Substituted chromanon-2-yl alkanols and derivatives thereof

This invention relates to substituted chromanon-2-yl alkanols and derivatives thereof, which are useful as leukotriene D.sub.4 (LTD.sub.4) inhibitors and therefore useful in the treatment of allergies, inflammatory conditions, and coronary vasoconstriction.

BACKGROUND OF THE INVENTION 
(a) Field of the Invention 
This invention in its broadest aspect relates to inhibitors of metabolic 
pathways. In particular, the invention relates to novel compounds of 
Formula I, which are inhibitors of leukotriene D.sub.4 (LTD.sub.4) and 
which therefore are useful to prevent or alleviate the symptoms associated 
with LTD.sub.4, such as allergic reactions, particularly asthma, see M. 
Griffin et al., N. Engl. J. Med., 308, 436 (1983); inflammatory 
conditions; and coronary vasoconstriction. 
LTD.sub.4 is a product of the 5-lipoxygenase pathway and is the major 
active constituent of slow reacting substance of anaphylaxis (SRS-A), a 
potent bronchoconstrictor that is released during allergic reactions. See 
R. A. Lewis and K. F. Austen, Nature, 293, 103-108 (1981). When 
administered to humans and guinea pigs, LTD.sub.4 causes 
bronchoconstriction by two mechanisms: (1) directly by stimulating smooth 
muscle; and (2) indirectly through release of thromboxin A.sub.2, which 
causes contraction of respiratory smooth muscle. Because antihistamines 
are ineffective in the management of asthma, SRS-A is believed to be a 
mediator of the bronchoconstriction occurring during an allergic attack. 
LTD.sub.4 may also be involved in other inflammatory conditions such as 
rheumatoid arthritis. Furthermore, LTD.sub.4 is a potent coronary 
vasoconstrictor and influences contractile force in the myocardium and 
coronary flow rate of the isolated heart. See F. Michelassi et al., 
Science, 217, 841 (1982); J. A. Burke et al., J. Pharmacol. and Exp. 
Therap., 221, 235 (1982). 
(b) Prior Art 
Certain 2-alkylated chromanon-2-yl derivatives have been disclosed in the 
prior art. European Patent Application No. 0079637 and U.S. Application 
Ser. No. 06/560355, the latter having the same assignees as the present 
invention, disclose 2-alkylated chromanon-2-yl alkanoic acids. Since none 
of the compounds claimed in the present invention possesses a carboxylic 
acid function, they are distinguishable from chromanon-2-yl alkanoic acids 
of the prior art. 
By combination of elements disclosed and claimed, Ser. No. '355 appears 
also to disclose certain 2-alkylated chromanon-2-yl alkanediols and 
ketoalkanols related to those claimed herein. However, the particular 
combination of elements that are characteristic of this invention, 
particularly the 2-alkyl-2-ketoalkanols and 2-alkyl-2-alkanediols, are not 
described in the prior art, nor are enabling methods for the preparation 
of compounds of this invention described. As described in Ser. No. '355, 
the side-chain keto group (or a hydroxymethylene group subsequently formed 
by reduction of the keto group) must always be attached directly to the 
chromanone nucleus. (That is, in Formula I, below, Z must be attached 
directly to the 2-position of the chromanone nucleus, with no intervening 
methylene carbon atoms). The compounds of this invention always possess an 
intervening alkylene chain. Moreover, all prior art compounds in Ser. No. 
'355 having a side-chain ketone function must be formed as acylation 
products of 2-carboxychromanones and not of 2-alkylchromanones. In 
contrast, the compounds of this invention are formed by a ring closure 
(see Scheme A, below) that does not require a 2-carboxyl function and 
permits the ketone group to be separated from the chromanone ring. 
SUMMARY OF THE INVENTION 
The invention relates to compounds of Formula I: 
##STR1## 
wherein Y is: (a) --(CH.sub.2).sub.m -- 
(b) --(CH.sub.2).sub.p --CHOH--(CH.sub.2).sub.q -- 
(c) --(CH.sub.2).sub.r --CO--(CH.sub.2).sub.s -- 
wherein Z is: 
(a) 
##STR2## 
(b) 
##STR3## 
(c) 
##STR4## 
(d) 
##STR5## 
wherein R.sup.1, R.sup.2, and R.sup.3 are alkyl of 1 to 6 carbon atoms, 
inclusive, each being the same or different; wherein R.sup.4 is: 
(a) hydrogen; or 
(b) alkyl of 1 to 6 carbon atoms, inclusive; 
wherein R.sup.5 and R.sup.6, each being the same or different, are: 
(a) hydrogen; or 
(b) alkanoyl of 2 to 6 carbon atoms, inclusive; 
wherein R.sup.7 and R.sup.8 are: 
(a) hydrogen; or 
(b) alkanoyl of 2 to 6 carbon atoms, inclusive; 
wherein R.sup.9 is alkyl of 1 to 6 carbon atoms, inclusive; wherein n is an 
integer from 1 to 10, inclusive; wherein m is an integer from 2 to 7, 
inclusive; wherein each of p and q is an integer from 1 to 5, inclusive, 
with the proviso that the sum (p+q) is no greater than 6; wherein each of 
r and s is an integer from 1 to 5, inclusive, with the proviso that the 
sum (r+s) is no greater than 6. 
