US 4,132,847 AGrant
4-Pyrone Prostaglandin Antagonists
Issue Date:1979-01-02
•12 Claims
Abstract
Novel 2,3,6-substituted-4-pyrones having activity as prostaglandin antagonists are disclosed, together with intermediates useful for the preparation thereof. Methods of using the compounds of this invention as prostaglandin antagonists are described.
Metadata
Assignee
- Pfizer Inc.
Inventors
- Donald E. Kuhla
- Jacob J. Plattner
Application Information
Application Number:US 8180431
Filing Date:1977-07-22
Priority Date:1977-07-22
Art Unit:126
Classifications
IPC:
C07D30922A61K 3135
Field of Search:
260542345.7 R;345.8 R;345.7 P;345.8 P441
Patent Drawings
This patent does not have any drawings.
Description
BACKGROUND OF THE INVENTION
This invention relates to 2,3,6-substituted-4-pyrone derivatives having prostaglandin antagonist activity and to intermediates useful in the preparation of such 4-pyrones. Methods of using these compounds are also disclosed.
Prostaglandin antagonists are those compounds which selectively inhibit the action of prostaglandins at their site of action. Relatively few compounds are known which have utility in this respect, those that are known mainly belonging to three chemically unrelated classes, dibenzoxepine derivatives, polyphloretin phosphates and 7-oxaprostaglandins. These and other known prostaglandin antagonists are reviewed by Sanner, Arch. Intern. Med. 133, 133 (1974) and by Bennett, Advances in Drug Research, 8, 83 (1974).
Prostaglandins have been associated with a number of diseases or undesirable conditions. For example, an increased physiological availability of prostaglandins may be associated with pain, inflammation, diarrhea, habitual labor, hypertension, glaucoma, sickle-cell anemia and other such conditions. Prostaglandin antagonists offer a method of treating and alleviating such undesirable conditions by inhibiting the action of the responsible prostaglandin at the site of action.
SUMMARY OF THE INVENTION
The present invention relates to novel prostaglandin antagonists which are 2,3,6-substituted-4-pyrones of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 6 carbon atoms;
R is selected from hydrogen, methyl, ethyl, n-propyl and 1-hydroxyalkyl, wherein said alkyl is methyl, ethyl and n-propyl;
Y is selected from methyl, phenyl and monosubstituted phenyl, wherein said substituent is methyl, methoxy, chloro or fluoro; and
N is an integer from 1 to 4; and
The pharmaceutically acceptable salts of said compounds wherein R.sub.1 is hydrogen.
Preferably, the group R is selected from hydrogen, methyl and hydroxymethyl and preferably the group Y is selected from methyl and phenyl. Especially preferred are compounds where R is hydrogen, including the compound wherein R.sub.1 is ethyl, n is 4 and Y is methyl and the compound wherein R.sub.1 is ethyl, n is 2 and Y is phenyl. Of the preferred compounds where R is methyl, especially preferred is the compound wherein R.sub.1 is ethyl, n is 4 and Y is methyl. Of the preferred compounds where R is hydroxymethyl, especially preferred is the compound wherein R.sub.1 is methyl, n is 4 and Y is methyl.
Intermediates useful for the preparation of the 4-pyrone derivatives of the present invention are those having the formula ##STR2## wherein R.sub.1 is hydrogen or alkyl of 1 to 6 carbon atoms; and R.sub.2 is selected from hydrogen, methyl, ethyl, n-propyl and ##STR3## wherein R.sub.3 is selected from hydrogen, methyl and ethyl and R.sub.4 is selected from alkyl of 1 to 4 carbon atoms or phenyl.
Preferred intermediates of this formula are those useful for preparing the preferred 2,3,6-substituted-4-pyrones of formula I described above herein, for example, those intermediates where R.sub.2 is hydrogen, methyl or ##STR4## where R.sub.4 is alkyl of 1 to 4 carbon atoms.
