US2750380A - 20-pyridyl-5, 16-pregnadien-3, 20-diols and lower alkyl derivatives thereof - Google Patents
20-pyridyl-5, 16-pregnadien-3, 20-diols and lower alkyl derivatives thereof Download PDFInfo
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- US2750380A US2750380A US471119A US47111954A US2750380A US 2750380 A US2750380 A US 2750380A US 471119 A US471119 A US 471119A US 47111954 A US47111954 A US 47111954A US 2750380 A US2750380 A US 2750380A
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- the present invention relates to a new group of pyridyl derivatives of pregnadiendiols and, more particularly, to 20-pyridyl-5,l6-pregnadien-3,20diols and lower alkyl derivatives thereof which can be represented by the general structural formula wherein R and R represent hydrogen or lower alkyl radicals, such as methyl, ethyl, propyl, butyl and the like.
- These compounds can be synthesized by treatment of 3-hydroxy-5,16-pregnadien-20-one or a readily hydrolyzable ester thereof such as a lower alkanoyl or benzoyl ester with an organometallic pyridinesderivative such as pyridyl lithium, pyridyl sodium, methylpyridyl lithium, dimethylpyridyl lithium, ethylpyridyl sodium and the like.
- organometallic pyridinesderivative such as pyridyl lithium, pyridyl sodium, methylpyridyl lithium, dimethylpyridyl lithium, ethylpyridyl sodium and the like.
- the bases described herein form salts which are nontoxic in therapeutic dosage with a variety of inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, .sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic, gluconic, benzoic, cinnamic, and related acids.
- inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, .sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic, gluconic, benzoic, cinnamic, and related acids.
- The-compounds of this invention are valuable intermediates in the synthesis of medicinally active compounds. They are especially valuable as starting materials for the preparation of solanidinoidal alkaloids.
- pregnadienJ-ones of the type ,Conventional treatmentof the 3,2 0-diols of this invention with an equivalent of an alkanoyl or aroyl halide or'an alkanoic acid anhydride yields the 3-monoesters.
- a special utility of the compounds of this invention is their stimulant action on the hypodynamic or failing heart manifested by a restoration of the deficient contractility of the heart muscle and of the deficient cardiac output. This effect is quite different from the jervinelike depressant cardiac action shown by the corresponding 16,17-dihydro derivatives.
- Example 1 A solution of butyl lithium in 70 parts of ether is prepared from 1.87 parts of lithium and 16 parts of 1bromobutane. This solution is cooled to 40 C. and stirred while 17.7 parts of a-bromopyridine are added dropwise in the course of minutes. While stirring is continued a solution of 10 parts of 3,3-acetoxy-5,16-preguadien-20- one in 350 parts of anhydrous ether is added rapidly. The cooling bath is removed and the solution is stirred for 2 hours at room temperature. After standing at room temperature for hours, the solution is treated with 250 parts of water. The ether layer is separated, washed with water to neutrality, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
- the residue is applied in benzene solution to a chromatography column containing 900 parts of silica gel.
- the column with 7000 parts of a 4% and 7000 parts of an 8% solution of ethyl acetate in benzene removes some impurities.
- Further elution with 22,500 parts of an 8% solution of ethyl acetate in benzene causes elution of one of the epimeric isomers of -(a-pyridyl) -5,16- pregnadien-3B,20-diol.
- a second epimer is eluted with 12,000 parts of a 20% solution of ethyl acetate in benzene.
- the ultraviolet absorption spectrum shows a maximum at 256 millimicrons with a molecular extinction coefiicient of 3800,
- the ultraviolet spectrum shows two maxima at 256 and 261.5 millimicrons and a shoulder at 270 millimicrons; the molecular extinction coefiicients are 4170, 4600, and 2790, respectively. Infrared maxima are observed at about 2.94, 5.75, 6.29, 6.97, 8.00, and 9.63 microns.
- Example 4 Substitution of an equal amount of 3-bromopyridine for the 2-bromopyridine used in Example 1 leads to formation of a mixture of two isomers of 20-(fl-pyridyl)- 5,16-pregnadien-3,20-diol epimeric at carbon 20.
- the ultraviolet absorption spectrum shows maxima at 25 7 and 263 millimicrons with molecular extinction coefiicients of about 3900 and 4300, respectively. Infrared maxima are observed at about 2.90, 3.06, 6.30, and 6.98 microns.
- Example 5 A solution of butyl lithium in parts of ether, prepared from 3.74 parts of lithium and 32 parts of l-bromobutane is cooled to 40 C. and then treated by dropwise addition with 35.4 parts of 4-bromopyridine in the course of 10 minutes. Stirring is continued while 20 parts of B-hydroxy-S,16-pregnadien-20-one in 1000 parts of ether are added. The mixture is then stirred at 25 C. for 6 hours, after which 500 parts of water are added. The ether layer is Washed with water to neutrality, filtered and concentrated to dryness. The resulting product is repeatedly recrystallized from acetone to yield 20(y-pyridyl)-5,16-pregnadien-3,20-diol.
