US2753357A - Lactones of 1, 12-dimethyl-6, 10-dihydroxy-9-oxo-1, 2, 3, 4, 9, 10, 11, 12-octahydrophenanthrene-1-carboxylic acid - Google Patents
Lactones of 1, 12-dimethyl-6, 10-dihydroxy-9-oxo-1, 2, 3, 4, 9, 10, 11, 12-octahydrophenanthrene-1-carboxylic acid Download PDFInfo
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- US2753357A US2753357A US471523A US47152354A US2753357A US 2753357 A US2753357 A US 2753357A US 471523 A US471523 A US 471523A US 47152354 A US47152354 A US 47152354A US 2753357 A US2753357 A US 2753357A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/38—Unsaturated compounds containing keto groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
Definitions
- This invention pertains to a new group of lactones related to 1,12-dimethyl-6,10-dihydroxy-9-oxo-l,2,3,4,9, l0,ll,lZ-octahydrophenanthrene-l-carboxylic acid and lower alkyl ethers thereof. It is specifically concerned with lactones having the structural formula OR CH OR CH3 1120 COOH wherein R is a member of the group consisting of hydrogen and lower alkyl radicals.
- lactones which comprise this invention are also equivalent to the hydroxy carboxylic acids which can be represented by the structural formula OR CH3 HsC O O O H OH wherein R is a member of the group consisting of hydrogen and lower alkyl radicals, and which are related to the lactones by a process of intramolecular dehydration.
- a suitable starting material for preparing the compounds of this invention is an alkyl O-alkylpodocarpate, such as methyl O-methylpodocarpate.
- An oxo group is first introduced into the 9-position by means of a controlled oxidation with chromium trioxide.
- this 9-oxo derivative is brominated in a halogenated hydrocarbon solvent with a selective brominating agent such as N-bromosuccinimide, a bromine atom is introduced into the l0-position.
- an O-alkylpodocarpic acid such as O-methylpodocarpic acid is converted to the 9-0Xo derivative with chromium trioxide, and the resulting 1,lZ-dimethyl-6-methoxy-9-oxo-1,2,3,4,9,10,1 1, l2-octahydrophenanthrene-l-carboxylic acid is treated with N-bromosuccinimide. While an intermediate 10- bromo derivative is believed to exist in this reaction mixture, elimination of the bromine atom as hydrogen bromide and ring closure occur spontaneously, with the result that the lactone can be isolated directly from the mixture.
- the compounds which constitute this invention have valuable hormonal and anti-inflammatory properties. Specifically, they have been found to inhibit the hyperemia that is associated with states of inflammation of the iris.
- the claimed compounds are also useful as intermediates in chemical syntheses.
- Example 1 A solution of 100 parts of methyl O-methylpodocarpate in 1050 parts of hot glacial acetic acid is stirred and cooled to 17 C. and treated at that temperature, by slow addition, with 72 parts of chromium trioxide in 166 parts of acetic acid in the course of 30 minutes. Stirring is continued for another 10 minutes after which the mixture is stored at 5 C. for 3 days and then at room temperature for 2 days. It is then poured with stirring into 1000 parts of ice-cold water and extracted with ether. The ether extract is washed with 10% aqueous sodium hydroxide until the washings are no longer colored and then with water to neutrality.
- the washed ether solution is dried over anhydrous calcium sulfate, filtered and stripped of solvent under vacuum.
- the slightly yellow solid residue is recrystallized twice from aqueous ethanol to yield clusters of beautiful white prisms melting at about 122-124 C.
- a 1% solution in absolute alcohol gives a specific rotation of +124".
- the infrared spectrum exhibits strong bands at 5.82, 6.02, 6.28, 6.39, and 6.76 microns.
- the ultraviolet spectrum shows a peak at 227 millimicrons with a molecular extinction coeflicient of 13,000 and a peak at 276 millimicrons with a molecular extinction coeflicient of 15,800.
- the methyl ester of OCHs OH I
- the purified material melts at 198200.5 C. and exhibits a specific rotation of about +85 Ultraviolet absorption maxima are observed at 231 and 291 millimicrons. Infrared absorption maxima appear at 5.67, 6.93, 6.25, and 6.39 microns.