Further intermediates useful for the preparation of the 4-pyrone derivatives of the present invention are those having the formula ##STR5## wherein R.sub.1 is hydrogen, alkyl of 1 to 6 carbon atoms; and R.sub.2 is selected from hydrogen, methyl, ethyl, n-propyl and ##STR6## wherein R.sub.3 is selected from hydrogen, methyl and ethyl and R.sub.4 is selected from alkyl of 1 to 4 carbon atoms or phenyl;
Y is selected from methyl, phenyl and monosubstituted phenyl wherein said substituent is methyl, methoxy, chloro or fluoro; and
n is an integer from 1 to 4.
Preferred intermediates are those useful for preparing the preferred 2,3,6-substituted-4-pyrones of formula I described above herein, for example, those intermediates where R.sub.2 is hydrogen, methyl or ##STR7## wherein R.sub.4 is alkyl of 1 to 4 carbon atoms.
Also disclosed is a method of treating an undesired condition resulting from an abnormally increased physiological availability of prostaglandins of the PGE.sub.2 series in an animal, which comprises administering to said animal a compound of formula I in an amount effective to alleviate said undesired condition.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of formula I wherein R is hydrogen, methyl, ethyl or n-propyl may be conveniently prepared by the reaction sequence shown in Scheme A.
The reactions described above are also used to form the compounds of the present invention where the group R is 1-hydroxyalkyl, wherein alkyl is methyl, ethyl and n-propyl, from the appropriate 2-hydroxymethyl-3-hydroxy-6-(1-hydroxyalkyl)-4-pyrones, which are described in U.S. Pat. No. 3,468,915. However, before following the above described reaction sequence it is necessary to protect the 1-hydroxy group of the 6-substitutent of the pyrone ring. The reaction sequence for the formation of compounds of formula I wherein R is 1-hydroxyalkyl is represented in Scheme B.
This may be effected by hydrolysis in the presence of a base, such as an alkali metal hydroxide, alkoxide or carbonate, the sodium and potassium compounds generally being preferred. The reaction may be conducted in a hydroxylic solvent such as alkyl alcohol having 1 to 4 carbon atoms or in alcohol-water mixtures at temperatures between about 0.degree. C. and 50.degree. C.
The compounds of formula I wherein R.sub.1 is alkyl of 1 to 6 carbon atoms may, if desired, be prepared from the corresponding compounds wherein R.sub.1 is hydrogen by any means known in the art for conversion of an acid to an ester. Thus, for example, a compound of formula I wherein R.sub.1 is hydrogen may be reacted with an appropriate diazoalkane, or with the appropriate alkyl alcohol in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, sulfonic ion-exchange resins and the like.
Also included in this invention are the pharmaceutically-acceptable salts of those compounds of formula I wherein R.sub.1 is hydrogen. The salts are prepared by reaction of these acids with the appropriate inorganic or organic base. The salts possess the same prostaglandin antagonist activity as the parent acids when administered to an animal. Suitable pharmaceutically-acceptable cations are those derived from the alkali metals, for example, sodium, lithium and potassium, and from the alkaline earth metals, such as magnesium and calcium. Other pharmaceutically-acceptable metal ions may, however, be employed. Suitable salts also include those containing ammonium, quaternary ammonium or amine cations. Examples of suitable pharmaceutically-acceptable quatenary ammonium cations include tetramethylammonium, tetraethylammonium and the like. Examples of pharmaceutically-acceptable amine cations include those derived from primary, secondary or tertiary amines, such as methyl amine, dimethyl amine, trimethyl amine, ethyl amine and dibutyl amine. Many other suitable pharmaceutically-acceptable cations will be well known to those skilled in the art and the specific examples described above are not intended to limit the invention in any way.
