US3591583A - Steroidal lactones - Google Patents

Steroidal lactones Download PDF

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Publication number
US3591583A
US3591583A US801828A US3591583DA US3591583A US 3591583 A US3591583 A US 3591583A US 801828 A US801828 A US 801828A US 3591583D A US3591583D A US 3591583DA US 3591583 A US3591583 A US 3591583A
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hydroxy
trien
butenoic acid
epoxy
steroid
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US801828A
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Yvon Lefebvre
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Wyeth LLC
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring

Definitions

  • the 3-hydroxy group on the steroid nucleus may also carry an acyl substituent containing from 2 to 4 carbon atoms, an alkyl substituent containing from 1 to 4 carbon atoms or a cycloalkyl substituent containing from 5 to 6 carbon atoms.
  • the process for preparing the steroidal lactones of this invention comprises treating the corresponding 17a-furyl-substituted steroids with an organic peracid in the presence of a nucleophilic reagent, thus obtaining as intermediates the corresponding steroidal 4,4-dihydroXy-2-butenoic acid lactones, in which the 4-hydroXy group may be acylated, if desired. Treatment of said intermediates with sodium borohydrides yields the steroidal lactones of this invention. Said last-named compounds are highly active estrogens and methods for their use are also disclosed.
  • This invention relates to steroid lactones comprising a 4-hydroxy-2-butenoic acid lactone joined to the C-17 position of a steroid nucleus to intermediates used in their preparation, and to processes for preparing the lactones of this invention.
  • lactones of this invention are potent estrogens substantially free from side effects when administered orally or subcutaneously.
  • the high oral potency of these lactones allows them to be used therapeutically in more sparing amounts than the corresponding natural estrogen from which they may be derived.
  • the preferred embodiment of this invention relates to compounds of Formula I in which Q represents the rings A, B, and C of a 3-substituted estrane nucleus.
  • Q represents the rings A, B, and C of a 3-substituted estrane nucleus.
  • Such compounds are represented by general Formulae II, III and IV.
  • R represents a hydrogen atom, an alkyl group containing from one to four carbon atoms, a cycloalkyl group containing from five to six carbon atoms or an acyl group containing from two to four carbon atoms.
  • the steroid lactones of this invention of general Formulae II, III, and IV possess estrogenic activity. More particularly, these steroid lactones exhibit potent oral activity when tested in standard laboratory tests for estrogenic activity, such as, for example the Allen Doisy test described by C. W. Emmens in Hormone Assay, Academic Press, New York 1955, p. 401. This high degree of estrogenic activity readily distinguishes the compounds of this invention from the steroid lactones described in my co-pending US. application S.N. 629,358, now US. Patent No. 3,431,258, which are isomeric with respect to the point of attachment of the lactone portion thereof.
  • these steroid lactones When these steroid lactones are employed as estrogenic agents in warm-blooded mammals, for example, rats, they may be administered alone or in dosage forms combined with pharmaceutically acceptable excipients.
  • the proportion of the excipients used is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solution or suspensions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
  • the dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 0.5 mcg. to about 500 mcg. per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 5 mcg. to about 100 mcg. per kilo per day is most satisfactory. Such doses may be administered once or twice a day as required.
  • the preferred process for preparing the steroid lactones of general Formulae II, III, and IV may be schematically represented by Formulae V- VI I in which Q represents rings A, B, and C of the steroid lactones II to IV as defined above and R represents a hydrogen atom or an acyl group containing from two to four carbon atoms, such as, for example, an acetyl group, with the limitation that when R of the steroid nucleus Q is hydrogen, R must also be hydrogen.
  • the l7ot-[3-furyl]-17,B-hydroxy steroids represented by general Formula V in which Q represents rings A, B and C of the steroid lactones II and III as defined above are the preferred starting materials for the preparation of the steroid lactones of this invention of general Formulae II and III, respectively. These starting materials are described in U.S. Pat. No. 3,271,392.
  • the 17w[3-furyl]-17fi-hydroxy steroids represented by general Formula V in which Q represents rings A, B, and C of the steroid lactone IV as defined above are the preferred starting materials for the preparation of the steroid lactones of this invention of General Formula IV defined above.
  • These starting materials are prepared by treating the appropriate 3-alkyl or 3-cycloalkyl ethers of equilin, or the 3-tetrahydropyranyl ether of equilin with a peracid, preferably, m-chloroperbenzoic acid, described by L. F. Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, New York, 1967, p.