- This compound is the lactone of 1,12-dimethyl 6 methoxy-9-oxo-l0-hydroxy1,2,3,4,9,10,11,12- octahydrophenanthrene-l-carboxylic acid and it has the following structural formula OCH:
- Example 4 A solution of parts of O-methylpodocarpic acid and 1070 parts of glacial acetic acid is stirred and maintained at 1518 C. while a solution of 65.4 parts of chromium trioxide in a mixture of 32 parts of water and 134 parts of glacial acetic acid is added in the course of 30 minutes. The reaction mixture is stirred at 5l0 C. and then stored at 810 C. for 3 days. After further storage at room temperature for 2 days, 40 parts of ethanol are added slowly with good mixing in order to decompose any unreacted chromium trioxide. The entire reaction mixture is stirred into 3000 parts of warm water and then extracted exhaustively with ether.
- the combined ether extracts are washed with dilute hydrochloric acid until the washings are no longer colored and then with Water to neutrality.
- the solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a light yellow, viscous oil.
- the product is decolorized by boiling a methanolic solution with activated charcoal.
- the 1,12-dimethyl-6-methoxy-9-oxo-l,2,3,4,9, 10,11,1Z-octahydrophenanthrene-l-carboxylic acid crystallizes from aqueous methanol in small, colorless, gleaming prisms which melt at about 183-185 C.
- the infrared spectrum shows well-defined bands at 2.83, 5.90, 5.98, 6.27, and 7.82 microns.
- the ultraviolet absorption spectrum has peaks at 226 and 276 millimicrons with molecular extinction coeificients of 13,600 and 15,700.
- the compound has the structural formula 0 CH: OH:
- Example 5 A slurry prepared from 4.00 parts of 1,12-dimethyl-6- methoxy-9-oxo-1,2,3,4,9,10,1 1, l2-octahydrophenanthrenel-carboxylic acid, 2.52 parts of N-bromosuccinimide and 320 parts of anhydrous carbon tetrachloride is allowed to stand, with occasional stirring, for 30 hours at room temperature. This reaction is promoted by light, and for good results it is advisable to expose the mixture to sunlight for a substantial portion of the reaction time.
- the precipitated material which consists largely of succinimide, is collected on a filter and the desired reaction product is recovered from the filtrate after removal of the solvent by a vacuum distillation.
- the residual material by recrystallization from aqueous methanol, gives the same purified lactone of 1,12-dimethyl-6-methoxy-9-oxo-10- hydroxy 1,2,3,4,9,10,1l,12 octahydrophenanthrene 1 carboxylic acid that is obtained by the procedure of Example 3.
- the residue obtained by evaporation of the crystallization liquors is extracted with dilute sodium hydroxide solution, the fraction which remains undissolved by this treatment yields more of the pure lactone when it is recrystallized from aqueous methanol.
- Example 6 To a solution of 400 parts of methyl podocarpate and 120 parts of sodium hydroxide in 1100 parts of water and 1600 parts of 95% ethanol are added all at once 330 parts of diethyl sulfate. The reactants are quickly mixed and then allowed to stand until a thick white precipitate forms. This precipitate is collected on a filter, washed with dilute ethanol, and recrystallized from methanol to yield methyl O-ethylpodocarpate as thin, colorless needles melting at about 144147.5 C.
- a stirred solution of parts of methyl O-ethylpodocarpate in 1000 parts of hot glacial acetic acid is cooled to 15 C. and treated at that temperature with 68 parts of chromium trioxide in 156 parts of 80% acetic acid in the course of 30 minutes. Stirring is continued for a few more minutes after which the mixture is maintained at 10 C. for 2 days and then at room temperature for 2 days. It is then poured, with stirring, into 1000 parts of ice and water and extracted with ether. This extract is washed with 10% aqueous potassium hydroxide until the washings are colorless and then with water to neutrality. The ether solution is dried over anhydrous calcium sulfate, filtered and concentrated in vacuo.
- Example 7 A mixture of parts of the lactone of 1,12-dimethyl- 6-methoxy-9 oxo hydroxy-1,2,3,4,9,10,11,12-octahydrophenanthrene-l-carboxylic acid, 37 parts of glacial acetic acid and 30 parts of 48% hydrobromic acid is heated under reflux for a period of 1 hour. The reaction mixture is then cooled and poured, with stirring, into about 350 parts of water. The insoluble material is washed by decantation with several portions of fresh water and it is then extracted with mixtures of chloroform and ether. The organic solution is washedwith dilute potassium bicarbonate solution and then with several portions of water. All aqueous washings are discarded.