The compounds of formula I are useful pharmacological and therapeutic agents. Specifically, they may be used to antagonize the action of prostaglandins of the PGE.sub.2 type and consequently may be used to treat or alleviate undesirable conditions or diseases associated with an abnormal physiological excess of such prostaglandins in an animal. Such conditions include habitual abortion, diarrhea, bone resorption, sickle-cell anemia, glaucoma, fever, inflammation and pain, see Sanner, Arch. Int. Med. 133, 133 (1974). The novel compounds of this invention can be used in a variety of pharmaceutical preparations which contain the compound or pharmaceutically-acceptable salts thereof, and may be administered by a variety of routes, including orally, parenterally and topically. They may also be administered in slow release, long acting formulations.
The dosage required will vary according to the method of administration and with the species of animals to be treated and the particular result desired. The physician will, in any event, determine the particular dosage most suitable for the individual patient. When used parenterally, the compounds of formula I in the present invention may be used in sterile solutions in doses of about 0.2 to 20 mg/kg body weight of the subject to be treated. When administered orally, the compounds may be administered in the form of tablets or capsules at doses of about 2 to 200 mg/kg/day.
To prepare any of the above dosage forms, or any of the numerous other forms possible, various inert diluents, excipients or carriers may be employed. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkyline glycols, petroleum jelly, cholesterol and other known carriers for medicaments. If desired, these pharmaceutical compositions may contain auxiliary substances such as preserving agents, wetting agents, binding agents, stabilizing agents, flavoring agents, coating agents or other therapeutic agents such as antibiotics.
The prostaglandin antagonist activity of the 2,3,6-substituted-4-pyrone derivatives of formula I may be demonstrated in pharmacological tests. A suitable test for this purpose is based on the enhancement of cyclic AMP (adenosine-3',5'-monophosphate) levels in tissues due to adenyl cyclase stimulated by the action of prostaglandins of the PGE.sub.2 type. An exemplification of such a test used to determine the antagonist activity of the compounds of the present invention is as follows. A BC 57/BL (Jackson Laboratories) mouse is sacrificed and the thymus gland removed and teased apart to provide thymus cells which are suspended in a culture medium. The degradation of c-AMP is blocked by addition of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Hoffman-LaRoche, Ro 20-1724), a c-AMP phosphodiesterase inhibitor. A measured dose of the compound under test is added to the suspension of cells and the suspension is incubated at 37.degree. C. for ten minutes. A measured dose of PGE.sub.2 is added to the suspension, which is then incubated for a further period of 30 minutes. The cells are then centrifuged, washed and the c-AMP extracted with ethanol. The ethanol extract is evaporated to dryness, redissolved in buffer solution and the c-AMP level determined by a radioimmunoassay, see Zimmerman et al, Anal. Biochem. 71, 79 (1976) and Steiner et al, J. Biol. Chem. 247, 1106 (1972). Comparison of the enhancement of c-AMP levels produced by PGE.sub.2 alone and by PGE.sub.2 together with the compound under test allow determination of the antagonist activity.
An example of the results from this test are those obtained with 2-(3-hydroxy-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone. The initial c-AMP level of the cell culture was measured as 1.9 .+-. 0.7 picomole c-AMP/10.sup.7 cells. Incubation with 10.sup.-5 M PGE.sub.2 alone enhanced the level to 88 .+-. 7 picomole c-AMP/10.sup.7 cells. By comparison, when the cells were incubated for ten minutes with 7 .times. 10.sup.-5 M of the test compound the c-AMP level was measured at 2 .+-. 0.1 picomole c-AMP/10.sup.7 cells. Following incubation for 30 minutes with 10.sup.-5 M PGE.sub.2 the level was measured as 51 .+-. 5 picomole c-AMP/10.sup.7 cells. Similarly, in a second experiment, after ten minutes incubation with 7 .times. 10.sup.-6 M of the test compound, the c-AMP level was measured at 1.4 .+-. 0.2 picomoles c-AMP/10.sup.7 cells; after 30 minutes incubation with 10.sup.-5 M PGE.sub.2 the c-AMP level was measured as 69 .+-. 8 picomoles c-AMP/10.sup.7 cells. Under the same test conditions 5 .times. 10.sup.-5 M of the known dibenzoxazepine derivative SC-19220 (Sanner, Arch. Int. Pharmacodyn. Ther., 180, 46 (1969)) caused a 30% inhibition of c-AMP accumulation and the Fried compound, 7-oxa-13-prostynoic acid (Fried et al, Ann. New York Acad. Sci., 180, 38 (1971)) at a concentration of 10.sup.-4 M caused a 45% inhibition of the accumulation of c-AMP by PGE.sub.2. Both of these compounds are well known in the art as prostaglandin antagonists.