  • the latter compound is hydrolyzed under mildly acidic conditions, for example, dilute hydrochloric acid in methanol, to yield the corresponding free 3-hydroxy derivative of Formula V in which Q represents rings A, B, and C of the steroid lactone IV in which R represents hydrogen, which together with its corresponding 3-acyl derivatives are the remaining preferred starting materials of Formula V.
  • Said 3-acyl derivatives are readily prepared by treating the above 3-hydroxy derivative of Formula V with an appropriate acid anhydride or acid halide in pyridine at room temperature.
  • the tetrahydropyranyl ether of equilin is preferably used rather than equilin. This preference is based on my observation that, 'when equilin is used in this process, the consequential presence of the free 3-hydroxy group during the treatment with the reagent, 3-furyllithium, allows a complex to be formed between the reagent and the hydroxy group causing a waste of the reagent and adversely affecting the yield of the process.
  • the 3-alkyl and 3-cycloalkyl ethers of equilin, used for the preparation of the above starting materials, are prepared from equilin according to the methods described by F. Glockling and D. Kingston, Chemistry and Industry, 1037 (1961) and the 3-tetrahydropyranyl ether of equilin is prepared according to the method of A. D. Cross et al., Steroids, vol. 4, 423 (1964).
  • Equilin is a well-known naturally occurring steroid, see L. F. Fieser and M. Fieser, Steroids, Reinhold Publishing Corporation, New York, 1959.
  • 3-furyllithium is prepared according to the method of S. Gronowitz and G.
  • the above starting materials of Formula V are converted to the intermediates of Formula VI, in which Q represents rings A, B, and C of the steroid lactones II, III, and IV in which R represents a hydrogen atom or an alkyl, cycloalkyl or acyl group defined as above, and R represents hydrogen, by treatment with an organic peracid in the presence of a nucleophilic reagent such as acetic acid or water.
  • a nucleophilic reagent such as acetic acid or water.
  • a buffer such as sodium acetate, is employed during the course of the reaction and approximately the same molar amounts of nucleophilic reagent and steroid starting material are employed.
  • acylates of the above intermediates are readily prepared by treatment with the appropriate aliphatic acid anhydride or acyl halide in the presence of pyridine. If a free hydroxy group should also be present at the 3-position of the steroid nucleus, it also will be acylated during this reaction.
  • the intermediates of Formula VI, in which Q represents ring A, B, and C of the steroid lactone IV in which R is as defined above may be prepared directly from 1711- [3-furyl] estra- 1,3,5 ,7-tetraene-3,17- diol and its corresponding 3-alkyl, 3-cycloalkyl or 3-acyl derivatives, described in US. Patent No. 3,271,392, by treatment with an organic peracid as described above.
  • a preferred range for reaction time is from 30 minutes to three hours and a preferred range of reaction temperature is from to C.
  • the product is isolated by conventional means, usually the methanol is evaporated from the reaction mixture, the residue is taken up in water, acidified by the addition of an acid, preferably 10 percent hydrochloric acid and extracted with ether. After evaporation of the extract, crystallization or chromatography is used to purify the product. During the course of this reaction, a 3-acy1 group, if present, will be removed affording the corresponding 3-hydroxy derivative.
  • steroid lactones of this invention of Formulae II, III, and IV in which R is an acyl group, as defined above are readily obtained from the corresponding steroid lactone of Formulae II, III or IV in which R is hydrogen, prepared as described above, on treatment with the appropriate aliphatic acyl anhydride or acyl chloride in pyridine solution.
  • Example 1 The higher ether homologues of equilin are prepared by the method of F. Glockling and D. Kingston, described in Chem. and Ind., 1037 (1961), by the action of the corresponding alkyl halides on the sodium or potassium salts of the phenols. Accordingly, equilin 3-methyl ether, equilin 3-ethyl ether, equilin 3-propyl ether, equilin 3-isopropyl ether, equilin 3-n-butyl ether, equilin 3-sec.-butyi ether, equilin 3-cyclopentyl ether, and equilin 3-cyclohexyl ether are obtained.
  • the corresponding tetrahydropyranyl ether is prepared according to the method described by A. D. Cross et al. in Steroids, vol. 4, p. 423 (1964).
  • Example 2 m-Chloroperbenzoic acid (4.05 g.) is added by portions, over a period of 30 minutes, to a stirred, ice-cold solution of equilin 3-methyl ether (5 g.). The mixture is stirred for an additional 2 hours in the ice-bath and then for 30 minutes at room temperature. The solution is washed with a 5% sodium carbonate solution and with water, dried and evaporated. The colour is removed from the crude crystalline product by filtration through a column of alumina.
