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Description  |
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DETAILED DESCRIPTION OF THE INVENTION
This invention relates to benzopyrans and more particularly to 9-hydroxy-7,
8, 9, 10-tetrahydro-6H-dibenzo [b] [d] pyrans and pyranones represented by
the formula
##STR2##
wherein R.sub.1 is methyl or R.sub.1 R.sub.1 is oxygen; R.sub.2 is alkyl
or halogen substituted phenyl alkyl; and R.sub.3 is hydrogen, loweralkyl,
loweralkenyl or loweralkynyl.
As used herein the term "loweralkyl" refers to C.sub.1 -C.sub.6 straight or
branched chain alkylene groups including methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,
neo-pentyl, n-hexyl and the like.
The term "alkyl" refers to straight and branched chain alkyl radicals
having from 1 to 20 carbons atoms such as methyl, n-amyl,
3-methyl-2-octyl, 2-nonyl,2-eicosanyl and the like.
The term "halogen" includes chlorine, fluorine, bromine and iodine.
The term "loweralkenyl" refers to straight and branched chain C.sub.2
-C.sub.6 alkyl radicals from which a hydrogen atom has been removed from
each of two adjacent carbon atoms to produce ethylenic unsaturation; e.g.,
vinyl, allyl, methallyl, 1-pentenyl and the like.
The term "loweralkynyl" refers to C.sub.2 -C.sub.6 alkyl groups as defined
above, from which two hydrogen atoms have been removed from each of two
adjacent carbon atoms to produce acetylenic unsaturation; e.g., ethynyl,
propargyl, 2-butnynyl, 1-pentynyl and the like groups.
The present compounds are prepared according to the following reaction
scheme:
##STR3##
In the reaction illustrated above, the starting material,
5-hydroxy-4-methyl-7-alkylcoumarin-3-propionate (I), is obtained by
reaction of 5-alkylresorcinol with dialkyl .beta.-acetylglutarate in the
presence of phosphorus oxychloride. The coumarin (I) is then cyclized to
1-hydroxy-3-alkyl-6, 9-dioxo-7, 8, 9, 10-tetrahydro-6H-dibenzo [b] [d]
pyran (II) with sodium hydride in dimethyl sulfoxide, which, in turn, is
reduced with sodium borohydride to 1, 9-dihydroxy-3-alkyl-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran (III). Compound (III) is then
converted to 1, 9-dihydroxy-6, 6-dimethyl-3-alkyl-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran (IV) with methyl magnesium bromide.
The compounds of this invention are useful as analgesic agents and
tranquilizers. The compounds are effective at dosages generally from 1 to
10 mg./kg. of body weight daily. The analgesic activity was established in
the standard mouse writhing test [Whittle, Brit. J. Pharmacol., 22,296
(1964)] and confirmed in the hot plate assay [Woolfe, G. and MacDonald, A.
D., J. Pharmacol. Exper. Therap., 80,300, (1944)] and the rat tail flick
test.
The following examples further describe and illustrate the present
invention.
EXAMPLE 1
Ethyl 5-Hydroxy-4-Methyl-7-(3-Methyl-2-Octyl)Coumarin-3-Propionate
##STR4##
A mixture of 262 g. (1.109 mole) of 5-(3-methyl-2-octyl)resorcinol, 283 g.
(1.23 mole) of diethyl .alpha.-acetylglutarate, and 170 g. (1.11 mole) of
phorphorus oxychloride protected from atmospheric mositure is stirred at
room temperature for 12 days. The mixture is taken up in benzene-ether and
the solution is washed several times with water, aqueous sodium
bicarbonate, water and dried over anhydrous magnesium sulfate. After
removal of the solvent, 441 g. of an oil is obtained, which solidifies on
standing.
EXAMPLE 2
Ethyl
7-[5-(p-Fluorophenyl)-2-Pentyl]-5-Hydroxy-4-Methylcoumarin-3-Propionate
##STR5##
Ethyl
7-[5-(p-fluorophenyl)-2-pentyl]-5-hydroxy-4-methylcoumarin-3-propionate is
prepared by reaction of 5-[5-(p-fluorophenyl)-2-pentyl]resorcinol, diethyl
.alpha.-acetylglutarate, and phosphorus oxychloride according to the
method of Example 1.
EXAMPLE 3
1-Hydroxy-3-(3-Methyl-2-Octyl)-6, 9-Dioxo-7, 8, 9, 10-Tetrahydro-6H-Dibenzo
[b] [d] Pyran
##STR6##
To a stirred solution of 43.8 g. (0.1088 mole) of ethyl
5-hydroxy-4-methyl-7-(3-methyl-2-octyl)coumarin-3-propionate in 325 ml. of
dry reagent grade dimethyl sulfoxide is added, portionwise, 19.6 g. (0.466
mole) of 57% sodium hydride in mineral oil. The mixture is stirred at room
temperature overnight and poured into 1200 ml. of ice and water. The dark
solution is extracted twice with ether to remove the mineral oil.
