield.

Analysis - Calculated for C ₂₀ H ₂₉ BrO _4: C, 58,12; H, 7.07; Br 19.33;

Found: C, 58.00; H, 7.19; Br 19.33.

Example 73. Using the method and molar ratios of Example 71, 1 g of racemic-6-hydroxy-

3,4-Dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid is alkylated with 1,5dibromopentane to give racemic-6 - / (5-bromopentyl) oxy ester / -

3,4-Dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a colorless solid, m.p. 72.5 ° - 74.5 ° C and 90% yield after purification by chromatography on silica gel.

Analysis - Calculated for C ₂₀ H ₂₉ BrO _4: C

58.12; H, 7.07; Br 19.33;

Found: C, 58.13; H, 7.15; Br 19.30.

Example 74. A mixture of 7.35 g (17.8 mmol) of (R) - (+) - 6poMecTepHH4 product of Example 71, 3.85 g (19.8 mmol) of 2 ', 4'-dihydroxy-3' propylacetophenone, 8.93 g (64.7 mmol) of anhydrous potassium carbonate, 154 dry acetone and 77 ml of dry N, N-dimethylformamide were stirred and refluxed for 5.5 h. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 10.8 g of an oil. This product was purified by flash chromatography on silica gel using 2: 1 hexane-ethyl acetate for mobile phase. 9.1 g (97%) of (N) - (+) - 6- (S) (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyloxy] -3,4-dihydro-2 methyl ester is obtained , 5,7,8-Tetramethyl-2H-1-benzopyran-2carboxylic acid as a yellow oil, (a / D) + 26,62 (c2, CHCl ₃ ).

Analysis - Calculated for C ₃₁ H ₄₂ O ,: C 70.70; H, 8.04;

Found: C, 70.06; H, 8.18.

Example 75. Using the method of Example 74 (8) - (-) - the bromoester product of Example 72 (8.4 g) was converted by alkylation with 2 ', 4'-dihydroxy-3'-propylacetophenone (4,4 g) in (S) - (-) - 6- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-

2,5,7,8-Tetramethyl-2H-1-benzopyran-2-carboxylic acid in 91% yield. The ester is a yellow oil.

Analysis - Calculated for C ₃₁ H ₄₂ O _7: C, 70.70; H, 8.04;

Found: C, 70.13; H, 7.73.

Example 76. Using the method and the molar ratios described in Example 74, 1.2 g of the racemic bromoester product of Example 73 was converted by alkylation with 2 ', 4'-dihydro-3'-propylacetophenone (0.834 g) in methyl Racemic 6- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-dihydro-2,5,7,8-tetramethyl2H-1-benzopyran-2-carboxylic acid ester with 72 % yield, in the form of pale yellow oil.

Analysis - Calculated for C _{3 |} H ₄₂ O ₇ : C 70.70; H, 8.04;

Found: C, 70.44; H, 7.97.

Example 77. A mixture of 7.55 g (14.3 mmol) of the (S - (+) - ester product of Example 74, 140 ml of tetrahydrofuran, 90 ml of water and 12.6 g (0.21 mol) of lithium hydroxide monohydrate The mixture is poured into cold 3 N hydrochloric acid, the organic products are extracted three times with ethyl acetate, the extracts are combined, washed with water and brine. , dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure The residue is a yellow glassy mass (7.3 g) which is chromium was silica gel (350 g) eluted with 4: 1, 2: 1 and 1: 1 toluene-ethyl acetate to give the desired acid (5 g) which was recrystallized from acetonitrile to give 2.49 g ( 34%) (10 - (+) - 6- / 5- (4-acetyl-3-hydroxy-

2-propylphenoxy) pentyloxy / 3,4-dihydro-

2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a colorless solid, m.p. 92,5 ° - 95 ° C, / a / D ²⁵ + 37,86 ° (c 2, CHC1 _3).

Analysis - Calculated for C _w H ₄₀ O ₇ : C 70.29; H, 7.87;

Found: C, 70.25; H, 7.92.