Description
United States Patent LACTONES 0F 1,12 DIMETHYL 6,10 DIHY- DROXY 9 0X0 1,2,3,4,9,10,11,12 OCTAHY- DROPHENANTHRENE 1 CARBOXYLIC ACID Roy H. Bible, Jr., Morton Grove, Ill., assignor, by mesne assignments, to G. D. Searle & C0., Skokie, 111., a corporation of Delaware Application November 26, 1954, Serial No. 471,523
5 Claims. (Cl. 260343.3)
N 0 Drawing.
This invention pertains to a new group of lactones related to 1,12-dimethyl-6,10-dihydroxy-9-oxo-l,2,3,4,9, l0,ll,lZ-octahydrophenanthrene-l-carboxylic acid and lower alkyl ethers thereof. It is specifically concerned with lactones having the structural formula OR CH OR CH3 1120 COOH wherein R is a member of the group consisting of hydrogen and lower alkyl radicals.
For some purposes the lactones which comprise this invention are also equivalent to the hydroxy carboxylic acids which can be represented by the structural formula OR CH3 HsC O O O H OH wherein R is a member of the group consisting of hydrogen and lower alkyl radicals, and which are related to the lactones by a process of intramolecular dehydration.
Although for certain applications, such as reactions involving transesterifications, the latter two structural species may play an important role, I have found that ice the lactonic forms of these compounds are more stable under normal condtions and I have developed methods for preparing these lactones in good yield and in high states of purity.
A suitable starting material for preparing the compounds of this invention is an alkyl O-alkylpodocarpate, such as methyl O-methylpodocarpate. An oxo group is first introduced into the 9-position by means of a controlled oxidation with chromium trioxide. When this 9-oxo derivative is brominated in a halogenated hydrocarbon solvent with a selective brominating agent such as N-bromosuccinimide, a bromine atom is introduced into the l0-position. When the resulting methyl ester of 1,12-dimethyl 6 methoxy-9-oxo-l0-bromo-l,2,3,4,9,10, l1,1.2-octahydrophenanthrene-l-carboxylic acid is heated with a nitrogenous base such as 2,4,6-trimethylpyridine, ring closure occurs with the loss of the elements of methyl bromine and the formation of the desired lactone.
In an alternative method for the preparation of the lactones which comprise this invention, an O-alkylpodocarpic acid such as O-methylpodocarpic acid is converted to the 9-0Xo derivative with chromium trioxide, and the resulting 1,lZ-dimethyl-6-methoxy-9-oxo-1,2,3,4,9,10,1 1, l2-octahydrophenanthrene-l-carboxylic acid is treated with N-bromosuccinimide. While an intermediate 10- bromo derivative is believed to exist in this reaction mixture, elimination of the bromine atom as hydrogen bromide and ring closure occur spontaneously, with the result that the lactone can be isolated directly from the mixture.
In preparing the lactone of this invention wherein R is hydrogen, that is, the lactone of 1,12-dimethyl-6,l0- dihydroxy 9 oxo 1,2,3,4,9,l0,11,12-octahydrophenanthrene-l-carboxylic acid, it is preferred to dealkylate a corresponding 6-alkoxy derivative by such means as heating it with a mixture of glacial acetic acid and hydrobromic acid.
The compounds which constitute this invention have valuable hormonal and anti-inflammatory properties. Specifically, they have been found to inhibit the hyperemia that is associated with states of inflammation of the iris. The claimed compounds are also useful as intermediates in chemical syntheses.
My invention will appear in greater detail from the following examples. However, it is not to be construed as limited thereby in spirit or in scope. In these examples temperatures are given in degrees centigrade and quantities of materials are given in parts by Weight.