Examples of alkyl of 1 to 6 carbon atoms, inclusive, are methyl, ethyl, 
propyl, butyl, pentyl, hexyl, and the isomeric forms thereof, generally 
referred to as alkyl. 
Examples of alkanoyl of 2 to 6 carbon atoms, inclusive, are acetyl, 
propanoyl, butanoyl, pentanoyl, and the isomeric forms thereof. 
DESCRIPTION OF THE INVENTION 
The compounds of this invention may be prepared by any of several methods 
known to those skilled in the art. For example, the particular sequence of 
reactions joining the aromatic rings through the linking group Y may be 
selected for synthetic convenience or for maximization of yields. The 
following Schemes illustrate some of the possible methods used to prepare 
the compounds of this invention. Compounds described below are typically 
purified by column chromatographic methods known to those skilled in the 
art. 
Scheme A illustrates a method for preparing dihydropyranone intermediates 
of Formula VII. 
SCHEME A 
Base-catalyzed condensation of 3-substituted dihydroxyacetophenones of 
Formula II and alkenones of Formula III affords alkenyl-substituted 
dihydrobenzopyranones of 
##STR6## 
Formula IV. Preferred condensation conditions include heating the 
compounds at reflux in an unreactive organic solvent, such as toluene, 
with provision, such as a Dean-Stark trap, for removing water that is 
formed during the condensation. After the second phenolic hydroxyl 
function is protected, for example by acetylation to form compound V, the 
alkenyl function can be epoxidized to the intermediate compound of Formula 
VI. A preferred acetylation method employs acetic anhydride in pyridine. A 
preferred epoxidation method employs m-chloroperbenzoic acid in an 
unreactive organic solvent, such as dichloromethane. Basic hydrolysis then 
is used to remove the acetyl protecting group, affording the intermediate, 
Formula VII. Preferred hydrolysis conditions include stirring with 
potassium carbonate or sodium carbonate in methanol. 
Scheme B illustrates an alternative method of preparing intermediates of 
Formula V (see Scheme A). 
SCHEME B 
Alkenyl compounds of Formula VIII (that is, Formula IV where R.sup.4 is 
hydrogen) may be oxidatively cleaved to the aldehyde, Formula IX. One 
method for this cleavage employs sodium periodate and osmium tetroxide in 
an organic solvent such as t-butyl alcohol or dioxane. An ylide or Wittig 
reaction converts the aldehyde to the extended alkenyl intermediate, 
Formula V (where R.sup.4 is alkyl). A preferred method involves converting 
an alkyltriphenylphosphonium halide salt to the 
##STR7## 
phosphorane reagent by reaction with a strong base, such as butyllithium, 
in an inert solvent. The phosphorane thus formed may be diluted with a 
cold solvent, such as dimethylsulfoxide at -20.degree., where it is 
allowed to react with the aldehyde. 
Scheme C illustrates a method for joining the two aromatic moieties of the 
compounds of this invention. 
SCHEME C 
Alkylation of 3-substituted dihydroxyacetophenones of Formula X with 
omega-bromoalkanols affords intermediates of Formula XI. A preferred 
method employs phase-transfer conditions: the reactants are stirred at 
reflux in a mixture of tetrabutylammonium hydrogen sulfate, aqueous sodium 
hydroxide, and dichloromethane. The resultant intermediates of Formula XI 
are coupled with compounds of Formula VII (see Scheme A) to form compounds 
of this invention, Formula XII. A preferred condensation method employs 
triphenylphosphine and diethyl azodicarboxylate in an unreactive organic 
solvent, such as tetrahydrofuran. Compounds in Formula XII may be used to 
prepare other compounds of this invention. For example, the epoxide 
function can be ring-opened by reaction with sodium acetate in acetic acid 
to form acetoxy alcohols of this invention, Formulas XIII and XIV. Other 
acylated compounds of this invention may similarly be prepared. The 
position isomers may be separated, for instance by chromatogaphic 
techniques, or they may be used as a mixture in subsequent reactions, 
after 
##STR8## 
which the resultant product compounds may be separated. Schemes E through 
G illustrate further elaboration of the compounds of this invention 
derived from compounds of Formulas XIII and XIV. 
Scheme D illustrates one of the possible subsequent reactions to form other 
compounds of this invention. 
SCHEME D 
The individual compounds of Formulas XII and XIV or a mixture of the 
unseparated compounds may be hydrolyzed to give a dihydroxy compound of 
Formula XV. A preferred hydrolysis method employs lithium hydroxide in 
aqueous methanol. 
Scheme E illustrates one method for preparing ketones of this invention. 
SCHEME E 
An acetoxy alcohol compound of Formula XIII, employed either in a mixture 
with a compound XIV or in pure form, is subjected to oxidation conditions 
which will form the ketone of Formula XVI. A preferred oxidation method 
employs Jones reagent (an adduct of chromic anhydride and aqueous sulfuric 
acid used in acetone solution). Removal of the acetyl group by hydrolysis 
under basic conditions, such as potassium carbonate in methanol, affords a 
ketoalcohol of Formula XVII. 
##STR9## 
Under the conditions described in Scheme E, some of the compounds of 
Formula XIV will oxidize to different products from those of Formula XIII, 
as shown in Scheme F. 