Example 78. Using the method of Example 77, 9.35 g (17.8 mmol) of the (S) - (-) ester product of Example 75 was saponified. (S) - (-) - 6- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1 is obtained -benzopyran-2-carboxylic acid as a colorless solid, m.p. 90 "- 93.5" C, / a / D ^{25 to} 38.18 "(c2, CHC1 ₃₎ after recrystallisation from acetonitrile.

Analysis calculated for C 25 H 27 N 4 O: C 70.29; H, 7.87;

Found: C, 70.50; H, 8.11.

Example 79. Using the method of Example 77, 5.8 g (11 mmol) of the racemic ester of Example 76 was saponified. 2.77 g (49%) of racemic-6- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-dihydro-

2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a colorless solid, m.p. 92.5 ° - 95 ° C.

Analysis - Calculated for C _M H _{4 (|} O, C 70.29;

H, 7.87;

Found: C, 70.28; H, 7.98.

Example 80. A mixture of 2 g (4 mmol) of racemic-6-acetyl-7- (5) (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H -

I-Benzopyran-2-carboxylic acid in 155 ml of water was treated with 40 ml (4 mmol) of 0.1 N aqueous sodium hydroxide solution. The mixture was stirred for 2 h at room temperature, then filtered under vacuum. The filtrate was freeze-dried to give a solid residue which was dissolved in hot ethyl acetate containing small amounts of ethanol. Hexane was added to give a precipitate. The mixture was allowed to stand at 0 ° C, then filtered under vacuum. The precipitate was washed with ethyl acetate-hexane (2: 1) and the recrystallization was repeated. Drying under high vacuum at 60 ° C gave 1.6 g (77%) of the starting acid monosodium salt as a colorless solid.

Analysis - Calculated for C ₂₈ H ₃₃ NaO _8: C, 64.61; H, 6.39; At 4.17;

Found: C, 64.50; H, 6.50; At 4.17.

Example 81 To a solution of 2 g (4 mmol) of racemic-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro2H-1-benzopyran-2-carboxyl acid in 15 ml of ethanol was added a solution of 0.242 g (2 mmol) of d - (+) - methylbenzylamine in 4 ml of ether. The resulting solution was diluted with 10 ml of ether and left at 0 ° C. The precipitate was filtered off under vacuum and washed with ether. Recrystallization from ethanol gave 0.742 g (60%) of a colorless solid, m.p. 167 ° 170 ° C, which is mainly the (S) -acid d-amino salt. This salt was suspended in ethyl acetate and shaken with 1 N HCl. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to give 0.58 g (S) of 6-acetyl-7- / 5- (4-acetyl) -3-hydroxy-2-propylphenoxy) -pentyloxy / -3,4-dihydro-2H-

1-Benzopyran-2-carboxylic acid in the form of a solid. A sample of this product is esterified with diazomethane. The resulting methyl ester was analyzed for its enantiomeric composition by liquid chromatography on a 30 cm Pirkle covalent phenylglycine column. The analysis shows that the acid produced in this separation process consists of 95.3% (5) -enantiomer (less polar methyl ester) and 4.7% of (R) enantiomer (more polar methyl ester).

Example 82. A mixture of 6 g (27 mmol) of racemic-3,4-dihydro-7-hydroxy-2H -1-benzopyran-2-carboxylic acid ethyl ester, 6.8 g (54 mmol) of benzyl chloride, 7.5 g (54 mmol) of anhydrous potassium carbonate and 4.5 g (27 mmol) of potassium iodide in 100 ml of acetone were stirred at reflux for 7 h. Most of the acetone was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 17.4 g of a yellow oil which was chromatographed on silica gel. It was eluted with 19: 1 toluene-ethyl acetate to give 6.9 g (78%) of racemic-3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-carboxylic acid ethyl ester as yellow oil.

Example 83 The ether ester product of Example 82 (6.9 g, 22 mmol) was dissolved in 70 ml of toluene and the solution cooled to -78 ° C (in a dry ice bath and acetone). With stirring, 15.6 ml of a 25% solution of diisobutylaluminum hydride in toluene are added dropwise. The reaction mixture was stirred at -78 ° C for 2 h, then carefully added 2.5 ml of methanol, followed by 2 N hydrochloric acid and ice. The mixture was extracted with ethyl acetate and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 9: 1 toluene-ethyl acetate to give 5.6 g (70%) of racemic-3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2- carboxaldehyde as a pale yellow oil.