Example 1 A solution of 100 parts of methyl O-methylpodocarpate in 1050 parts of hot glacial acetic acid is stirred and cooled to 17 C. and treated at that temperature, by slow addition, with 72 parts of chromium trioxide in 166 parts of acetic acid in the course of 30 minutes. Stirring is continued for another 10 minutes after which the mixture is stored at 5 C. for 3 days and then at room temperature for 2 days. It is then poured with stirring into 1000 parts of ice-cold water and extracted with ether. The ether extract is washed with 10% aqueous sodium hydroxide until the washings are no longer colored and then with water to neutrality. The washed ether solution is dried over anhydrous calcium sulfate, filtered and stripped of solvent under vacuum. The slightly yellow solid residue is recrystallized twice from aqueous ethanol to yield clusters of beautiful white prisms melting at about 122-124 C. A 1% solution in absolute alcohol gives a specific rotation of +124". The infrared spectrum exhibits strong bands at 5.82, 6.02, 6.28, 6.39, and 6.76 microns. The ultraviolet spectrum shows a peak at 227 millimicrons with a molecular extinction coeflicient of 13,000 and a peak at 276 millimicrons with a molecular extinction coeflicient of 15,800. The methyl ester of OCHs OH: I
HBO/\C 0 0113 Example 2 A mixture of 4.9 parts of the methyl ester of 1,12-dimethyl 6 methoxy-9-oxo-1,2,3,4,9,10,11,12-octahydrophenanthrene-1-carboxylic acid and 2.8 parts of N-bromosuccinimide in 80 parts of anhydrous carbon tetrachloride is allowed to stand, with occasional stirring, at room temperature for 30 hours. This reaction is promoted by light, and for good results it is advisable to expose the mixture tosunlight for a substantial portion of the reaction time. At the end of this period of time the succinirnide formed in the reaction is removed by filtration; it amounts to about 1.3 parts. The solvent is removed from the filtrate by a vacuum distillation, leaving a residual yellow oil which gradually crystallizes. This brominated derivative is purified by recrystallization from aqueous methanol. In this manner it is obtained as well-formed needles which, after thorough drying, melt at about 142-1445 C. This methyl ester of 1,l2-dimethyl-6-meth0xy-9-0X0-l0- bromo-1,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid has the structural formula OOH:
CH3 l A mixture of 3.0 parts of the methyl ester of 1,12- dimethyl 6 methoxy-9-oxo-l0- romo-1,2,3,4,9,10,l1,l2- octahydrophenanthrene-l-carboxylic acid, and 23 parts of 2,4,6-trimethylpyridine is heated under reflux for a period of 2 hours. The mixture is then poured, with stirring, into 200 parts of water, and the resulting suspension is acidified with dilute hydrochloric acid. The almost colorless precipitate which remains is collected on a filter. For purification, it is recrystallized from a mixture of benzene and petroleum ether. Another good method of purification is by sublimation in a vacuum. The purified material melts at 198200.5 C. and exhibits a specific rotation of about +85 Ultraviolet absorption maxima are observed at 231 and 291 millimicrons. Infrared absorption maxima appear at 5.67, 6.93, 6.25, and 6.39 microns. This compound is the lactone of 1,12-dimethyl 6 methoxy-9-oxo-l0-hydroxy1,2,3,4,9,10,11,12- octahydrophenanthrene-l-carboxylic acid and it has the following structural formula OCH:
Example 4 A solution of parts of O-methylpodocarpic acid and 1070 parts of glacial acetic acid is stirred and maintained at 1518 C. while a solution of 65.4 parts of chromium trioxide in a mixture of 32 parts of water and 134 parts of glacial acetic acid is added in the course of 30 minutes. The reaction mixture is stirred at 5l0 C. and then stored at 810 C. for 3 days. After further storage at room temperature for 2 days, 40 parts of ethanol are added slowly with good mixing in order to decompose any unreacted chromium trioxide. The entire reaction mixture is stirred into 3000 parts of warm water and then extracted exhaustively with ether. The combined ether extracts are washed with dilute hydrochloric acid until the washings are no longer colored and then with Water to neutrality. The solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a light yellow, viscous oil. The product is decolorized by boiling a methanolic solution with activated charcoal. The 1,12-dimethyl-6-methoxy-9-oxo-l,2,3,4,9, 10,11,1Z-octahydrophenanthrene-l-carboxylic acid crystallizes from aqueous methanol in small, colorless, gleaming prisms which melt at about 183-185 C. The infrared spectrum shows well-defined bands at 2.83, 5.90, 5.98, 6.27, and 7.82 microns. The ultraviolet absorption spectrum has peaks at 226 and 276 millimicrons with molecular extinction coeificients of 13,600 and 15,700.
respectively. The compound has the structural formula 0 CH: OH:
HaC C O OH Example 5 A slurry prepared from 4.00 parts of 1,12-dimethyl-6- methoxy-9-oxo-1,2,3,4,9,10,1 1, l2-octahydrophenanthrenel-carboxylic acid, 2.52 parts of N-bromosuccinimide and 320 parts of anhydrous carbon tetrachloride is allowed to stand, with occasional stirring, for 30 hours at room temperature. This reaction is promoted by light, and for good results it is advisable to expose the mixture to sunlight for a substantial portion of the reaction time. The precipitated material, which consists largely of succinimide, is collected on a filter and the desired reaction product is recovered from the filtrate after removal of the solvent by a vacuum distillation. The residual material, by recrystallization from aqueous methanol, gives the same purified lactone of 1,12-dimethyl-6-methoxy-9-oxo-10- hydroxy 1,2,3,4,9,10,1l,12 octahydrophenanthrene 1 carboxylic acid that is obtained by the procedure of Example 3. When the residue obtained by evaporation of the crystallization liquors is extracted with dilute sodium hydroxide solution, the fraction which remains undissolved by this treatment yields more of the pure lactone when it is recrystallized from aqueous methanol.