SCHEME F 
Where R.sup.4 is alkyl, Jones oxidation will transform compounds of Formula 
XIV to acetoxy ketones of Formula XVIII, which are position isomers of 
compounds of Formula XVI (see Scheme E). Basic hydrolysis, as described in 
Scheme E, will convert acetoxy ketones XVIII to corresponding 
ketoalcohols, Formula XIX. Where R.sup.4 is hydrogen, however, Jones 
oxidation will transform compounds of Formula XIV all the way to 
carboxylic acids of Formula XX. (Note that the mixture of Jones oxidation 
products formed from a mixture of acetoxy alcohols XIII and XIV can thus 
initially be separated by extraction of carboxylic acid XX into aqueous 
base.) Basic hydrolysis followed by acidification will afford the 
corresponding alcohols, Formula XXI. 
As shown in Scheme G, milder oxidation of compounds of Formula XIV, where 
R.sup.4 is hydrogen, affords aldehydes of Formula XXII rather than 
carboxylic acids. 
SCHEME G 
A preferred milder oxidation method employs Collins reagent (a complex of 
chromic anhydride and two equivalents of pyridine) 
##STR10## 
in an unreactive organic solvent, such as dichloromethane, at 
approximately 0.degree. to 25.degree. C. Alternatively, oxidation with 
pyridinium chlorochromate in dichloromethane at room temperature also 
affords aldehydes. As described before, basic hydrolysis of the acetoxy 
compounds. Formula XXII, affords corresponding alcohols of Formula XXIII. 
Compounds of this invention having an alcohol or ketone group in the 
bridging group Y (see Formula I) are prepared by somewhat different 
methods from those described above in Schemes A through G. Scheme H 
illustrates one general method. 
SCHEME H 
Epoxy acetophenone derivatives of Formula XXIV react with 
alkenyl-substituted dihydropyranones of Formula IV (see Scheme A) to form 
compounds of Formula XXV, in which the bridging chain possesses a hydroxyl 
functionality. Preferred reaction conditions included heating the 
compounds with a base, such as benzyltrimethylammonium hydroxide, in a 
polar organic solvent, such as dimethylformamide, at 
110.degree.-120.degree. for about two days. The alkenyl function may then 
be converted to the corresponding diol, thereby forming compounds of this 
invention, Formula XXVI. A preferred method employs N-methylmorpholine 
N-oxide and a catalytic amount of osmium tetroxide in an aqueous t-butyl 
alcohol-acetone solution. Compounds of Formula XXVI in which R.sup.4 is 
hydrogen may conveniently be converted to keto compounds of Formula 
XXVIII. The primary hydroxyl group is 
##STR11## 
selectively protected before oxidation. A preferred protecting group is 
triphenylmethyl (trityl), which forms the ether shown in Formula XXVII by 
reaction of compounds XXVI with trityl chloride in dry pyridine. 
Subsequent Jones oxidation, as described above (see Schemes E and F), and 
removal of the trityl group under acid conditions, preferably 90% aqueous 
trifluoroacetic acid in t-butyl alcohol, affords compounds of this 
invention, Formula XXVIII. This latter method of oxidizing the protected 
compounds of Formula XXVII may also be used to convert compounds of 
Formula XV (see Scheme D) to compounds of Formula XVII (see Scheme E), 
although in each case R.sup.4 is preferably hydrogen. 
The preferred embodiments of this invention include compounds of the 
following general structure, Formula XXIX. 
##STR12## 
More specifically, the preferred embodiments include compounds of Formula 
XXIX wherein Z is the following: 
(a) 
##STR13## 
(b) 
##STR14## 
(c) 
##STR15## 
(d) 
##STR16## 
wherein R.sup.4 is hydrogen or lower alkyl (that is, consisting of 1 to 6 
carbon atoms, inclusive); wherein R.sup.5 and R.sup.6 are both hydrogen, 
or one of R.sup.5 and R.sup.6 is hydrogen and the other is lower alkanoyl 
(that is, consisting of 2 to 6 carbon atoms, inclusive); wherein R.sup.7 
and R.sup.8 are hydrogen or lower alkanoyl; wherein R.sup.9 is lower 
alkyl; and wherein n is an integer from 2 to 4. 
The most preferred embodiments of this invention include compounds of the 
following general structure, Formula XXX. 
##STR17## 
More specifically, the preferred embodiments include compounds of Formula 
XXX wherein Z is the following: 
(a) 
##STR18## 
(b) 
##STR19## 
(c) 
##STR20## 
wherein R.sup.4 is hydrogen or lower alkyl (that is, consisting of 1 to 6 
carbon atoms, inclusive); wherein R.sup.6 is hydrogen or lower alkanoyl 
(that is, consisting of 2 to 6 carbon atoms, inclusive); and wherein 
R.sup.7 is hydrogen or lower alkanoyl. 
The compounds of this invention exhibited antiallergy activity in guinea 
pigs, as indicated by antagonism in vitro (isolated ileum segments) of 
LTD.sub.4 -induced smooth muscle contractions and by antagonism in vivo of 
LTD.sub.4 -induced bronchoconstriction. The antiallergy activity of the 
compounds of this invention illustrated in the examples was tested by the 
following methods. 