Example 84. Using the method of Example 30, 2.7 g (10 mmol) of the aldehyde product of Example 83 was condensed with 3.7 g (10.6 mmol) (carbethoxymethylene) -triphenylphosphorane in 30 ml of toluene (1, 5 h at 100 ° C). Chromatography of the crude product on 50 g of silica gel (eluting with toluene) afforded 3.0 g (88.8%) of racemic-3,4-dihydro-7- (phenylmethoxy) -2H- ethyl ester.

1 - benzopyran - 2 - propenoic acid (mixture of

E- and Z-isomers) as a pale yellow oil.

Example 85. The propene ester of Example 84 (3 g; 8.0 mmol) was hydrogenated at atmospheric pressure and at room temperature over 0.3 g of 10% palladium on carbon in ethyl acetate (35 ml) to give the racemic ethyl ester -3,4-Dihydro-7-hydroxy-2H-1-benzopyran-2-propanoic acid (2.4 g) as a viscous oil, after filtration of the catalyst and evaporation of the solvent.

Example 86. Using the method of Example 41, the propane ester product of Example 85 was converted to 1.4 g (54%) of racemic-6-acetyl-3,4-dihydro-7H-hydroxy-2H-1-benzopyran ethyl ester. 2-propanoic acid, as a yellow oil which crystallizes on standing after being chromatographed on silica gel and eluted with 19: 1 toluene-ethyl acetate.

Example 87. Using the method of Example 65, the ethyl propane ester product of Example 86 (1.4 g, 4.79 mmol) was converted to racemic-6-acetyl-7- ((5-bromopentyl) oxy) ethyl ester. 3,4-dihydro-2H-

1-Benzopyran-2-propanoic acid in 76% yield (1.6 g) which, after chromatography on silica gel and eluting with 19: 1 toluethylethyl acetate, is a yellow oil which crystallizes on standing.

Example 88. Using the method of Example 67, the bromester of Example 87 (1.6 g; 3.63 mmol) was converted to racemic-6-acetyl-7- (5- (4-acetyl-3- hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H-1-benzopyran-2-propanoic acid by alkylation with 2 ', 4'-dihydroxy-3'propylacetophenone After purification by chromatography on silica gel (eluting with 9 : 1 and 4: 1 toluene-ethyl acetate), the ester product was obtained in 79% yield (1.6 g) as a pale yellow oil.

Example 89. Using the method of Example 69, the ester of Example 88 (1.6 g; 2.89 mmol) was saponified to give 1 g (66%) of racemic-6-acetyl-7- / 5- (4 -acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -

3,4-dihydro-2H-1-benzopyran-2-propanoic acid, which after recrystallization from ethyl acetate-hexane and then from acetonitrile is a colorless solid, m.p. 126.5 ° 129 ° C.

Analysis calculated for C 24 H 25 N 3 O: C 68.42; H, 7.27;

Found: C, 68.42; H, 7.49.

Example 90. Using the method of Example 30, 2.7 g (10 mmol) of the aldehyde of Example 5 83 was condensed with 4.4 g (12 mmol) of ethyl 4- (triphenylphosphoranylidene) -2-butenoate in 30 ml of toluene (3.5 h at 100 ° C). Chromatography of the crude product on silica gel 100 g and elution with toluene and 19: 1 10 toluene-ethyl acetate gave 1.1 g (30%) of racemic-5- / 3,4-dihydro7- (phenylmethoxy) -2H -1-benzopyran-2-yl / -

2,4-pentadienoic acid (mixture of E and Z isomers) as a yellow oil. 15

Example 91. The diene ester of Example 90 (1.1 g; 3.02 mmol) was hydrogenated at atmospheric pressure and room temperature in 15 ml of ethyl acetate over 0.95 g of 10% palladium on carbon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran ethyl ester.

2-pentanoic acid (0.9 g; 100%) as a pale yellow oil. 25

Example 92. Using the method of Example 41, the pentane ester of Example 91 was converted to racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-pentanoic acid ethyl ester (0.4 g ; 41%) as 30 yellow oil which crystallizes on standing.