The present invention is further illustrated by the following examples. It should be noted, however, that the invention is not limited to the specific details of these examples. Unless otherwise noted, all temperatures in the following examples are in .degree. C.
EXAMPLE 1
Preparation of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution of 2.75 g (0.042 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 5.93 g (0.042 mole) of 2-hydroxymethyl-3-hydroxy-4-pyrone, and the resulting mixture heated to 50.degree.. A 12.4 g (0.046 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atomsphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO.sub.3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 6.34 g (54%) of oily product, 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone: NMR (CDCl.sub.3): .delta.1.22 (3H, t, J = 7Hz), 2.30 (2H, t, J = 5.5 Hz), 4.63 (2H, s), 6.35 (1H, d, J = 6 Hz), 7.73 (1H, d, J = 6 Hz).
EXAMPLE 2
Preparation of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution of 6.35 g (0.022 mole) of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone in 250 ml of acetone was added 12 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil. The oil was triturated with hexane/ether to give the crystalline aldehyde, 2-formyl-3-(5-carboethoxypentyloxy)-4- pyrone, weighing 4.1 g (65%), m.p. 32-34.5.degree..
Analytical: Calcd. for C.sub.14 H.sub.18 O.sub.6 : C, 59.56; H, 6.42. Found: C, 59.16; H, 6.37.
EXAMPLE 3
Preparation of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution, under nitrogen, of 0.224 g (4.7 mmole) of sodium hydride (50% dispersion in mineral oil) in 15 ml of dry THF was added dropwise 1.32 g (5.95 mmole) of dimethyl (2-oxoheptyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.2 g (4.25 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to a pH of about 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 1.16 g (73%) of pure enone, 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone, as an oil. NMR (CDCl.sub.3): .delta. 0.88 (3H, t, J = 5 Hz); 1.22 (3H, t, J = 7 Hz), 2.26 (2H, t, J = 6.5 Hz); 2.60 (2H, t, J = 6.5 Hz); 3.85-4.31 (4H, m).
EXAMPLE 4
Preparation of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution, cooled under nitrogen to -78.degree., of 0.200 g (0.53 mmol) of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 2 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70.degree. to -75.degree., 0.53 ml (0.53 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 0.5 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.131 g (65%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl.sub.3, 100 M Hz): .delta.0.90 (3H, t, J = 4.5 Hz), 2.33 (2 H, t, J = 6 Hz), 4.13 (4H, m), 4.35 (1H, m).
EXAMPLE 5
Preparation of 8-oxo-4,8-dihydro-6-(hydroxymethyl)-2-phenyl-4H-pyrano[3,2-d]-m-dioxin
A solution of 2,6-dihydroxymethyl-3-hydroxy-4-pyrone (34.4 g, 0.2 mole), benzaldehyde diethylacetal (43.2 g, 0.24 mole), and p-toluenesulfonic acid (2.4 g) in 120 ml of dimethylsulfoxide was heated at 95.degree. for 1 hr. Benzene was then added and the mixture was heated until 1.2 l of the benzene/ethanol azetrope was collected by distillation. The cooled mixture was diluted with ethyl acetate and the resulting organic solution was washed successively with aqueous Na.sub.2 CO.sub.3 and brine. After drying over magnesium sulfate the solvent was removed to give 28 g of crude product. Recrystallization from CH.sub.2 Cl.sub.2 /hexane afforded 23 g of pure 8-oxo-4,8-dihydro-6-(hydroxymethyl)-2-phenyl-4H-pyrano[3,2-d]-m-dioxin, m.p. 171.degree.-172.degree..
