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USRE28690E - 17α-Ethinyl-18-methyl-19-nortestosterone esters - Google Patents

17α-Ethinyl-18-methyl-19-nortestosterone esters Download PDF

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Publication number
USRE28690E
USRE28690E US05/490,022 US49002274A USRE28690E US RE28690 E USRE28690 E US RE28690E US 49002274 A US49002274 A US 49002274A US RE28690 E USRE28690 E US RE28690E
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US
United States
Prior art keywords
nortestosterone
ethinyl
methyl
ester
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US05/490,022
Inventor
Hans-Gunter Lehmann
Heinz Gibian
Rudolf Wiechert
Friedmund Neumann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Priority to US05/490,022 priority Critical patent/USRE28690E/en
Application granted granted Critical
Publication of USRE28690E publication Critical patent/USRE28690E/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • This invention relates to 17 ⁇ -monoesters and 3-enol-17 ⁇ -diesters of 17 ⁇ -ethinyl-18-methyl-19-nortestosterone esters. More particularly, this invention is concerned with an improved method for preparing and securing them.
  • 17 ⁇ -monoesters and 3-enol-17 ⁇ -diesters of 17 ⁇ -ethinyl-18-methyl-19-nortestosterone constituting new therapeutic compounds having outstanding properties possess progestive activity and are active when administered orally or subcutaneously.
  • They are readily soluble in the conventional pharmaceutical carriers used for steroid hormones as, for example, vegetable oils such as sesame oil, castor oil, cotton seed oil, sunflower oil, olive oil, and the like, as well as in synthetic solvents, for instance glycols, lactic acid esters, benzyl benzoate and the like. Because of their considerable solubility, it is possible to employ solutions of the esters of the invention as injectibles and thereby also to utilize them as hormone depots.
  • the active compounds of the invention are prepared by reacting 17 ⁇ -ethinyl-18-methyl-19-nortestosterone with an organic carboxylic acid or reactive derivative thereof in the conventional manner to produce the ester.
  • the 3-enol ester group of the primarily formed 3-enol-17 ⁇ -diester is thereafter under regeneration of the 3-keto- ⁇ 4 -group partially saponified.
  • the new esters demonstrate central inhibiting activity and are accordingly suitable as highly effective ovulation inhibiting agents.
  • the ovulation inhibiting activity was demonstrated in normal female rats (Sprague-Dawley) where following oral administration the conventional tube inspection tests were carried out and established for 17 ⁇ -ethinyl-18-methyl-19-nortestosterone-acetate a ED 50 of only 3 mg. In comparison, the free 17 ⁇ -ethinyl-18-methyl-19-nortestosterone had a ED 50 of 10 mg. (the ED 50 is that dosage which results in inhibition of ovulation in 50% of the experimental animals). Side effects such as weight gain, liver incompatibility or estrogen side reactions were not observed.
  • the new compounds accordingly are indicated as therapeutic agents for medical conditions where inducing a quiet state in the ovaries is recommended.
  • the compounds can be used for example, in the treatment of dysmenorrhea, endometriosis, cyclic disturbances, and functional sterility.
  • the compounds of the invention are administered in the conventional dosage forms, such as capsules, granulates, solutions, dragees, and tablets and are compounded together with suitable pharmaceutical carriers.
  • suitable pharmaceutical carriers When tablets are prepared they may be made in various sizes (total weight of 50 - 150 mg.) containing from about 0.1 - 0.5 mg. of the drug suitably in combination with another hormone component having estrogenic activity as, for instance, 0.05 mg. ethinyl estradiol.
  • the tablets are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactone or the like. If desired, these tablets may be coated with sugar or shellac preparations in accordance with the common practices in the tablet manufacturing art.
  • the higher esters are characterized by an excellent and protracted activity.
  • the active compounds can be prepared by the conventional methods of steroid chemistry.
  • the esterification with the desired acid can be conducted in an acid or an alkaline reaction medium.
  • an acid esterification there is directly produced the 17-mono-ester.
  • an aromatization of the A-ring takes place.
  • the undesired side reaction can be avoided through the intermediate protection of the 3-keto group, for instance, by ketalization. This procedure implies two steps in the formation of the 17-mono-ester, i.e., ketal formation and ketal splitting.
  • An alternate reaction is the alkaline esterification effected in the presence of an organic nitrogen base, as for instance pyridine, quinoline, etc., whereby there is produced as the primary product a 3-enol-17 ⁇ -diacyl ester.
  • the reaction mixture containing the primary product is further worked up, for example, by treatment with neutral ice water or extraction, or through prolonged stirring in alkaline ice water and the resulting 17-mono-acyl-ester isolated.
  • any of the acids suitable in steroid chemistry can be used.
  • suitable acids are aliphatic carboxylic acids having 1 - 11, and most preferably 1 - 8, carbon atoms in the acid group, for example, acetic acid, propionic acid, caproic acid, onanthic acid, undecylic acid.
  • the acids can be saturated or unsaturated, branched or not, polybasic or substituted in the known manner such as trimethylacetic, t.butylacetic, phenylacetic, cyclopentyl-propionic, halogen-acetic, amino-acetic, oxypropionic, benzoic, succinic, adipic acids, etc.
  • the esterification is advantageously carried out at elevated temperatures, preferably at temperatures of from 130° - 200°C.
  • the time required for the reaction is directly dependent on the reaction temperature.
  • the diester is produced after 6 hours with a reaction temperature of 160° C., and in 5 hours with a reaction temperature of 170° C.
  • the said diester, i.e., 3-enol-17 ⁇ -diacyl ester is thereafter partially saponified in the 3-position.
  • inert protective gases as, for instance, argon.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)