Example 93. Using the method of Example 65, the acetyl-pentane ester of Example 92 (0.4 g; 1.25 mmol) was converted to the racemic-6-acetyl-7 - / (5-bromopentyl) oxy-ethyl ester. (-3,4-Dihydro-2H-1-benzopyran-2-pentanoic acid as a yellow oil after column chromatography on silica gel eluting with 19: 1 toluene-ethyl acetate in 40% yield 51% (0.3 g).

Example 94. Using the method of Example 67, the bromester of Example 93 (0.3 g; 0.64 mmol) was converted to racemic-6-acetyl-7- / 5- (4-acetyl-3-hydro ethyl ester) - 45 Roxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H -1-benzopyran-2-pentanoic acid by alkylation with 2 ', 4'-dihydroxy-3'propylacetophenone. After purification by chromatography on silica gel (eluting with 50 19: 1 toluene-ethyl acetate), the ester product was obtained in 80% yield (0.3 g) as a yellow oil.

Example 95. Using the method of Example 69, the ester of Example 94 (0.3 g; 0.51 mmol) was saponified to give 0.137 g (48%) of racemic-6-acetyl-7- / 5- (4 -acetyl-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H-1-benzopyran-2-pentanoic acid as a colorless solid, m.p. 116 ° 120.5 ° C after recrystallization from acetonitrile.

Analysis - Calculated for C ₃₂ H ₄₂ O _8: C, 69.29; H, 7.63;

Found: C, 69.35; H, 7.66.

Example 96. Aerosol Form (Freon Aerosol Suspension)

Ingredients mg / 100ml lmg lOmg 25mg rac-6-acetyl-7- [5 (4-acetyl-3-hydroxy2-propylphenoxy) pentyloxy] -3,4- lmg lOmg 25mg dihydro-2H -1-benzopyran-2-carboxylic acid (micronized) glyceryl trioleate 0.03mg 3.0mg 7.5mg Freon 114 ⁺ 30 parts and Freon 12 70 parts total up to 100 100 100y <Z

⁺ Freon 11 can be replaced.

Way of working:

Racemic-6-acetyl-7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyloxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is air-jet milled to sizes from 1 to 10 and placed in a suitable container. Glyceryl trioleate was added at room temperature. The freon was cooled to -30 ° C and then added to the mixture. Immediately after the addition of the freon, the container is closed with a precision suitable metering nozzle and the container is placed in an ultrasonic generator to disperse the racemic-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy ) -3,4-Dihydro-2H-1-benzopyran-2-carboxylic acid in freon.

Example 97. Aerosol Form (Freon Aerosol Suspension of Sodium Salt)

Ingredients mg / 100y <1 l, 0mg 10, Omg 25, Omg rac-6-acetyl-7- / 5 (4-acetyl-3-hydroxy-

2-propylphenoxy) pentyloxy / -3,4-lmg 10mg 25mg dihydro-2H-1benzopyran-2-sodium carboxylate (micronized) oleic acid 0.01 to 1.0 to 3.0 to 0.03mg3.0mg 7.5mg Freon 114 ⁺ 30 parts and Freon 12 70 parts in total up to lOO ^ il 100 ^ 1 lOQul ⁺ Freon 11 can be replaced.

Way of working:

The racemic-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro2H-1-benzopyran-2-carboxylic acid air salt is micronized to size 1 - Pick up the particles and place them in a suitable container. Glyceryl trioleate was added at room temperature. The freon was cooled to -30 ° C and added to the mixture. Immediately after the addition of the freon, the container is closed with a precision suitable metering nozzle and the container is placed in an ultrasonic generator to disperse the racemic-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) sodium salt ) pentyloxy / -3,4-dihydroxy2H-1-benzopyran-2-carboxylic acid in freon.