Analytical: Calcd. for C.sub.14 H.sub.12 O.sub.5 : C, 64.61; H, 4.65 Found: C, 64.45; H, 4.74.
EXAMPLE 6
Preparation of 8-oxo-4,8-dihydro-6-(trimethylacetoxymethyl)-2-phenyl-4H-pyrano[3,2-d]-m-d ioxin
To a solution of 28 g (0.11 mole) of 8-oxo-4,8-dihydro-6-(hydroxymethyl)-2-phenyl-4H-pyrano[3,2-d]-m-dioxin in 125 ml of methylene chloride and 13 ml of pyridine was added 16 ml (0.13 mole) of trimethylacetyl chloride, and the mixture was stirred at 40.degree. overnight. The mixture was then diluted with additional methylene chloride and the organic solution washed successively with 1N HCl, aqueous NaHCO.sub.3 and aqueous NaCl. The dried solution was evaporated under reduced pressure to give a dark oil. Chromatography on silica gel eluting with ethyl acetate furnished the purified product, 8-oxo-4,8-dihydro-6-(trimethylacetoxymethyl)-2-phenyl-4H-pyrano[3,2-d]-m-d ioxin, as an oil. Trituration with hexane gave 24.5 g (66%) of crystalline product, m.p. 110.degree.-112.degree..
Analytical: Calcd. for C.sub.19 H.sub.20 O.sub.6 : C, 66.26, H, 5.85. Found: C, 65.77, H, 5.92.
EXAMPLE 7
Preparation of 2-hydroxymethyl-3-hydroxy-6-(trimethylacetoxymethyl)-4-pyrone
A solution of 8-oxo-4,8-dihydro-6-(trimethylacetoxymethyl-2-phenyl-4H-pyrano[3,2-d]-m-di oxin (24.5 g, 0.07 mole) in 250 ml of 65% aqueous acetic acid was heated at 70.degree. for 3 hr. The solvents were removed in vacuo to a residue which was triturated with hexane to give 16.2 g of solid. Recrystallization from benzene furnished 14 g (78%) of pure product, 2-hydroxymethyl-3-hydroxy-6-(trimethylacetoxymethyl)-4-pyrone, m.p. 124.degree.-125.degree..
Analytical: Calcd. for C.sub.12 H.sub.16 O.sub.6 : C, 56.24; H, 6.29 Found: C, 56.22; H, 6.33.
EXAMPLE 8
Preparation of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-py rone
To a solution of 1.84 g (0.028 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 6.76 g (0.026 mole) of 2-hydroxymethyl-3-hydroxy-6-(trimethylacetoxymethyl)-4-pyrone, and the resulting mixture heated to 50.degree.. An 8.3 g (0.03 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO.sub.3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 2.9 g (27%) of oily product, 2-hydroxy-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone. NMR (CDCl.sub.3): .delta.1.22 (3H, t, J = 7 Hz), 1.23 (9H, s), 2.30 (2H, t, J = 5.5 Hz), 6.32 (1H, s).
EXAMPLE 9
Preparation of 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone
To a solution of 2.3 g of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-py rone in 75 ml of acetone was added 4 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil. The oil was chromatographed on silica gel to give the oily aldehyde, 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone weighing 1.6 g (70%). NMR (CDCl.sub.3): .delta.1.28 (3H, t, J = 7 Hz), 1.30 (9H, s), 2.31 (2H, t, J = 5.5 Hz), 4.17 (2H, q, J = 7 Hz), 4.48 (2H, t, J = 7Hz).