- Two isomers epimeric at carbon-20 can be separated by chromatography on silica gel by the method of Example 1.
- the compound shows an ultraviolet maximum at about 251 millimicrons with a molecular extinction coefficient of about 4300. Infrared maxima are observed at 2.94, 3.08, 6.3, and 7.0 microns.
- Example 6 Substitution of 41.6 parts of 2-bromo-4,6-dimethyl pyridine for the 4-bromopyridine used in the preceding example, yields 20-(4',6'-dimethyl-2'-pyridyl)-5,16-pregnadien-3,20-diol.
- the compound shows an ultraviolet plateau at about 260-270 millimicrons with an extinction coefficient of about 4000. It has the structural formula CH3 CH3 5 What is claimed is: 1.
- a compound of the structural formula 6 wherein R and R' are members of the class consisting of hydrogen and lower alkyl radicals.
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Description
United States Patent 20-PYRIDYL-5,16-PREGNADlEN-3,20-DIOLS AND LOWERI ALKYL DERIVATIVES THEREOF Raymond M. Dodson, ParkRidge, and Clarence G. Bergstrom,.Chicago, lll.,, assignors, by mesne assignments, to G. D. Searle & Co., Skokie, 111., a corporation of Delaware No Drawing, Application November 24, 1954, Serial No. 471,119
6 Claims. (Cl. 260-2395) The present invention relates to a new group of pyridyl derivatives of pregnadiendiols and, more particularly, to 20-pyridyl-5,l6-pregnadien-3,20diols and lower alkyl derivatives thereof which can be represented by the general structural formula wherein R and R represent hydrogen or lower alkyl radicals, such as methyl, ethyl, propyl, butyl and the like.
These compounds can be synthesized by treatment of 3-hydroxy-5,16-pregnadien-20-one or a readily hydrolyzable ester thereof such as a lower alkanoyl or benzoyl ester with an organometallic pyridinesderivative such as pyridyl lithium, pyridyl sodium, methylpyridyl lithium, dimethylpyridyl lithium, ethylpyridyl sodium and the like.
The bases described herein form salts which are nontoxic in therapeutic dosage with a variety of inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, .sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic, gluconic, benzoic, cinnamic, and related acids.
The-compounds of this invention are valuable intermediates in the synthesis of medicinally active compounds. They are especially valuable as starting materials for the preparation of solanidinoidal alkaloids. Thus, a compound of the type 2,750,380 atented,- June 12-; .956.
ice
2 by boiling in diluteethanol to yield a dehydrosolanidinoid containing an aromatic ring-F of the formula which can then be hydrogenated using sodium or lithium in ethanol or ammonia to form a compound of the type Esterification of the latter with a lower alkanoyl halide or anhydride. followed by quaternization with methyl sulfate yields a solanidinium type of quaternary salt of the cationic formula which has a veratrine type of action on the heart muscle. The compounds of this invention can also be oxidized by Qpenauer oxidation to form the corresponding 4,16-
pregnadienJ-ones of the type ,Conventional treatmentof the 3,2 0-diols of this invention with an equivalent of an alkanoyl or aroyl halide or'an alkanoic acid anhydride yields the 3-monoesters.
A special utility of the compounds of this invention is their stimulant action on the hypodynamic or failing heart manifested by a restoration of the deficient contractility of the heart muscle and of the deficient cardiac output. This effect is quite different from the jervinelike depressant cardiac action shown by the corresponding 16,17-dihydro derivatives.
The following examples will illustrate in further detail some of the compounds which constitute this invention and methods for their preparation. However, this invention is not to be construed as limited thereby in spirit or in scope, since modifications in materials and operating conditions can be adopted without departing from the invention. In these examples temperatures are indicated in degrees centigrade and quantities of materials in parts by weight.
Example 1 A solution of butyl lithium in 70 parts of ether is prepared from 1.87 parts of lithium and 16 parts of 1bromobutane. This solution is cooled to 40 C. and stirred while 17.7 parts of a-bromopyridine are added dropwise in the course of minutes. While stirring is continued a solution of 10 parts of 3,3-acetoxy-5,16-preguadien-20- one in 350 parts of anhydrous ether is added rapidly. The cooling bath is removed and the solution is stirred for 2 hours at room temperature. After standing at room temperature for hours, the solution is treated with 250 parts of water. The ether layer is separated, washed with water to neutrality, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue is applied in benzene solution to a chromatography column containing 900 parts of silica gel. the column with 7000 parts of a 4% and 7000 parts of an 8% solution of ethyl acetate in benzene removes some impurities. Further elution with 22,500 parts of an 8% solution of ethyl acetate in benzene causes elution of one of the epimeric isomers of -(a-pyridyl) -5,16- pregnadien-3B,20-diol. A second epimer is eluted with 12,000 parts of a 20% solution of ethyl acetate in benzene. Repeated crystallization from acetone of the first epimer produces a pure product melting at about 186 187 C. The optical rotation of an 0.705% chloroform solution is [a] =66. Ultraviolet maxima are observed at 255.5 and 261 millimicrons with molecular extinction coefiicients of 3820 and 4310, respectively. The infrared spectrum shows prominent bands at 2.93, 3.10, 6.30, 7.00, 7.28, 9.38, 10.38, and 13.24 microns.