Example 98. Aerosol Form (Freon Aerosol Solution)

Ingredients _____ mg / 100 / </ l, 0mg 10.0mg25.0mg rac-6-acetyl-7- / 5 (4-acetyl-3-hydroxy-

2-propylphenoxy) pentyloxy / -3,4-l.Omg 10,0mg25,0mg dihydro-2H-1benzopyran-2-carboxylic acid dimethylsulfoxide 3,0µ 1 10,0µ 1 20,0µ 1 ethanol 99,9% -en 6 , 0μ1 6,0μ1 6,0μ1 methylene chloride ΙΟμΙ ΙΟμΙ ΙΟμΙ

Freon 12 to ΙΟΟμΙ ΙΟΟμΙ ΙΟΟμΙ

Way of working:

In a suitable container, racemic-6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-

1-Benzopyran-2-carboxylic acid was dissolved in dimethyl sulfoxide at room temperature. Ethanol and methylene chloride are added to the mixture. The pre-cooled to -30 ° C freon is then added. Immediately after the addition of the freon, the vessel is closed with a precise dosing nozzle.

Example 99. Aerosol Form (Freon Aerosol Solution)

Ingredients rac-6-acetyl-7- / 5- (4-acetyl-

3-hydroxy-50.0mg

2-propylphenoxy) -pentyloxy / -3,4 dihydro-2H-1-benzopyran-

2-carboxylic acid dimethyl sulfoxide150µl ethanol 99.9% -en0.3ml methylene chloride0.5ml

Freon 124.2ml

Total volume of 5.0ml concentration of active substance lmg / 0, lml

Way of working:

This example works as described in Example 98.

Example 100 Fog Form (Fog Form Solution)

Ingredients mg / ml

25.0mg 50.0mg 100, Omg rac-6-acetyl-7- / 5 (4-acetyl-hydroxy-25, Omg 50, Omg 100, Omg si-2-propylphenoxy) pentyloxy / -3,4 dihydro-2H -1benzopyran-2-carboxylic acid phosphate buffer containing sodium 1.0ml 1.0ml 1.0ml pH 7.8 base

Way of working:

Racemic-6-acetyl-7- / 5- (4-acetyl-

3-hydroxy-2-propylphenoxy) pentyloxy / -

3,4-Dihydro-2H-1-benzopyran-2-carboxylic acid was dissolved in phosphate buffer containing an equimolar amount of sodium hydroxide to provide a pH of 7.8.

Example 101. Capsule Form

Ingredients mg / capsule

25mg 50mg 100mg 200mg rac-6-acetyl-7 / 5- (4-acetyl-25 50 100 200

3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro-2H-1-benzopyran-2-pentanoic acid

lactose 375 155 200 140 starch 30 30 35 40 talc 20 15 15 20

weight per ---------------------------- one capsule 450mg 250mg350mg400mg

Way of working:

Racemic-6-acetyl-7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy-3,4-dihydro-2H-1-benzolated-2-pentanoic acid, lactose and starch are ground in a suitable mill mixer. Talc is added and mixed well. It is encapsulated with suitable apparatus.

Example 102. Tablet Form (Wet Granulation)

Ingredients mg / tablet _______

25mg50mg 100mg200mg rac-6-acetyl-7- /

5- (4-acetyl- 25 50 100 200

3-hydroxy-2-propylphenoxy) pentyloxy / -

3,4-Dihydro-2H-1-benzopyran-2-pentanoic acid

lactose 280153 187 171 modified starch 55 25 35 45 pre-gelatinized starch 35 20 25 30 distilled water q.s. - - - - magnesium stearate 5 2 3 4

tablet weight 400mg 250mg350mg450mg

Way of working:

The racemic-6-acetyl-7- / 5- (4-acetyl-3-hydroxy-

2-propylphenoxy) pentyloxy / -3,4-dihydro2H-1-benzopyran-2-pentanoic acid, lactose, modified starch and pregelatinized starch. Granulate with sufficient distilled water to obtain the appropriate consistency. She was grinding. Dry in a suitable oven. Grind and mix with magnesium stearate for 3 min. It is compressed into a suitable press fitted with the appropriate dies.

Example 103. Tablet Form (Direct Compression)

Ingredients 25 mg / tablet rac-6-acetyl-7 / 5- (4-acetyl-3-hydroxy-25

2-propyl phenoxy) pentyloxy / -3,4-dihydro-2H-1-benzopyran-2-pentanoic acid lactose181 avicel55 starch35 magnesium stearate 4 tablet weight 300mg

Way of working:

Racemic-6-acetyl-7- / 5- (4-acetyl-

3-hydroxy-2-propylphenoxy) pentyloxy / -

3,4-Dihydro-2H-1-benzopyran-2-pentanoic acid is digested with an equal amount of lactose. It mixes well with avicel and starch and the rest of the lactose. It is compressed with a suitable press fitted with the appropriate dies.