EXAMPLE 10
Preparation of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxyme thyl)-4-pyrone
To a solution, under nitrogen, of 0.206 g (4.3 mmole) of sodium hydride (50% dispersion in mineral oil) in 15 ml of dry THF was added dropwise 1.04 g (4.69 mmole) of dimethyl (2-oxoheptyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.55 g (3.9 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography of silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.425 g (22%) of pure 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-trimethylacetoxymet hyl)-4-pyrone as an oil. NMR (CDCl.sub.3): .delta.0.88 (3H, t, J = 5 Hz); 1.25 (9H, s), 2.27 (2H, t, J = 6.5 Hz); 2.60 (2H, t, J = 6.5 Hz); 4.91 (2H, s).
EXAMPLE 11
Preparation of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypentyloxy)-6-(trimethy lacetoxymethyl)-4 -pyrone
To a solution, cooled under nitrogen to -78.degree., of 0.715 g (1.45 mmol) of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxyme thyl)-4-pyrone in 10 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70.degree. to -75.degree., 1.7 ml (1.7 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 5 drops of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.290 g (40%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypentyloxy)-6-(trimethy lacetoxymethyl)-4-pyrone. NMR (CDCl.sub.3): .delta.0.90 (3H, t, J = 4.5 Hz), 2.31 (2H, t, J = 6 Hz), 4.88 (2H, s).
EXAMPLE 12
Preparation of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carbomethoxypentyloxy)-6-hydroxym ethyl-4-pyrone
To a solution of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-5-(carboethoxypentyloxy)-6-(trimethyla cetoxymethyl)-4-pyrone (290 mg, 0.6 mmole) in 5 ml of dry methanol was added 167 mg (1.2 mmole) of anhydrous potassium carbonate, and the suspension stirred for 30 min at room temperature. Excess methylene chloride was added, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate to give 133 mg (55%) of oily product, 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carbomethoxypentyloxy)-6 -hydroxymethyl-4-pyrone. NMR (CDCl.sub.3, 100 M Hz) .delta.0.88 (3H, t, J = 4.5 Hz), 2.33 (2H, t, J = 6 Hz), 3.68 (3H, s), 4.46 (2H, s).
EXAMPLE 13
Preparation of 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution, under nitrogen, of 0.187 g (3.9 mmole) of sodium hydride (50% dispersion in mineral oil) in 10 ml of dry THF was added dropwise 1.2 g (4.95 mmole) of dimethyl (2-oxo-4-phenylbutyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.0 g (3.54 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone, prepared by the procedure of Examples 1 and 2, in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.90 g (64%) of pure 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone, m.p. 38.5-40.degree.. NMR (CDCl.sub.3): .delta.1.26 (3H, t, J = 7 Hz); 2.35 (2H, t, J = 6.5 Hz).
Analytical: Calcd. for C.sub.24 H.sub.28 O.sub.6 : C, 69.90; H, 6.84 Found: C, 69.90; H, 6.78
EXAMPLE 14
Preparation of 2-[(3RS)-3-hydroxy-5-phenyl-trans-1-pentenyl]-3-(5-carboethoxypentyloxy)-4 -pyrone
To a solution, cooled under nitrogen to -78.degree., of 0.823 g (1.99 mmol) of 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 4 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70.degree. to -75.degree., 1.89 ml (1.89 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 2.0 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.233 g (28%) of 2-[(3RS)-3-hydroxy-5-phenyl-trans-1-pentenyl]-3-(5-carboethoxypentyloxy)-4 -pyrone. NMR (CDCl.sub.3, 100 M Hz): .delta.1.26 (3H, t, J = 7.0 Hz), 2.32 (2H, t, J = 6 Hz).
EXAMPLE 15
Preparation of 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution of 2.00 g (0.0304 mole) of potassium hydroxide in 33 ml of ethanol and 5 ml of water was added 4.75 g (0.0304 mole) of 2-hydroxymethyl-3-hydroxy-6-methyl-4-pyrone, and the resulting mixture heated to 50.degree.. A 7.8 g (0.029 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO.sub.3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 5.4 g (60%) of oily product, 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl.sub.3): .delta.1.22 (3H, t, J = 7 Hz), 2.26 (3H, s); 4.61 (2H, m); 6.17 (1H, s).