  • Example 3 A solution of 3-iodofuran (5 g.), ether ml.), and a 1.47 N ethereal solution of n-butyllithium (13.6 ml.), is stirred at -60 C. for 30 minutes. A solution of 70:,8- epoxy-3-rnethoxyestra-1,3,5(10)-trien-17-one (5 g.), obtained in Example 2, in toluene (200 ml.), is then added and the mixture is stirred at room temperature for 16 hours. Ether and water are added. The organic phase is separated and further washed with water.
  • Example 4 A solution of 7a,8-ep0xy-17u-[3'-furyl]-3-tetrahydropyranyloxyestra 1,3,5(10) trien 17 01 (31.1 g.), obtained as described in Example 3, in methanol (1244 ml.) is stirred for one hour at room temperature with a 0.1 N solution of hydrochloric acid (311 ml.). Water (1800 ml.) is added and the resulting sOlid is filtered, washed well with water and dried.
  • Example 5 A solution of 7a-8-epoxy-17a-[3'-furyl]estra-1,3,5(10)- triene-3,17-diol, (5 g.), obtained in Example 4, in pyridine (50 ml.), and acetic anhydride (50 ml.), is stirred at room temperature for 2 /2 hours. The solution is diluted with ice-water and is extracted with ether. The ether is washed with dilute sulfuric acid, water, sodium bicarbonate, and water, again to neutrality. The solution is dried and evaporated to yield 3-acetoxy-7u,8-epoxy-17ot[3-furyl]-estra- 1,3,5(10)-trien-17-ol as an amorphous solid,
  • Example 6 A mixture of the 17a-[3-furyl]-l7fl-hydroxy steroid, 17w[3-furyl]-3-rnethoxyestra 1,3,5(10)-trien 17 01 (17 g.), described in US. Pat. No. 3,271,392, chloroform (850 ml.), sodium acetate (17 g), acetic acid (17 ml.) and m-chloroperbenzoic acid (85%) (23.65 g.) is stirred at room temperature for 1 hour. Ether is added. The organic solution is washed with sodium bicarbonate and water, dried and evaporated. The residue is chromatographed on silica gel.
  • 17a-[3'-furyl]estra-1,3,5(10),7- tetraen-3,17-diol, its appropriate corresponding 3-alkyl and 3-cycloalkyl ether and its appropriate corresponding 3-acyl derivatives prepared as described in US. Pat. No. 3,271,392 are oxidized with m-chloroperbenzoic acid to the corresponding intermediates of Formula VI described above.
  • Example 7 A solution of the intermediate of Formula VI, 4,4-dihydroxy-3-[17fl-hydroxy-3'-methoxyestra 1,3',5'(10')- trien-17'-yl]-2-butenoic acid lactone, prepared as described in Example 6, 5.8 g., in pyridine (50 ml.), and acetic anhydride (50 ml.) is stirred at room temperature for three hours. The reaction mixture is diluted with water and extracted with chloroform. The chloroform extract is washed with dilute sulfuric acid, water, sodium bicarbonate solution, and water, dried over sodium sulfate, filtered and evaporated to dryness. The residue is subjected to chromatography on silica gel.
  • Example 8 (A) Sodium borohydride (16 g.) is added portionwise to a solution of the intermediate of Formula VI, 3-[3'- cyclopentyloxy 17'B hydroxyestra- 1,3,5(l0)-trier1- 17'-yl]-4,4-dihydroxy-2-butenoic acid lactone (8 g.), prepared as described in Example 6, in methanol (320 ml.). After 20 minutes the methanol is removed under reduced pressure. The residue is dissolved in water and the resultant solution is extracted with ether. The aqueous phase is separated and acidified with 10% sulfuric acid solution. The mixture is extracted with ether. The ether extract is washed with water, dried and evaporated.
  • Example 9 By using the same procedure as described in Example 5, but substituting an equivalent amount of 4-hydroxy- 3-[3',17-dihydroxyestra 1,3,5(10') trien-17-yl]-2- butenoic acid lactone, 4-hydroxy-3-[3,17'-dihydr0xyestra- 1',3,5(10),6',8'-pentaen 17 yl]-2-butenoic acid lactone, or 3-[7'u,8'-epoxy-3,17B dihydroxyestra-1,3',5 (10') trien 17' yl]-4-hydroxy-2-butenoic acid lactone for 7a,8-epoxy 17a [3'-furyl]estra-1,3,5(10)-triene- 3,17-diol, and using the appropriate aliphatic acyl anhydride, acetic anhydride, propionic anhydride or butyric anhydride, the corresponding steroid lactones of this invention of Formulae II, III and IV
  • R is selected from the group which consists of hydrogen, alkyl containing fiom one to four carbon atoms, cycloalkyl containing from five to six carbon atoms and acyl containing from two to four carbon atoms.
  • R is selected from the group which consists of hydrogen, alkyl containing from one to four carbon atoms, cycloalkyl containing from five to six carbon atoms and acyl containing from two to four carbon atoms.
  • R is selected from the group which consists of hydrogen, alkyl containing from one to four carbon atoms, cycloalkyl containing from five to six carbon atoms and acyl containing from two to four carbon atoms; and R is selected from the group which consists of hydrogen and acyl containing from two to four carbon atoms; R being hydrogen when R is hydrogen.

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CA (1) CA937563A (enrdf_load_stackoverflow)
CH (1) CH564036A5 (enrdf_load_stackoverflow)
DE (1) DE2008645A1 (enrdf_load_stackoverflow)
FR (1) FR2034564A1 (enrdf_load_stackoverflow)
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GB1264050A (en) 1972-02-16
DE2008645A1 (de) 1970-09-03
CH564036A5 (enrdf_load_stackoverflow) 1975-07-15
NL7002614A (enrdf_load_stackoverflow) 1970-08-26
CA937563A (en) 1973-11-27
FR2034564A1 (enrdf_load_stackoverflow) 1970-12-11

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