ANTAGONISM OF LTD.sub.4 -INDUCED SMOOTH MUSCLE CONTRACTIONS 
Segments of ileum tissue isolated from guinea pigs were mounted in a 
modified Tyrode solution (8.046 g/l of sodium chloride, 0.200 g/l of 
potassium chloride, 0.132 g/l of calcium chloride monohydrate, 0.106 g/l 
of magnesium chloride hexahydrate, 1.00 g/l of sodium bicarbonate, 0.058 
g/l of sodium dihydrogen phosphate, and 1.00 g/l of dextrose) containing 
0.1 mcg/ml atropine sulfate and 1.0 mcg/ml of pyrilamine maleate and 
aerated at 37.degree. C. with 95% oxygen and 5% carbon dioxide. The tissue 
segments were stimulated with two or more concentrations of either 
LTD.sub.4 or bradykinin triacetate (agonists), producing reproducible 
muscle contractions. The control solution was replaced by a solution or 
suspension of test compound (1.0.times.10.sup.-5 M) and incubated for 30 
minutes. Each agonist was again introduced to the appropriate solutions 
and increased doses were added, if necessary, until contractions were 
approximately equal to those of the previously determined controls or 
until excessive quantities of agonist were added. For each combination of 
test compound and agonist, the following dose ratio was calculated: the 
ratio of agonist concentration in the presence of test compound to the 
agonist concentration in the absence of test compound that will produce 
the same contractile response. A concentration of test compound was 
considered active if it produced a dose ratio against LTD.sub.4 
significantly (P&lt;0.05) greater than a dose ratio obtained in a series of 
blank treatment tests. (Duplicate tests were conducted for each 
concentration of test compound, and third tests were conducted if the 
first two tests were inconsistent.) Compounds that were active against 
LTD.sub.4 but not against bradykinin triacetate were considered selective 
LTD.sub.4 antagonists. 
A further measure of receptor affinity, pA.sub.2, was also determined for 
selective LTD.sub.4 antagonists. A pA.sub.2 value is defined as the 
negative logarithm of the molar concentration of the antagonist which 
produces a dose ratio of 2. The pA.sub.2 values were calculated by the 
method of Arunlakshana and Schild, Br. J. Pharmacol., 2, 189 (1947), using 
Schild plot slopes constrained to -1. See R. J. Tallarida and R. B. 
Murray, Manual of Pharmacologic Calculations with Computer Programs (New 
York: Springer-Verlag, 1981), pp. 33-35. 
ANTAGONISM OF LTD.sub.4 -INDUCED BRONCHOCONSTRICTION 
Fasted adult male Hartley guinea pigs weighing 300 to 350 grams were used 
in this assay. All test animals were pretreated with propranolol and 
pyrilamine to block the bronchoconstrictive effects of endogenous 
epinephrine and histamine, respectively, and with indomethacin to block 
the synthesis of thromboxane A.sub.2. The animals were anesthetized with 
pentobarbital and attached to a rodent respirator. Continuous measurements 
of intratracheal insufflation pressure were obtained through an 
intratracheal pressure transducer. After a baseline record was obtained, 
LTD.sub.4 (200 ng) was administered intravenously and agonist-induced 
changes in intratracheal insufflation pressure were measured. Compounds 
which antagonize the direct component of LTD.sub.4 action on respiratory 
smooth muscle inhibit intratracheal insufflation pressure increases caused 
by LTD.sub.4. To determine the effect of test compounds on LTD.sub.4 
-induced bronchoconstriction, the compounds were administered to the 
animals either intravenously (10 mg per kg body weight) or 
intragastrically (100 mg per kg of body weight) at an appropriate interval 
prior to the LTD.sub.4 challenge. Test compounds were rated active if 
intratracheal insufflation pressure was significantly (P&lt;0.05) reduced 
relative to vehicle control animals, as assessed by a Student's one-tail 
t-test. 
By virtue of their activity as LTD.sub.4 antagonists, the compounds of 
Formula I are useful in treating asthma and other anaphylactic conditions, 
inflammation, and coronary vasoconstriction in mammals. A physician or 
veterinarian of ordinary skill can readily determine whether a subject 
exhibits one of these conditions. The preferred utility relates to 
treatment of asthma. Regardless of the route of administration selected, 
the compounds of the present invention are formulated into 
pharmaceutically acceptable dosage forms by conventional methods known to 
those skilled in the art. 
The compounds may be administered in a number of dosage forms. A preferred 
method of delivery would be oral or a means that would localize the action 
of the drug. For example, for asthma the compounds could be inhaled using 
an aerosol or other appropriate spray. For an inflammatory condition such 
as rheumatoid arthritis the compounds could be injected directly into the 
affected joint. The compounds can also be administered in such oral dosage 
forms as tablets, capsules, pills, powders, or granules. They may also be 
administered intravascularly, intraperitoneally, subcutaneously, or 
intramuscularly, using forms known to the pharmaceutical art. In general, 
the preferred form of administration is oral. An effective but non-toxic 
quantity of the compound is employed in treatment. The dosage regimen for 
preventing or treating the conditions with the compounds of this invention 
is selected in accordance with a variety of factors, including the type, 
age, weight, sex, and medical condition of the patient; the severity of 
the condition; the route of administration; and the particular compound 
employed. An ordinarily skilled physician or veterinarian can readily 
determine and prescribe the effective amount of the drug required to 
prevent or arrest the progress of the disease state. In so proceeding, the 
physician or veterinarian could employ relatively low doses at first and 
subsequently increase the dose until a maximum response is obtained. 