Example 6 To a solution of 400 parts of methyl podocarpate and 120 parts of sodium hydroxide in 1100 parts of water and 1600 parts of 95% ethanol are added all at once 330 parts of diethyl sulfate. The reactants are quickly mixed and then allowed to stand until a thick white precipitate forms. This precipitate is collected on a filter, washed with dilute ethanol, and recrystallized from methanol to yield methyl O-ethylpodocarpate as thin, colorless needles melting at about 144147.5 C.
A stirred solution of parts of methyl O-ethylpodocarpate in 1000 parts of hot glacial acetic acid is cooled to 15 C. and treated at that temperature with 68 parts of chromium trioxide in 156 parts of 80% acetic acid in the course of 30 minutes. Stirring is continued for a few more minutes after which the mixture is maintained at 10 C. for 2 days and then at room temperature for 2 days. It is then poured, with stirring, into 1000 parts of ice and water and extracted with ether. This extract is washed with 10% aqueous potassium hydroxide until the washings are colorless and then with water to neutrality. The ether solution is dried over anhydrous calcium sulfate, filtered and concentrated in vacuo. When the residual methyl ester of 1,12-dimethy1-6- ethoxy-9-oxo-l,2,3,4,9,l0,11,12 octahydrophenanthrenel-carboxylic acid is treated with N-bromosuccinimide by the procedure of Example 2, and the resultant methyl ester of 1,1Z-dimethyl-6-ethoxy-9-oxo-10-bromo-1,2,3,4, 9,l0,1l,12-octahydrophenanthrene-l-carboxylic acid is treated with boiling 2,4,6-trimethylpyridine by the procedure of Example 3, there is obtained the lactone of 1, lZ-dimethyl-6-ethoxy-9-oxo- 10-hydroxy-1,2,3,4 ,9', 10, 1 1, 1Z-octahydrophenanthrene-l-carboxylic acid. This compound has the following structural formula Example 7 A mixture of parts of the lactone of 1,12-dimethyl- 6-methoxy-9 oxo hydroxy-1,2,3,4,9,10,11,12-octahydrophenanthrene-l-carboxylic acid, 37 parts of glacial acetic acid and 30 parts of 48% hydrobromic acid is heated under reflux for a period of 1 hour. The reaction mixture is then cooled and poured, with stirring, into about 350 parts of water. The insoluble material is washed by decantation with several portions of fresh water and it is then extracted with mixtures of chloroform and ether. The organic solution is washedwith dilute potassium bicarbonate solution and then with several portions of water. All aqueous washings are discarded. When the organic phase is dried, filtered and evaporated to dryness there is obtained a crystallizate of a lactone of 1,12-dimethyl-6,10-dihydroxy-9-oxo- 1,2,3,4,9,10,11,12-octahydr0phenanthrene 1 carboxylic acid in which the hydroxyl group participating in laetone formation is that occupying the 10-position. This compound has the following structural formula OH CH:
6 I claim:
1. A compound having the structural formula OR CH;
structural formula HaC C- wherein R is a member of the group consisting of hydrogen and lower alkyl radicals, the steps which comprise dissolving a compound having the structural formula 0 R CH1 H O COOR' wherein R and R are each members of the group consisting of hydrogen and lower alkyl radicals, in a halogenated hydrocarbon solvent, mixing the solution thus obtained with N-bromosuccinimide, and allowing it to stand in the presence of light.
References Cited in the file of this patent UNITED STATES PATENTS Ritchie Mar. 8, 1955 Bible et a1. Apr. 5, 1955 OTHER REFERENCES Zeiss: Chem. Reviews, vol. 42, pp. 163-87 (1948). Pschorr: Berichte, 39, pp. 3106-24 (1906).