Repeated crystallization from acetone of the epimer second to be luted yields a product melting at about 180-182 C. The specific rotation of a 1.1% chloroform solution is -31.6. Ultraviolet maxima are observed at 257 and 261 millimicrons with molecular extinction coefficients of 3940 and 4310, respectively. The infrared spectrum shows prominent bands at 2.94, 3.04, 6.29, 6.99, 7.32, 9.43, 9.56, 10.34, and 13.25 microns.
The same reaction can also be carried out with the 3a-epimer of 3-acetoxy-5,l6-pregnadien-20-one. The unacetylated 3-hydroxy-5,l6-pregnadien-20-one can likewise be used.
Example 2 A solution of 95 parts of 20-(a-pyridyl)-5,16-pregnadien-3,B,20-diol, melting at about 186-187 C., is added to a mixture of 1000 parts of pyridine and 1100 parts of acetic anhydride. After standing at room temperature for 12 hours, the mixture is treated with water to cause precipitation of a 3 9-acetoxy-20-(a-pyridyl)-5,16- pregnadien-20-ol which on recrystallization from acetone melts at about 167-168 C. The rotation of an 0.3% chloroform solution is [a] =49.5. The ultraviolet absorption spectrum shows a maximum at 256 millimicrons with a molecular extinction coefiicient of 3800,
Elution of 7 4 v a maximum at 261 millimicrons with a molecular extinction coeflicient of 4300, and a shoulder at about 270 millimicrons with a molecular extinction coeflicient of 2150. The infrared spectrum shows maxima at 2.84, 5.76, 6.31, 6.98, 7.24, 7.34, 7.98, 9.64, 12.75, and 13.17 microns, respectively.
Example 3 A solution of 97 parts of the epimer of 20-(a-pyridyl)- 5,l6-pregnadien-3B,20-diol melting at about 180-182 C. in 1000 parts of pyridine and 1050 parts of acetic anhydride is maintained at room temperature for 12 hours and then treated with Water. The resulting pre cipitate is collected on a filter and crystallized from acetone to yield a 3,8-acetoxy-20-(a-pyridyl)-5,16-pregnadien-20-ol melting at about 174-176 C. The specific rotation of an 0.64% chloroform solution is u =26.6. The ultraviolet spectrum shows two maxima at 256 and 261.5 millimicrons and a shoulder at 270 millimicrons; the molecular extinction coefiicients are 4170, 4600, and 2790, respectively. Infrared maxima are observed at about 2.94, 5.75, 6.29, 6.97, 8.00, and 9.63 microns.
Example 4 Substitution of an equal amount of 3-bromopyridine for the 2-bromopyridine used in Example 1 leads to formation of a mixture of two isomers of 20-(fl-pyridyl)- 5,16-pregnadien-3,20-diol epimeric at carbon 20. The ultraviolet absorption spectrum shows maxima at 25 7 and 263 millimicrons with molecular extinction coefiicients of about 3900 and 4300, respectively. Infrared maxima are observed at about 2.90, 3.06, 6.30, and 6.98 microns.
Example 5 A solution of butyl lithium in parts of ether, prepared from 3.74 parts of lithium and 32 parts of l-bromobutane is cooled to 40 C. and then treated by dropwise addition with 35.4 parts of 4-bromopyridine in the course of 10 minutes. Stirring is continued while 20 parts of B-hydroxy-S,16-pregnadien-20-one in 1000 parts of ether are added. The mixture is then stirred at 25 C. for 6 hours, after which 500 parts of water are added. The ether layer is Washed with water to neutrality, filtered and concentrated to dryness. The resulting product is repeatedly recrystallized from acetone to yield 20(y-pyridyl)-5,16-pregnadien-3,20-diol. Two isomers epimeric at carbon-20 can be separated by chromatography on silica gel by the method of Example 1. The compound shows an ultraviolet maximum at about 251 millimicrons with a molecular extinction coefficient of about 4300. Infrared maxima are observed at 2.94, 3.08, 6.3, and 7.0 microns.