Dosages of the compounds of the invention are ordinarily in the range of 
0.1 to 10 mg/kg up to about 50 mg/kg orally.

The following examples further illustrate details for the preparation of 
the compounds of this invention. The invention, which is set forth in the 
foregoing disclosure, is not to be construed or limited either in spirit 
or in scope by these examples. Those skilled in the art will readily 
understand that known variations of the conditions and processes of the 
following preparative procedures can be used to prepare these compounds. 
All temperatures are degrees Celsius unless otherwise noted. 
DESCRIPTION OF THE EMBODIMENTS 
EXAMPLE 1 
2-(3-butenyl)-3,4-dihydro-7-hydroxy-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR21## 
A mixture of 25 g (129 mmole) of 2,4-dihydroxy-3-propylacetophenone, 15 ml 
(ca. 129 mmole) of 5-hexen-2-one, and 5.4 ml (64 mmole) of pyrrolidine in 
160 ml of toluene was heated at reflux for six hours under a Dean-Stark 
trap. Upon cooling, the reaction mixture was diluted with ethyl acetate 
and washed successively with water, 2N hydrochloric acid, and water. The 
organic phase was dried over magnesium sulfate, filtered, and concentrated 
in vacuo to a residue that crystallized upon standing. The crude solid was 
triturated with hexane and collected by filtration. Further purification 
by high performance column chromatography on silica gel (using 10% by 
volume ethyl acetate-toluene as eluent) afforded 23.5 g of the title 
compound as an analytically pure solid, m.p. 97.5.degree.-98.5.degree.. 
nmr (CDCl.sub.3): .delta. (ppm) 0.96 (t, 3H, propyl CH.sub.3); 1.38 (s, 
3H, 2-methyl CH.sub.3); 4.98 (m, 2H, alkenyl CH.sub.2); 5.75 (m, 1H, 
alkenyl CH); 6.52, 7.72 (sets of d's, aromatic) 
Analysis calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42; H, 8.08. Found: 
C, 74.47; H, 8.14. 
EXAMPLE 2 
7-acetoxy-2-(3-butenyl)-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR22## 
To 4.0 g of the title product of Example 1 in 25 ml of pyridine was added 
3.0 ml of acetic anhydride. Upon completion of acetylation, the mixture 
was cooled to ca. 0.degree., stirred with methanol for 15 minutes, and 
extracted with diethyl ether. The ether layer was washed sequentially with 
cold 2% aqueous hydrochloric acid and brine, dried over sodium sulfate, 
filtered, and concentrated in vacuo, affording 4.92 g of the title 
compound as a nearly analytically pure oil. nmr (CDCl.sub.3): .delta. 
(ppm) 0.92 (t, 3H, propyl CH.sub.3); 1.38 (s, 3H, 2-methyl CH.sub.3); 2.31 
(s, 3H, acetyl CH.sub.3); 4.98 (m, 2H, alkenyl CH.sub.2); 5.75 (m, 1H, 
alkenyl CH); 7.65, 7.72 (sets of d's, aromatic) 
Analysis calcd. for C.sub.19 H.sub.24 O.sub.4 : C, 72.12; H, 7.65. Found: 
C, 71.54; H, 7.61. 
EXAMPLE 3 
7-acetoxy-2-(2-oxiranylethyl)-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran 
-4-one 
##STR23## 
Epoxidation of 5.2 g (17.9 mmole) of the title product of Example 2 with 
4.23 g (ca. 19.6 mmole) of 80% pure m-chloroperbenzoic acid in 50 ml of 
dichloromethane was initiated at 0.degree.. The reaction mixture was 
allowed to stand at room temperature for nine hours. Water was added and 
the mixture was extracted with diethyl ether. The organic phase was washed 
successively with 5% aqueous sodium bicarbonate and 5% aqueous sodium 
sulfite, and then dried over magnesium sulfate, filtered, and concentrated 
in vacuo. Purification by high performance column chromatography afforded 
the title compound (5.73 g) as an oil, which was used in subsequent 
reactions without further purification. 
nmr (CDCl.sub.3): .delta. (ppm) 0.92 (t, 3H, propyl CH.sub.3); 1.38 (s, 3H, 
2-methyl CH.sub.3); 2.32 (s, 3H, acetyl CH.sub.3); 6.66, 7.72; (sets of 
d's, aromatic); Infrared (CHCl.sub.3): 1762, 1690, 1598, 1429, 1100, 1020 
cm.sup.-1. 
EXAMPLE 4 
2-(2-oxiranylethyl)-3,4-dihydro-7-hydroxy-2-methyl-8-propyl-2H-1-benzopyran 
-4-one 
##STR24## 
To a solution of 5.7 g of the title product of Example 3 in 80 ml of 
methanol was added 6 g of potassium carbonate. After stirring at room 
temperature, the mixture was concentrated in vacuo to a residue that was 
partitioned between water and ethyl acetate. The organic phase was 
concentrated to dryness and the residue redissolved in 1:1 (by volume) 
ethyl acetate-hexane. Filtration through a thick (ca. 7 cm) pad of silica 
gel and concentration of the filtrate afforded the title compound (4.29 g) 
as an oil, which was used in subsequent reactions without further 
purification. 
nmr (CDCl.sub.3): .delta. (ppm) 0.95 (t, 3H, propyl CH.sub.3); 1.37 (s, 3H, 
2-methyl CH.sub.3); 6.45, 7.62 (sets of d's, aromatic); Infrared 
(CHCl.sub.3): 3600, 3350, 1675, 1600, 1438, 1100, 1013 cm.sup.-1. 