Abstract

.Iadd.
A therapeutic compound for inhibiting ovulation comprising a 17-ester of 17α-ethinyl-18-methyl-19-nortestosterone wherein the said 17-ester group is formed from an aliphatic carboxylic acid having from six to 11 carbon atoms in the ester residue..Iaddend.

Description

This invention relates to 17 β-monoesters and 3-enol-17β-diesters of 17α-ethinyl-18-methyl-19-nortestosterone esters. More particularly, this invention is concerned with an improved method for preparing and securing them.
In accordance with the present invention, there are provided 17β-monoesters and 3-enol-17β-diesters of 17α-ethinyl-18-methyl-19-nortestosterone constituting new therapeutic compounds having outstanding properties. These compounds possess progestive activity and are active when administered orally or subcutaneously. They are readily soluble in the conventional pharmaceutical carriers used for steroid hormones as, for example, vegetable oils such as sesame oil, castor oil, cotton seed oil, sunflower oil, olive oil, and the like, as well as in synthetic solvents, for instance glycols, lactic acid esters, benzyl benzoate and the like. Because of their considerable solubility, it is possible to employ solutions of the esters of the invention as injectibles and thereby also to utilize them as hormone depots.
The active compounds of the invention are prepared by reacting 17α-ethinyl-18-methyl-19-nortestosterone with an organic carboxylic acid or reactive derivative thereof in the conventional manner to produce the ester. The 3-enol ester group of the primarily formed 3-enol-17β-diester is thereafter under regeneration of the 3-keto-Δ4 -group partially saponified.
The new esters demonstrate central inhibiting activity and are accordingly suitable as highly effective ovulation inhibiting agents.
The ovulation inhibiting activity was demonstrated in normal female rats (Sprague-Dawley) where following oral administration the conventional tube inspection tests were carried out and established for 17α-ethinyl-18-methyl-19-nortestosterone-acetate a ED50 of only 3 mg. In comparison, the free 17α-ethinyl-18-methyl-19-nortestosterone had a ED50 of 10 mg. (the ED50 is that dosage which results in inhibition of ovulation in 50% of the experimental animals). Side effects such as weight gain, liver incompatibility or estrogen side reactions were not observed.
The new compounds accordingly are indicated as therapeutic agents for medical conditions where inducing a quiet state in the ovaries is recommended.
As further applications, the compounds can be used for example, in the treatment of dysmenorrhea, endometriosis, cyclic disturbances, and functional sterility.
The compounds of the invention are administered in the conventional dosage forms, such as capsules, granulates, solutions, dragees, and tablets and are compounded together with suitable pharmaceutical carriers. When tablets are prepared they may be made in various sizes (total weight of 50 - 150 mg.) containing from about 0.1 - 0.5 mg. of the drug suitably in combination with another hormone component having estrogenic activity as, for instance, 0.05 mg. ethinyl estradiol. The tablets are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactone or the like. If desired, these tablets may be coated with sugar or shellac preparations in accordance with the common practices in the tablet manufacturing art.
In addition, the higher esters are characterized by an excellent and protracted activity.
The active compounds can be prepared by the conventional methods of steroid chemistry.
The esterification with the desired acid can be conducted in an acid or an alkaline reaction medium. As a result, of the acid esterification, there is directly produced the 17-mono-ester. There must, however, be accepted a higher loss of desired product as simultaneously with the esterification an aromatization of the A-ring takes place. The undesired side reaction can be avoided through the intermediate protection of the 3-keto group, for instance, by ketalization. This procedure implies two steps in the formation of the 17-mono-ester, i.e., ketal formation and ketal splitting.