Claims (15)

Claims A compound of formula o wherein R 1 is hydrogen or lower alkyl; R ₂ is hydrogen or halogen; R ₃ , R ₄ and R ₅ , independently of one another, are hydrogen, alkanoyl, benzoyl or lower alkyl; R ₆ and R ₇ , independently of one another, are hydrogen or lower alkyl; X is alkylene containing 3 to 6 carbon atoms, and η is zero, provided that one of R ₃ , R ₄ or R ₅ is alkanoyl or benzoyl and the other two are independently hydrogen or lower alkyl and its enantiomer, or when R 1 is hydrogen, a salt thereof with a pharmaceutically acceptable base. The compound of claim 1, wherein R 1 is lower alkyl, R ₂ is hydrogen, R ₃ is alkanoyl or benzoyl and R ₄ , R ₃ , R ₆ and R are hydrogen. A compound according to claim 2, wherein X is alkylene containing 3 to 5 carbon atoms. The compound of claim 3, wherein R 1 is acetyl. 5. A compound according to claim 4 wherein it is propyl. The compound of claim 1, wherein the compound is racemic-6-acetyl-7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) - 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. A compound according to claim 1, wherein the compound is (S) - (+) -6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pessyloxy / -3,4-dihydro- 2H1-benzopyran-2-carboxylic acid. The compound of claim 1, wherein the compound is (R) - (-) -6-acetyl-7- / 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy / -3,4-dihydro- 2H1-benzopyran-2-carboxylic acid. The compound of claim 1, wherein the compound is racemic-6-acetyl-7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2H1-benzopyran-2-carboxylic acid . A pharmaceutical composition having SRS - A antagonist activity comprising an effective amount of a compound of formula x — odZl vJE l | - (CHjJ.COjR ¹ I, λλ ο T * R '»> in which R is hydrogen or lower alkyl; R ₂ is hydrogen or halogen; R ₃ , R ₄ and R _{5 are} independently hydrogen, alkanoyl, benzoyl or lower alkyl; R ₆ and R _{7 are} independently hydrogen or lower alkyl; X is alkylene containing 3 to 7 carbon atoms, and n is zero, provided that one of R ₃ , R ₄ or R ₃ is alkanoyl or benzoyl and the other two are independently hydrogen or lower alkyl and its enantiomer, or , when R ₇ is hydrogen, a salt thereof with a pharmaceutically acceptable base and an inert carrier. The composition of claim 10, wherein the compound of formula I is racemic-6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H1-benzopyran-2-carboxyl acid. The composition of claim 10, wherein the compound of formula I is (S) - (+) - 6-apethyl-7- [5- (4-acetyl-3-hydroxy-3-propyl phenoxy) pentyloxy] -3,4- dihydro-2H1-benzopyran-2-carboxylic acid. 13. A method of treating allergic conditions requiring SRS-A antagonist activity, which involves administering an effective amount of a compound of formula: wherein R1 is hydrogen or lower alkyl; R ₂ is hydrogen or halogen; R 1, R ₄ and R _s , independently of one another, are hydrogen, alkanoyl, benzoyl or lower alkyl, R ₆ and R ₆ are independently hydrogen or lower alkyl; X is alkylene of 3 to 7 carbon atoms, and η is zero, provided that one of R ,, R ₄ and R _s are an alkanoyl or benzoyl and the other two, independently of one another, are hydrogen or lower alkyl; an enantiomer thereof or, when R ₇ is hydrogen, a salt thereof with a pharmaceutically acceptable base. The method of claim 13, wherein the compound of formula I is racemic- 6-acetyl-7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-dihydro-2H1-benzopyran-2-carboxylic acid. 5 The method of claim 13, wherein the compound of formula I is (S) - (+) - 6-acetyl-7- [5- (4-acetyl-3-hydroxy-3-propylphenoxy) pentyloxy] -3,4-dihydro-2H1 -benzopyran-2-carboxylic acid.