EXAMPLE 5 
3-(4-acetyl-3-hydroxy-2-propylphenoxy)propanol 
##STR25## 
A mixture of 10.1 g (52 mmole) of 2,4-dihydroxy-3-propylacetophenone, 4.7 
ml (ca. 52 mmole) of 3-bromopropanol, 17.7 g (52 mmole) of 
tetrabutylammonium hydrogen sulfate, 34.6 ml (ca. 104 mmole) of 3N aqueous 
sodium hydroxide, and 100 ml of dichloromethane was stirred at reflux for 
2.5 hours. Upon cooling, the organic phase was dried over magnesium 
sulfate, filtered, concentrated in vacuo, and purified by column 
chromatography on silica gel (using 5% by volume of ethyl acetate-toluene 
initially, followed by 50% ethyl acetate-toluene), affording 10.7 g of the 
title compound. The product was used in subsequent reactions without 
further purification. 
nmr (CDCl.sub.3): .delta. (ppm) 0.93 (t, 3H, propyl CH.sub.3); 2.55 (s, 3H, 
acetyl CH.sub.3); 3.86, 4.18 (set of t's, each 2H, OCH.sub.2 's); 6.47, 
7.60 (sets of d's, aromatic). 
EXAMPLE 6 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-(2-oxiranylethyl)-3,4-d 
ihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR26## 
To a solution of 4.16 g (14.3 mmole) of the title product of Example 4, 
3.63 g (14.4 mmole) of the title product of Example 5, and 3.77 g (14.4 
mmole) of triphenylphosphine in 40 ml of tetrahydrofuran was added 2.27 ml 
(ca. 14.5 mmole) of diethyl azodicarboxylate. After two days at room 
temperature, the mixture was concentrated in vacuo, dissolved in diethyl 
ether, and filtered through silica gel. The filtrate was concentrated and 
the residue purified by high performance column chromatography on silica 
gel (using ca. 10 to 20% by volume ethyl acetate-toluene as eluent). The 
initial eluate fractions, upon concentration, afforded 3.92 g of 
analytically pure title compound. 
nmr (CDCl.sub.3): .delta. (ppm) 0.90 (t, 6H, propyl CH.sub.3 's); 1.36 (s, 
3H, 2-methyl CH.sub.3); 2.54 (s, 3H, acetyl CH.sub.3); 4.23 (t, 4H, 
OCH.sub.2 's); 6.47, 6.55, 7.56, 7.72 (sets of d's, aromatic). 
Analysis calcd. for C.sub.31 H.sub.40 O.sub.7 : C, 70.97; H, 7.68. Found: 
C, 70.64; H, 7.77. 
EXAMPLE 7 
2-(4-acetoxy-3-hydroxybutyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propo 
xy]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR27## 
and 
2-(3-acetoxy-4-hydroxybutyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)prop 
oxy]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR28## 
A solution of 3.9 g (7.4 mmole) of the title product of Example 6 and 0.61 
g (7.2 mmole) of anhydrous sodium acetate in 63 ml of acetic acid was 
allowed to stand at room temperature for three days and at 45.degree. for 
another two days. After concentrating in vacuo, the reaction mixture was 
chromatographed on silica gel (using ethyl acetate-toluene as eluant), 
giving 3.4 g of a ca. 2:1 mixture of the "4-acetoxy" and "3-acetoxy" 
position isomers of the title compounds. The isomeric mixture was used in 
subsequent reactions without further purification. 
nmr (CDCl.sub.3): .delta. (ppm) 0.89 (t, 6H, propyl CH.sub.3 's); 1.35 (s, 
3H, 2-methyl CH.sub.3); 2.07 (s, ca. 2H, "4-acetoxy" isomer) plus 2.03 (s, 
ca. 1H, "3-acetoxy" isomer); 2.54 (s, 3H, acetyl CH.sub.3); 3.5-4.3 (m's, 
7H, OCH.sub.2 's and OCH); 6.41, 6.53, 7.55, 7.70 (sets of d's, aromatic). 
Analysis calcd. for C.sub.33 H.sub.44 O.sub.9 : C, 67.79; H, 7.58. Found: 
C, 67.35; H, 7.61. 
EXAMPLE 8 
2-(4-acetoxy-3-oxobutyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]- 
3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR29## 
To a cold (0.degree.) solution of 1.0 g (2 mmole) of the product mixture 
of Example 7 in 5 ml of acetone was added 0.43 ml of 8N Jones reagent. 
After the mixture was warmed to room temperature, water was added and the 
crude product was extracted into diethyl ether. The organic phase was 
washed with 2% aqueous sodium bicarbonate, dried over magnesium sulfate, 
filtered, and concentrated in vacuo. The residue was purified by 
chromatography on a silica-gel coated spinning disk (using ethyl 
acetate-hexane as eluent). The initial eluate fractions, upon 
concentration, yielded 419 mg of the title compound, m.p. 