Concentrated hydrochloric acid (75 ml.) is added to the stirred aqueous
solution and after 1 hour of stirring, the slurry is filtered and the
solid is washed well with water. The wet filter cake is heated on the
steam bath with excess concentrated sodium bicarbonate solution and is
filtered. The solid is washed well with water and recrystallized from
acetonitrile to give the pure product; m.p. 150-151.degree..
Analysis Calcd. for C.sub.22 H.sub.28 O.sub.4 : C, 74.13; H, 7.92; O,
17.95; Found: C, 73.70; H, 7.98; O, 18.34
EXAMPLE 4
3-[5-(p-Fluorophenyl)-2-Pentyl]-1-Hydroxy-6, 9-Dioxo-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR7##
3-[5-(p-Fluorophenyl)-2-pentyl]-1-hydroxy-6, 9-dioxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting ethyl
7-[5-(p-fluorophenyl)-2-pentyl]-5-hydroxy-4-methylcoumarin-3-propionate
with sodium hydride in dimethyl sulfoxide according to the method of
Example 3; m.p. 174.degree.-176.degree..
EXAMPLE 5
1, 9-Dihydroxy-3-(3-Methyl-2-Octyl)-6-Oxo-7, 8, 9, 10-Tetrahydro-6H-Dibenzo
[b] [d] Pyran
##STR8##
A mixture of 3.56 g. (0.01 mole) of 1-hydroxy-3-(3-methyl-2-octyl)-6,
9-dioxo-7, 8, 9, 10-tetrahydro-6H-dibenzo [b] [d] pyran, 3.8 g. (0.1 mole)
of sodium borohydride, 80 ml. of tetrahydrofuran, 5 ml. of 5% sodium
hydroxide solution and 5 ml. of water is stirred and refluxed for 20
hours. With addition of 40 ml. of water, the mixture is refluxed for
another one-half hour. The tetrahydrofuran is evaporated in vacuo, and the
residue is extracted with chloroform. After removal of the solvent, an
amorphous solid is obtained; m.p. 88.degree.-90.degree..
Analysis Calcd. for C.sub.22 H.sub.30 O.sub.4 : C, 73.71; H, 8.44; O,
17.85; Found: C, 73.49; H, 8.60; O, 17.97
EXAMPLE 6
3-[5-(p-Fluorophenyl)-2-Pentyl]-1, 9-Dihydroxy-6-Oxo-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR9##
A mixture of 11.3 g. (0.0286 mole) of
3-[5-(p-fluorophenyl-2-pentyl]-1-hydroxy-6, 9-dioxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran, 10.9 g. (0.286 mole) of sodium
borohydride, 200 ml. of tetrahydrofuran, 10 ml. of 5% sodium hydride
solution and 10 ml. of water is stirred and refluxed for 19 hours. With
addition of 60 ml. of water, the mixture is refluxed for another one-half
hour. The tetrahydrofuran is evaporated in vacuo, and the residue is
treated with water, acidified with dilute hydrochloric acid, and extracted
with chloroform. The chloroform solution is dried over magnesium sulfate,
and evaporated in vacuo. The residue is purified by chromatography on a
Florisil.RTM. column, using methanol/chloroform solvent mixtures to give
the pure product; m.p. 87.degree.-92.degree..
Analysis Calcd. for C.sub.24 H.sub.25 FO.sub.4 : C, 72.71; H, 6.36; Found:
C, 72.98; H, 6.36
EXAMPLE 7
1, 9-Dihydroxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR10##
A solution of 3.4 g. (0.00948 mole) of
1,9-dihydroxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9, 10-tetrahydro-6H-dibenzo
[b] [d] pyran in 75 ml. of ether is added dropwise to a stirred solution
of 31.6 ml. (0.0948 mole) of methyl magnesium bromide 3/M in ether. The
mixture is stirred and refluxed for 20 hours. The complex is decomposed by
addition of water, followed by ammonium chloride solution. The ether
solution is decanted and the gelatinous inorganic salt is washed well with
ether. The combined ether solution is dried and evaporated in vacuo. The
residue is dissolved in benzene and refluxed with a few crystals of
p-toluenesulfonic acid monohydrate for one-half hour, with a Dean-Stark
trap to remove the water formed. After removal of the solvent, the residue
is chromatographed on a Florisil.RTM. (60-100/mesh) column, using graded
methanol/chloroform solvent mixtures to yield the pure product.
Analysis Calcd. for C.sub.24 H.sub.36 O.sub.3 : C, 77.37; H, 9.74; O,
12.89; Found: C, 77.47; H, 9.80; O, 13.44
EXAMPLE 8
3-[5-(p-Fluorophenyl)-2-Pentyl]-1, 9-Dihydroxy-6, 6-Dimethyl-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR11##
3-[5-(p-Fluorophenyl)-2-pentyl]-1, 9-dihydroxy-6, 6-dimethyl-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting
3-[5-(p-fluorophenyl)-2-pentyl]-1, 9-dihydroxy-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo-[b] [d] pyran with methyl magnesium bromide
according to the method of Example 7. The crude product is purified by
chromatography on a Florisil.RTM. column, using chloroform as eluant.