An alternate reaction is the alkaline esterification effected in the presence of an organic nitrogen base, as for instance pyridine, quinoline, etc., whereby there is produced as the primary product a 3-enol-17β-diacyl ester. The reaction mixture containing the primary product is further worked up, for example, by treatment with neutral ice water or extraction, or through prolonged stirring in alkaline ice water and the resulting 17-mono-acyl-ester isolated.
For use in the esterification, any of the acids suitable in steroid chemistry can be used. Illustrative of suitable acids are aliphatic carboxylic acids having 1 - 11, and most preferably 1 - 8, carbon atoms in the acid group, for example, acetic acid, propionic acid, caproic acid, onanthic acid, undecylic acid. The acids can be saturated or unsaturated, branched or not, polybasic or substituted in the known manner such as trimethylacetic, t.butylacetic, phenylacetic, cyclopentyl-propionic, halogen-acetic, amino-acetic, oxypropionic, benzoic, succinic, adipic acids, etc. The esterification is advantageously carried out at elevated temperatures, preferably at temperatures of from 130° - 200°C. The time required for the reaction is directly dependent on the reaction temperature. Thus the diester is produced after 6 hours with a reaction temperature of 160° C., and in 5 hours with a reaction temperature of 170° C. The said diester, i.e., 3-enol-17β-diacyl ester is thereafter partially saponified in the 3-position.
The following examples are given in order to disclose more clearly the nature of the present invention. It should be understood, however, that the examples are not intended to be a limitation on the scope of the invention.
EXAMPLE 1
A solution of 2 g. 17α-ethinyl-18-methyl-19-nortestosterone in 26 ml. pyridine was reacted with 13 ml. acetanhydride and the reaction mixture heated to 160° C. in a bomb tube. The reaction mixture was then cooled and the cooled mixture poured into ice water. The precipitate which was produced was filtered off, washed with water until neutral and following drying chromatographed using silica gel. There were recovered 1.2 g crude 17α-ethinyl-18-methyl-Δ3,5 -estradiene-3, 17β-diol-diacetate, which following recrystallization from ether melted at 156° - 159° C. The yield amounted to 840 mg.
EXAMPLE 2
400 mg. 17α-ethinyl-18-Δ3,5 -estradiene-3, 17β-diol-diacetate were admixed with 400 mg. sodium bicarbonate in 40 ml. methanol and 4 ml. water and the mixture stirred at room temperature for 6 hours. Thereafter, the reaction mixture was poured into ice water and neutralized with glacial acetic acid. The precipitate which formed was separated off by filtration, washed with water and dried. There were thereby produced 350 mg. crude 17α-ethinyl-18-methyl-19-nortestosterone acetate having a melting point of 156° - 157° C. Following recrystallization from ether, 260 mg. of the acetate melting at 162° - 163° C. were obtained.
EXAMPLE 3
A solution of 400 mg. 17α-ethinyl-18-methyl-Δ3,5 -estradiene-3, 17β-diol-diacetate in 40 ml. methanol and 4 ml. water were refluxed in the presence of 4 ml. 37% HCl for 5 minutes. The reaction mixture was then poured into water and worked up according to the procedure of Example 2. There were recovered 355 mg. crude 17α-ethinyl-18-methyl-19-nortestosterone-acetate having a melting point of 157°C. After recrystallization from ether, there were obtained 256 mg. pure 17β-acetate which had a melting point of 163° C. and is identical with the material of Example 2.
EXAMPLE 4
2 g. 17β-ethinyl-18-methyl-19-nortestosterone in 26 ml. pyridine and 27 g. caproic acid anhydride were heated together under a nitrogen atmosphere for 7 hours at 160° C. Following cooling, the reaction mixture which contained the primary formed 17α-ethinyl-18-methyl-19-nortestosterone- 3-enol-17β-dicapronate was poured into bicarbonate water and stirred for 30 hours to saponify the excess caproic acid anhydride. Following filtration, there were obtained 2.1 g. of an oily, crude product. The crude product was purified chromatographically using silica gel and resulted in the recovery of 1.6 g. 17α-ethinyl-18-methyl-19-nortestosterone-caproate having a melting point of 112° - 113° C. After dissolution in pentane, there were recovered 1.5 g. of the caproate having an unchanged melting point.
In place of the nitrogen there can be used other inert protective gases as, for instance, argon.