Example 6 Substitution of 41.6 parts of 2-bromo-4,6-dimethyl pyridine for the 4-bromopyridine used in the preceding example, yields 20-(4',6'-dimethyl-2'-pyridyl)-5,16-pregnadien-3,20-diol. The compound shows an ultraviolet plateau at about 260-270 millimicrons with an extinction coefficient of about 4000. It has the structural formula CH3 CH3 5 What is claimed is: 1. A compound of the structural formula 6 wherein R and R' are members of the class consisting of hydrogen and lower alkyl radicals.
2. 20-pyridyl-5,l6-pregnadien-3,20-diol. 3. 20- u-pyridyl -5 1 6-pregnadien-3,20-diol. 5 4. 20-(fi-pyridyl) -5,l6-pregnadien3,20-diol. 5. 20- ('y-pyridyl) -5, 1 6-pregnadien-3,20-diol. 6 20 [(lower alkyl)pyridyl]5,16-pregnadien 3,20-
10 References Cited in the file of this patent I UNITED STATES PATENTS 2,665,274 Conbere Jan. 5, 1954
Claims (1)
1. A COMPOUND OF THE STRUCTURAL FORMULA
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US471119A US2750380A (en) | 1954-11-24 | 1954-11-24 | 20-pyridyl-5, 16-pregnadien-3, 20-diols and lower alkyl derivatives thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| US471119A US2750380A (en) | 1954-11-24 | 1954-11-24 | 20-pyridyl-5, 16-pregnadien-3, 20-diols and lower alkyl derivatives thereof |
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| US471119A Expired - Lifetime US2750380A (en) | 1954-11-24 | 1954-11-24 | 20-pyridyl-5, 16-pregnadien-3, 20-diols and lower alkyl derivatives thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2853487A (en) * | 1956-03-09 | 1958-09-23 | Hoffmann La Roche | 17-(2-piperidylmethyl)-androstanediols |
| US2862923A (en) * | 1956-04-02 | 1958-12-02 | Searle & Co | 17-(pyridineacrylyl)-4-androsten-3-ones |
| US2910469A (en) * | 1956-10-03 | 1959-10-27 | Ciba Pharm Prod Inc | New 21-hydroxy-steroid compounds substituted in 21-position by a heterocyclic radical and process of preparing same |
| US2911402A (en) * | 1956-12-11 | 1959-11-03 | Riker Laboratories Inc | delta22(28)-solanidene-3beta, 12beta-diol, delta5,22(28)-solanidiene-3beta, 12beta-diol, and process for the preparation thereof |
| US2965640A (en) * | 1955-12-12 | 1960-12-20 | Schering Corp | 16-nu-substituted steroids and process for manufacturing same |
| US3409611A (en) * | 1966-05-16 | 1968-11-05 | American Cyanamid Co | 16, 20-cyclosteroids |
| US3684799A (en) * | 1971-02-18 | 1972-08-15 | Thomas L Popper | Androsteno-2{40 ,5{40 -dimethyl-5{40 -alkyl-1{40 -pyrrolines, methods for their manufacture, and novel 16{60 (1{40 -amino-1{40 -alkylethyl)-pregnene intermediates produced thereby |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2665274A (en) * | 1952-04-30 | 1954-01-05 | Merck & Co Inc | Steroid pyridinium salts |
-
1954
- 1954-11-24 US US471119A patent/US2750380A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2665274A (en) * | 1952-04-30 | 1954-01-05 | Merck & Co Inc | Steroid pyridinium salts |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2965640A (en) * | 1955-12-12 | 1960-12-20 | Schering Corp | 16-nu-substituted steroids and process for manufacturing same |
| US2853487A (en) * | 1956-03-09 | 1958-09-23 | Hoffmann La Roche | 17-(2-piperidylmethyl)-androstanediols |
| US2862923A (en) * | 1956-04-02 | 1958-12-02 | Searle & Co | 17-(pyridineacrylyl)-4-androsten-3-ones |
| US2910469A (en) * | 1956-10-03 | 1959-10-27 | Ciba Pharm Prod Inc | New 21-hydroxy-steroid compounds substituted in 21-position by a heterocyclic radical and process of preparing same |
| US2911402A (en) * | 1956-12-11 | 1959-11-03 | Riker Laboratories Inc | delta22(28)-solanidene-3beta, 12beta-diol, delta5,22(28)-solanidiene-3beta, 12beta-diol, and process for the preparation thereof |
| US3409611A (en) * | 1966-05-16 | 1968-11-05 | American Cyanamid Co | 16, 20-cyclosteroids |
| US3684799A (en) * | 1971-02-18 | 1972-08-15 | Thomas L Popper | Androsteno-2{40 ,5{40 -dimethyl-5{40 -alkyl-1{40 -pyrrolines, methods for their manufacture, and novel 16{60 (1{40 -amino-1{40 -alkylethyl)-pregnene intermediates produced thereby |
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