Analysis Calcd. for C.sub.26 H.sub.31 FO.sub.3 : C, 76.07; H, 7.61; Found:
C, 75.57; H, 7.59
EXAMPLE 9
9-Hydroxy-1-Methoxy-3-(3-Methyl-2-Octyl)-6-Oxo-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR12##
A solution of 8.0 g. (0.0224 mole) of 1-hydroxy-3-(3-methyl-2-octyl)-6,
9-dioxo-7, 8, 9, 10tetrahydro-6H-dibenzo [b] [d] pyran in 50 ml. of
dimethyl formamide is added dropwise to a stirred suspension of 1.7 g.
(0.04 mole) of sodium hydride (57% in mineral oil). The mixture is stirred
and heated in an oil bath at 80.degree. for 2 hours. After cooling, 0.83
g. (0.005 mole) of potassium iodide is added, followed by dropwise
addition of 5.9 g. (0.042 mole) of methyl iodide. The mixture is stirred
at room temperature for 48 hours. After addition of 100 ml. of water, the
mixture is extracted with ether. The ether extract is washed with water,
dried, and evaporated in vacuo. The residue is reduced with sodium
borohydride according to Example 5. The crude produce is purified by
chromatography on a Florisil.RTM. column, using graded methanol/chloroform
solvent mixtures.
EXAMPLE 10
9-Hydroxy- 1-Methoxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR13##
9-Hydroxy-1-methoxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting
9-hydroxy-1-methoxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran with methyl magnesium bromide
according to the method of Example 7. The crude product is purified by
chromatography on a Florisil.RTM. column, using chloroform as eluant.
Analysis Calcd. for C.sub.25 H.sub.38 O.sub.3 : C, 77.67; H, 9.91; O,
12.42; Found: C, 77.43; H, 10.05; O, 12.21
EXAMPLE 11
1-Allyloxy-9-Hydroxy-3-(3-Methyl-2-Octyl)-6-Oxo-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR14##
1-Allyloxy-9-hydroxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting
1-hydroxy-3-(3-methyl-2-octyl)-6, 9-dioxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran with allyl bromide and reducing the
product with sodium borohydride according to the method of Example 9.
EXAMPLE 12
9-Hydroxy-3-(3-Methyl-2-Octyl)-1-(2-Propynyloxy)-6-Oxo-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR15##
9-Hydroxy-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting
1-hydroxy-3-(3-methyl-2-octyl)-6, 9-dioxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran with 2-propynyl bromide and
reducing the product with sodium borohydride according to the method of
Example 9.
EXAMPLE 13
1-Allyloxy-9-Hydroxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR16##
1-Allyloxy-9-hydroxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting
1-allyloxy-9-hydroxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran with methyl magnesium bromide
according to the method of Example 10.
EXAMPLE 14
9-Hydroxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-1-(2-Propynyloxy)-7, 8, 9,
10-Tetrahydro-6H-Dibenzo [b] [d] Pyran
##STR17##
9-Hydroxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting
9-hydroxy-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-6-oxo-7, 8, 9,
10-tetrahydro-6H-dibenzo [b] [d] pyran with methyl magnesium bromide
according to the method of Example 10.
The present invention includes within its scope, pharmaceutical
compositions comprising, as an active ingredient, at least one of the
compounds of this invention in association with a pharmaceutically
acceptable carrier or diluent. The compounds of this invention exhibit
both oral and parenteral activity and can be formulated in dosage forms
for oral, parenteral or rectal administration.
Solid dosage forms for oral administration include capsules, tablets,
pills, powders and granules. In such solid dosage forms, the active
compound is admixed with at least one inert diluent such as sucrose,
lactose or starch. Such dosage forms can also comprise, as is normal
practice, additional substances other than inert diluents, e.g.,
lubricating agents such as magnesium stearate, and sweetening and
flavoring agents. Tablets and pills can additionally be prepared with
enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups and elixirs
containing inert diluents commonly used in the art, such as water. Besides
inert diluents, such compositions can also include adjuvants, such as
wetting agents, emulsifying and suspending agents and sweetening,
flavoring and perfuming agents.
Preparations according to this invention for parenteral administration
include sterile aqueous or non-aqueous solutions, suspensions or
emulsions. Examples of non-aqueous solvents or vehicles are propylene
glycol, polyethylene glycol, vegetable oils, such as olive oil, and
injectable organic esters such as ester oleate. Such dosage forms may also
contain adjuvants such as preserving, wetting, emulsifying and dispersing
agents. They may be sterilized by, for example, filtration through a
bacteria-retaining filter, by incorporating sterilizing agents into the
compositions, by irradiating the compositions, or by heating the
compositions. They can also be manufactured in the form of sterile solid
compositions which can be dissolved in sterile water, or some other
sterile injectable medium immediately before use.
Compositions for rectal administration are suppositories which may contain
in addition to the active substance, excipients such as cocoa butter or a
suppository wax.
The dosage of active ingredient in the compositions of this invention may
be varied; however, it is necessary that the amount of the active
ingredient shall be such that a suitable dosage form is obtained. The
selected dosage depends upon the desired therapeutic effect, on the route
of administration and on the duration of the treatment.
* * * * *
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Description |
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