Claims (7)

What is claimed is as follows:
1. A therapeutic compound for inhibiting ovulation comprising .[.as active ingredient a compound selected from the group consisting of.]. a 17-ester of 17α-ethinyl-18-methyl-19-nortestosterone .[.and a 17α-ethinyl-18-methyl-Δ3,5 -estradiene-3, 17β-diol-3, 17β-diester.]. wherein the said 17-ester .[.and 3, 17β-diester groups are.]. .Iadd.group is .Iaddend.formed from .Iadd.an .Iaddend.aliphatic carboxylic .[.acids.]. .Iadd.acid .Iaddend.having from .[.1.]. .Iadd.six .Iaddend.to 11 carbon atoms in the ester residue .[.; and a pharmaceutical carrier for said compound.]..
2. The compound of claim 1 which is the 17β-.[.acetate.]. .Iadd.undecylate .Iaddend.of the said nortestosterone.
3. The compound of claim 1 which is the 17β-caproate of the said nortestosterone. .[.
4. The compound of claim 1 which is the 17β-diacetate of the said estradiene..]. .[.5. The compound of claim 1 which is the
17β-caproate of the said estradiene..]. 6. A therapeutic composition for inhibiting ovulation comprising as active ingredient the 17α-ethinyl-18-methyl-19-nortestosterone ester defined in claim 1 in an amount of 0.1 to 0.5 mg. and in admixture with a pharmaceutical
carrier. 7. A therapeutic composition for inhibiting ovulation according to claim 6, wherein said ester is 17α-ethinyl-18-methyl-19-nortestosterone-.[.acetate.].
.Iadd.undecylate.Iaddend.. 8. A method of providing steroid therapy which comprises administering to a subject a therapeutic composition according to claim 6.
US05/490,022 1965-05-05 1974-07-19 17α-Ethinyl-18-methyl-19-nortestosterone esters Expired - Lifetime USRE28690E (en)

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DT37001 1965-05-05
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5010070A (en) * 1987-06-15 1991-04-23 Warner-Lambert Company Graduated estrogen contraceptive
US6774122B2 (en) * 2000-01-10 2004-08-10 Astrazeneca Ab Formulation
US7576226B2 (en) 2003-06-30 2009-08-18 Richter Gedeon Vegyeszeti Gyar Rt. Process of making isomers of norelgestromin and methods using the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2601287A (en) * 1949-08-18 1952-06-24 Upjohn Co Partial synthesis of progesterone
US2798879A (en) * 1953-04-15 1957-07-09 Upjohn Co 19-nortestosterone acylates and 3-enol acylates thereof
US2868809A (en) * 1954-08-12 1959-01-13 Upjohn Co 19-nortestosterone phenyl alkanoates
US3006933A (en) * 1958-07-09 1961-10-31 American Cyanamid Co 11alpha-hydrocarbylsulfonyloxy-3,5-pregnadienes
US3231589A (en) * 1963-07-25 1966-01-25 American Home Prod 13beta-alkyl-4-gonen-3-ones

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2601287A (en) * 1949-08-18 1952-06-24 Upjohn Co Partial synthesis of progesterone
US2798879A (en) * 1953-04-15 1957-07-09 Upjohn Co 19-nortestosterone acylates and 3-enol acylates thereof
US2868809A (en) * 1954-08-12 1959-01-13 Upjohn Co 19-nortestosterone phenyl alkanoates
US3006933A (en) * 1958-07-09 1961-10-31 American Cyanamid Co 11alpha-hydrocarbylsulfonyloxy-3,5-pregnadienes
US3231589A (en) * 1963-07-25 1966-01-25 American Home Prod 13beta-alkyl-4-gonen-3-ones

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5010070A (en) * 1987-06-15 1991-04-23 Warner-Lambert Company Graduated estrogen contraceptive
US6774122B2 (en) * 2000-01-10 2004-08-10 Astrazeneca Ab Formulation
US20050043285A1 (en) * 2000-01-10 2005-02-24 Astrazeneca Ab Formulation
US7456160B2 (en) 2000-01-10 2008-11-25 Astrazeneca Ab Formulation
US8329680B2 (en) 2000-01-10 2012-12-11 Astrazeneca Ab Formulation
US8466139B2 (en) 2000-01-10 2013-06-18 Astrazeneca Ab Formulation
US7576226B2 (en) 2003-06-30 2009-08-18 Richter Gedeon Vegyeszeti Gyar Rt. Process of making isomers of norelgestromin and methods using the same
US7816546B2 (en) 2003-06-30 2010-10-19 Richter Gedeon Vegyeszeti Gyar Rt. Process for the synthesis of high purity d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime

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