114.degree.-117.degree.. Recrystallization from ethyl acetate-cyclohexane 
afforded analytically pure title compound, m.p. 118.degree.-120.degree.. 
nmr (CDCl.sub.3): .delta. (ppm) 0.89 (t, 6H, propyl CH.sub.3 's); 1.33 (s, 
3H, 2-methyl CH.sub.3); 2.15 (s, 3H, acetoxy CH.sub.3); 2.55 (s, 3H, 
acetyl CH.sub.3); 4.22 (t, 4H, OCH.sub.2 's); 4.64 (s, 2H, CO-CH.sub.2 O); 
6.40, 6.53, 7.55, 7.70 (sets of d's, aromatic). 
Analysis calcd. for C.sub.33 H.sub.42 O.sub.9 : C, 68.02; H, 7.26. Found: 
C, 67.86; H, 7.31. 
EXAMPLE 9 
2-acetoxy-4-[7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro- 
2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl]butanoic acid 
##STR30## 
The title compound is isolated from the aqueous bicarbonate wash described 
in Example 8 by acidification (pH 3) with dilute hydrochloric acid, 
extraction into diethyl ether, and concentration to dryness. 
EXAMPLE 10 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-(4-hydroxy- 
3-oxobutyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one hemihydrate 
##STR31## 
A mixture of 268 mg of the title product of Example 8 and 191 mg of 
potassium carbonate was stirred at 0.degree. in 7 ml of methanol. After 
one hour 0.70 ml of acetic acid and 30 ml of water were added, and the 
mixture was extracted with diethyl ether. The organic phase was washed 
with brine, dried over magnesium sulfate, filtered, and concentrated in 
vacuo. Purification by chromatography on a silica-gel coated spinning disk 
(using 60:40:1 by volume ethyl acetate-hexane-acetic acid as eluent) 
afforded 164 mg of analytically pure title compound. 
nmr (CDCl.sub.3): .delta. (ppm) 0.89 (t, 6H, propyl CH.sub.3 's); 1.40 (s, 
3H, 2-methyl CH.sub.3); 2.54 (s, 3H, acetyl CH.sub.3); 4.23 (t, 4H, 
OCH.sub.2 's); 6.41, 6.54, 7.55, 7.74 (sets of d's, aromatic). 
Analysis calcd. for C.sub.31 H.sub.40 O.sub.9.1/2H.sub.2 O: C, 67.76; H, 
7.52. Found: C, 67.93; H, 7.65. 
EXAMPLE 11 
4-[7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4 
-oxo-8-propyl-2H-1-benzopyran-2-yl]-2-hydroxybutanoic acid 
##STR32## 
The title product of Example 9 is saponified by stirring for four hours 
with 2% sodium hydroxide in 50% by volume aqueous methanol. The mixture is 
acidified (pH 3) with dilute aqueous hydrochloric acid and extracted into 
diethyl ether. Concentration of the ether layer affords the title 
compound. 
EXAMPLE 12 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-(3,4-dihydr 
oxybutyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one hydrate 
##STR33## 
To a solution of 500 mg of the product mixture described in Example 7 in 3 
ml of methanol was added a solution of 144 mg of lithium hydroxide in 1 ml 
of water. After standing overnight at room temperature, the reaction 
mixture was diluted with water and extracted with ethyl acetate. The 
organic phase was washed with brine, dried over magnesium, filtered, and 
concentrated in vacuo. Purification by chromatography on a silica-gel 
coated spinning disk (using 50:50:8 by volume ethyl 
acetate-cyclohexane-acetic acid as eluent) afforded 331 mg of analytically 
pure title compound. 
nmr (CDCl.sub.3): .delta. (ppm) 0.90 (t, 6H, propyl CH.sub.3 's); 1.36 (s, 
3H, 2-methyl CH.sub.3); 2.55 (s, 3H, acetyl CH.sub.3); ca. 3.5 (m, 
-CHOH-CH.sub.2 OH and H.sub.2 O); 4.22 (t, 4H, OCH.sub.2 's); 6.42, 6.53, 
7.55, 7.69 (sets of d's, aromatic). 
Analysis calcd. for C.sub.31 H.sub.42 O.sub.8.H.sub.2 O: C, 66.41; H, 7.91. 
Found: C, 66.09; H, 7.85. 
EXAMPLE 13 
3-(7-acetoxy-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)propa 
nal 
##STR34## 
To a solution of 3.16 g (10 mmole) of the title product of Example 2 in 60 
ml of t-butyl alcohol is added a solution of 4.5 g (21 mmole) of sodium 
periodate in 15 ml of water and 10 mg of osmium tetroxide. After about 
four hours the reaction mixture is filtered to remove sodium iodate and 
the filtrate concentrated in vacuo. The residue is dissolved in diethyl 
ether, washed sequentially with 2% aqueous sodium sulfite and brine, dried 
over magnesium sulfate, filtered, and concentrated in vacuo. The crude 
title compound is used immediately in subsequent reactions. 
EXAMPLE 14 
7-acetoxy-2-(3-pentenyl)-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-on 
e 
##STR35## 
To a cold (0.degree.) suspension of 4.5 g (12 mmole) of 
ethyltriphenylphosphonium bromide in 70 ml of dry tetrahydrofuran is added 
7.5 ml (ca. 12 mmole) of 1.6M butyllithium in hexane. After one hour the 
resultant phosphorane solution is diluted with 40 ml of dimethylsulfoxide 
and cooled to -20.degree.. Approximately 3.0 g of the title product of 
Example 13 is added, and the mixture is stirred at -20.degree. for about 
one hour and then allowed to warm to room temperature. Upon adding 1.0 ml 
of acetic acid, the mixture is diluted with 150 ml of diethyl ether, 
washed with brine, dried over magnesium sulfate, filtered, and 
concentrated in vacuo. Purification by chromatography on silica gel 
affords the title compound. 