EXAMPLE 16
Preparation of 2-formyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution of 4.25 g of 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone in 110 ml of acetonitrile was added 12 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil, 2-formyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone, weighing 4.0 g (94%). NMR (CDCl.sub.3): .delta.1.23 (3H, t, J = 7 Hz), 2.36 (3H, s), 6.32 (1H, s).
EXAMPLE 17
Preparation of 2-(3-oxo-trans-1-octenyl)-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone
To a solution, under nitrogen, of 0.561 g (11.6 mmole) of sodium hydride (50% dispersion in mineral oil) in 20 ml of dry THF was added dropwise 3.07 g (13.8 mmole) of dimethyl (2-oxoheptyl)-phosphate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 3.15 g (10.6 mmole) of the aldehyde in 10 ml of THF was added. The mixture was stirred for 15 min then was neutralized to a pH of about 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 3.1 g (75%) of pure 2-(3-oxo-trans-1-octenyl)-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone as an oil. NMR (CDCl.sub.3): .delta.0.88 (3H, t, J = 5 Hz); 1.22 (3H, t, J = 7 Hz), 2.32 (3H, s); 2.70 (2H, t, J = 7.0 Hz).
EXAMPLE 18
Preparation of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-6-methyl-3-(5-carboethoxypentyloxy)-4- pyrone
To a solution, cooled under nitrogen to -78.degree., of 1.8 g (4.6 mmol) of 2-(3-oxo-trans-1-octenyl)-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone in 20 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70.degree. to -75.degree., 30 ml (4.6 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 3.0 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.5 g (26%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-6-methyl-3-(5-carboethoxypentyloxy)-4- pyrone. NMR (CDCl.sub.3, 100 M Hz): .delta.0.90 (3H, t, J = 4.5 Hz), 2.33 (3H, s).
EXAMPLE 19
The aldehydes prepared in Examples 1 and 2, and Examples 5 through 9, and other 6-substituted analogs thereof, may be reacted with other dimethyl ketophosphonates to form products which may be further reacted by the procedures of Example 4 and Examples 11 through 14 to form compounds of formula I having various 2-substituent side chains, as follows:
Claims
What is claimed is:
1. A compound of the formula ##STR18## wherein R.sub.1 is hydrogen or alkyl of 1 to 6 carbon atoms; R is selected from hydrogen, methyl, ethyl, n-propyl and 1-hydroxyalkyl, wherein said alkyl is methyl, ethyl and n-propyl; Y is selected from methyl, phenyl and monosubstituted phenyl, wherein said substituent is methyl, methoxy, chloro or fluoro; and n is an integer from 1 to 4; and the pharmaceutically acceptable salts of said compounds wherein R.sub.1 is hydrogen.
2. A compound of claim 1 wherein R is hydrogen, methyl or hydroxymethyl.
3. A compound of claim 1 wherein Y is methyl or phenyl.
4. A compound of claim 2 wherein R is hydrogen.
5. A compound of claim 4 wherein R.sub.1 is ethyl, n is 4 and Y is methyl.
6. A compound of claim 4 wherein R.sub.1 is ethyl, n is 2 and Y is phenyl.
7. A compound of claim 2 wherein R is methyl.
8. A compound of claim 7 wherein R.sub.1 is ethyl, n is 4 and Y is methyl.
9. A compound of claim 2 wherein R is hydroxymethyl.
10. A compound of claim 9 wherein R.sub.1 is methyl, n is 4 and Y is methyl.
11. A compound of claim 1 wherein Y is methyl.
12. A compound of claim 1 when Y is selected from phenyl and monosubstituted phenyl, wherein said substituent is methyl, methoxy, chloro or fluoro.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3468916 | 1969-09-01 | Tate et al. |
Non-Patent Literature (2)
- Sanner, Arch. Intern. Med., 133, 133 (1974).
- Bennett, Advances in Drug Research, 8, 83, (1974).