Claims (1)
1. A COMPOUND HAVING THE STRUCTURAL FORMULA
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US471523A US2753357A (en) | 1954-11-26 | 1954-11-26 | Lactones of 1, 12-dimethyl-6, 10-dihydroxy-9-oxo-1, 2, 3, 4, 9, 10, 11, 12-octahydrophenanthrene-1-carboxylic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US471523A US2753357A (en) | 1954-11-26 | 1954-11-26 | Lactones of 1, 12-dimethyl-6, 10-dihydroxy-9-oxo-1, 2, 3, 4, 9, 10, 11, 12-octahydrophenanthrene-1-carboxylic acid |
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| US2753357A true US2753357A (en) | 1956-07-03 |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997041861A1 (en) * | 1996-05-06 | 1997-11-13 | Eli Lilly And Company | Anti-viral compounds |
| US6060484A (en) * | 1996-05-06 | 2000-05-09 | Eli Lilly And Company | Anti-viral method |
| US6096917A (en) * | 1997-05-02 | 2000-08-01 | Eli Lilly And Company | Anti-viral compounds |
| US6100426A (en) * | 1996-05-06 | 2000-08-08 | Eli Lilly And Company | Anti-viral compounds |
| US6103922A (en) * | 1996-05-06 | 2000-08-15 | Eli Lilly And Company | Anti-viral compounds |
| US6103923A (en) * | 1996-05-06 | 2000-08-15 | Eli Lilly And Company | Anti-viral compounds |
| US6124494A (en) * | 1996-05-06 | 2000-09-26 | Eli Lilly And Company | Anti-viral compounds |
| US6127422A (en) * | 1996-05-06 | 2000-10-03 | Eli Lilly And Company | Anti-viral method |
| US6156924A (en) * | 1996-05-06 | 2000-12-05 | Eli Lilly And Company | Anti-viral compounds |
| US6175034B1 (en) | 2000-04-10 | 2001-01-16 | Eli Lilly And Company | Anti-viral compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US2703809A (en) * | 1953-07-31 | 1955-03-08 | Hercules Powder Co Ltd | 7-acetyl-1, 2, 3, 4, 4alpha, 9, 10, 10alpha-octahydro-1, 4alpha-dimethyl-9-oxo-1-phenhrenecarboxylic acid and esters thereof |
| US2705725A (en) * | 1953-09-14 | 1955-04-05 | Searle & Co | 1-hydroxymethyl-1, 12 dimethyl-6-hydroxy 1, 2, 3, 4, 9, 10, 11, 12-octahydro-9-phenanthrone and derivatives thereof |
-
1954
- 1954-11-26 US US471523A patent/US2753357A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2703809A (en) * | 1953-07-31 | 1955-03-08 | Hercules Powder Co Ltd | 7-acetyl-1, 2, 3, 4, 4alpha, 9, 10, 10alpha-octahydro-1, 4alpha-dimethyl-9-oxo-1-phenhrenecarboxylic acid and esters thereof |
| US2705725A (en) * | 1953-09-14 | 1955-04-05 | Searle & Co | 1-hydroxymethyl-1, 12 dimethyl-6-hydroxy 1, 2, 3, 4, 9, 10, 11, 12-octahydro-9-phenanthrone and derivatives thereof |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997041861A1 (en) * | 1996-05-06 | 1997-11-13 | Eli Lilly And Company | Anti-viral compounds |
| US6060484A (en) * | 1996-05-06 | 2000-05-09 | Eli Lilly And Company | Anti-viral method |
| US6100426A (en) * | 1996-05-06 | 2000-08-08 | Eli Lilly And Company | Anti-viral compounds |
| US6103922A (en) * | 1996-05-06 | 2000-08-15 | Eli Lilly And Company | Anti-viral compounds |
| US6103923A (en) * | 1996-05-06 | 2000-08-15 | Eli Lilly And Company | Anti-viral compounds |
| US6124494A (en) * | 1996-05-06 | 2000-09-26 | Eli Lilly And Company | Anti-viral compounds |
| US6127422A (en) * | 1996-05-06 | 2000-10-03 | Eli Lilly And Company | Anti-viral method |
| US6156924A (en) * | 1996-05-06 | 2000-12-05 | Eli Lilly And Company | Anti-viral compounds |
| US6180815B1 (en) * | 1996-05-06 | 2001-01-30 | Eli Lilly And Company | Anti-viral compounds |
| US6180816B1 (en) | 1996-05-06 | 2001-01-30 | Eli Lilly And Company | Anti-viral compounds |
| US6096917A (en) * | 1997-05-02 | 2000-08-01 | Eli Lilly And Company | Anti-viral compounds |
| US6175034B1 (en) | 2000-04-10 | 2001-01-16 | Eli Lilly And Company | Anti-viral compounds |
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