EXAMPLE 15 
2-(3-methyloxiran-2-yl)ethyl]-3,4-dihydro-7-hydroxy-2-methyl-8-propyl-2H-1- 
benzopyran-4-one 
##STR36## 
The title compound is prepared from the title product of Example 14 by the 
general methods described in Examples 3 and 4. 
EXAMPLE 16 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-[2-(3-methyloxiran-2-yl 
)ethyl]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR37## 
The title compound is prepared from the title product of Example 15 by the 
general method described in Example 6. 
EXAMPLE 17 
2-(4-acetoxy-3-hydroxypentyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)prop 
oxy]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR38## 
and 
2-(3-acetoxy-4-hydroxypentyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)pro 
poxy]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR39## 
The title product mixture is prepared by a method similar to that described 
in Example 7, except for using a solution of benzyltrimethylammonium 
hydroxide and acetic acid in dimethylformamide instead of sodium acetate 
in acetic acid. The product mixture is used in subsequent reactions 
without further purification. 
EXAMPLE 18 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-(3,4-dihydr 
oxypentyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR40## 
The title compound is prepared by the method of Example 12 from the title 
product mixture of Example 17. 
EXAMPLE 19 
2-(4-acetoxy-3-oxopentyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy] 
-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR41## 
and 
2-(3-acetoxy-4-oxopentyl)-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy 
]-3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR42## 
The title compounds are prepared by the general method described in Example 
8. The chromatographic purification partially separates the two position 
isomer title compounds. 
EXAMPLE 20 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-(4-hydroxy- 
3-oxopentyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR43## 
Using the method described in Example 10, the isolates of chromatographic 
fractions of Example 19 containing predominantly the "4-acetoxy" position 
isomer are saponified. Chromatographic purification affords the title 
compound. 
EXAMPLE 21 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-(3-hydroxy- 
4-oxopentyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR44## 
Using the method described in Example 10, the isolates of chromatographic 
fractions of Example 19 containing predominantly the "3-acetoxy" position 
isomer are saponified. Chromatographic purification affords the title 
compound. 
EXAMPLE 22 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-(3-butenyl)-3 
,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR45## 
To a solution of 5.5 g (20 mmole) of the title product of Example 1 and 
7.5 g (30 mmole) of 2-hydroxy-4-(2-oxiranylethyl)-3-propylacetophenone in 
60 ml of dry dimethylformamide is added two drops of 
benzyltrimethylammonium hydroxide. The mixture is heated at 
110.degree.-120.degree. for about two days, then cooled and concentrated 
in vacuo to dryness. Purification by column chromatography on silica gel 
(using acetone-hexane as eluent) affords the title compound. 
EXAMPLE 23 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-3,4-dihydro-2-( 
3,4-dihydroxybutyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR46## 
To a solution of 7.8 g (15 mmole) of the title product of Example 22 in 
100 ml of 3:3:1 (by volume) of t-butyl alcohol-acetone-water is added 2.2 
g (16 mmole) of 4-methylmorpholine N-oxide monohydrate and 10 mg of osmium 
tetroxide. After stirring overnight at room temperature, the mixture is 
concentrated in vacuo. The residue is taken up in diethyl ether, washed 
successively with dilute aqueous hydrochloric acid and water, dried over 
magnesium sulfate, filtered, and concentrated in vacuo. Purification by 
chromatography on a silica-gel coated spinning disk affords the title 
compound. 
EXAMPLE 24 
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-oxopropoxy]-3,4-dihydro-2-(4-hy 
droxy-3-oxobutyl)-2-methyl-8-propyl-2H-1-benzopyran-4-one 
##STR47## 
A solution of 5.6 g (10 mmole) of the title product of Example 23 and 3.1 
g (11 mmole) of triphenylmethyl chloride (trityl chloride) in 50 ml of dry 
pyridine is heated at 100.degree. for about three hours. Upon cooling, 
about 5 ml of water is added and the mixture is concentrated in vacuo to a 
thick oil, which is triturated with three portions of water, carefully 
decanting the supernatant each time. The residue is dried thoroughly under 
vacuum. The crude intermediate product, in which the primary alcohol 
function of the starting material is protected by a trityl group, is used 
in the subsequent oxidation reaction without further purification. 
Oxidation of the two secondary alcohol functions is effected by the method 
described in Example 8, except that 4.0 ml of 8N Jones reagent is 
employed. The residue was purified by chromatography on a silica-gel 
coated spinning disk (using ethyl acetate-hexane as eluent). The purified 
trityl-protected intermediate is stirred in 40 ml of a ca. 3:1 mixture by 
volume of 90 % aqueous trifluoroacetic acid and t-butyl alcohol. After 
five minutes the mixture is neutralized with dilute aqueous sodium 
bicarbonate and concentrated in vacuo. The residue is taken up in ethyl 
acetate, washed sequentially with water and brine, dried over magnesium 
sulfate, filtered, and concentrated to dryness. Purification by 
chromatography on a silica-gel coated spinning disk affords the title 
compound.