GB2160873A - 11B-(4-Aminophenyl) estra-4,9-dienes - Google Patents
11B-(4-Aminophenyl) estra-4,9-dienes Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
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Abstract
Novel steroids (X) exhibit progestomimetic, antiprogestomimetic, antiglucocorticoid and contraceptive activities. <IMAGE> or a salt thereof, wherein either (a) R'=R''=CH3, and R''' is CO2H or CH2OH, (b) R'=R''=H and R''' is CH3, or (c) one of R' and R'' is H, the other is CH3 or COCH3, and R''' is CH3.
Description
SPECIFICATION 1 substituted steroids, their production and their use as medicaments
This invention relates to new 11p-subsituted steroids, their production and their use as medicaments.
European patent specification 57115A discloses new 19- nor steroids and 19-nor D-homosteroids which are substituted at the lip position and which have the formula:
wherein Rl represents an organic radical containing from 1 to 18 carbon atoms, and containing at least one nitrogen, phosphorus or silicon atom, the atom immediately adjacent to the carbon atom at position 11 being a carbon atom, R2 represents a hydrocarbon radical containing from 1 to 8 carbon atoms, X represents the residue of a pentagonal or hexagonal ring, optionally substituted and optionally carrying unsaturation, the group C=A at position 3 represents an oxo group, free or blocked in the ketal form, a group
a C=NOH group, a C=NO=alk3 group or a CH2 group, all,, alk2 and alk3 representing an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl group containing from 7 to 15 carbon atoms, as well as the acid addition salts of these steroids.
The European specification also describes the production of these products, their use as medicaments and pharmaceutical compositions containing these medicaments.
Among the products with formula (I), the European specification describes, in Example 4,11ss-(4-dime- thylaminophenyl)-17ss-hydroxy-17a-(1-propynyl)-estra-4, 9-dien-3-one, which has the formula:
The present invention provides estranes which fall within formula (I). These estranes and their salts are novel, however, and are outstanding over closely related compounds. The present compounds possess a surprisingly good combination of properties.
Accordingly, the invention provides a compound which is an estrane of formula (X):
or a salt thereof, wherein
R"' represents -CH2OH, -COOH or -CH3; and
when R"' represents -CH2OH or -COOH, R' and R" each represent a methyl group; and
when R"' represents -CH3, R' and R" each represent a hydrogen atom, or one represents a hydrogen atom and the other a methyl group or an acetyl group.
In a particular embodiment, the compound is an estrane of formula (A):
or a salt thereof, wherein R" represents a hydrogen atom or a methyl group.
It can be seen that the present estrane is:
11 P-[4-(dimethylamino)phenyl]-l 7p-hydroxy-1 7oL- (3-hydroxyprop-l-ynyl)-estra-4,9-dien-3-one; ii ss-(4-aminophenyl)-17ss-hydroxy-17α-(prop-1 -ynyl)- -estra-4,9-dien-3-one;
11 ss-[4-(methylamino )phenyl]-1 7ss-hydroxy-1 7a-(prop- 1-ynyl)-estra-4,9-dien-3-one; N-[4-[1 7p-hydroxy-3-oxo-1 7a-(prop-l-ynyl )-estra- 4,9-dien-ll ss-yl]phenyl]acetamide; or llp-[4-(dimethylamino)phenylj-1 7p-hydrnxy-3-oxo- 19-nor-i 7a-pregna-4,9-dien-20-yne-21 -carboxylic acid.
The invention also provides a process for preparing the present compound.
In particular, the invention provides a process for preparing the estrane of formula (A) or a salt thereof, which process comprises reacting a propyne of formula (C):
wherein R" is as defined above and K represents a protected ketone group in the ketal form, with a dehydrating agent able to free the ketone function.
The invention also provides a process for preparing the present estrane 11ss-[4-(dimethylamino)phenyl]- 17ss- hydroxy-3-oxo-19-nor-17α-pregna-4,9-dien-20-yne-21- carboxylic acid, which process comprises reacting a carboxypropyne of formula (E):
wherein K represents a protected ketone group in the ketal form and T represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, with a dehydrating agent able to free the ketone function, to produce a ketone of formula (F):
which, when T represents an alkyl radical, is reacted with a saponification agent so as to produce the desired compound.
The invention provides also a pharmaceutical composition comprising a pharmaceutically acceptable excipient together with a compound which is the present estrane or a pharmaceutically acceptable salt thereof.
The invention also provides the present estrane or pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
The invention provides also a method of contraception, which method comprises administering to a human or animal female an effective amount of the present estrane or pharmaceutically acceptable salt thereof.
The present compounds are likely to be metabolites of the 11P-[4-(dimethylamino)phenyl]-17p-hydrnxy 17O- (l-propynyl)-estra-4,9-dien-3-one described in the European specification. It is advantageous, however, to administer the present compounds.
The present compounds are particularly interesting from a pharmacological point of view; they possess in particular remarkable anti-glucocorticoid activity.
The study of these compounds has also revealed a remarkable anti-progestomimetic activity. The compounds can therefore be used as medicaments principally to combat the secondary effects of glucocorticoids; they also combat troubles due to hypersecretion of glucocorticoids and in particular combat ageing in general and more particularly combat hypertension, atherosclerosis, osteoporosis, diabetes or obesity, and also immuno-depression or insomnia.
The present compounds which possess anti-progestomimetic properties can also be used to prepare original contraceptives; they can also be used against hormone imbalances and, moreover, they are of interest in the treatment of hormone dependent cancers.
The present compounds can also exhibit progestomimetic properties, and can also be used in the treatment of amenorrhoea, dysmenorrhoea and luteal difficiencies.
The present compounds are thus of particular interest as pharmaceuticals. For this use, the present estranes can be employed in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts are formed with acids. The present compounds include therefore pharmaceutically acceptable addition salts of the estranes with acids.
The compounds must of course be non-toxic at the dose employed. The useful posology varies according to the condition treated and the administration route; it can vary for example from 10 mg to 1 g and preferably from 100 mg to 1 g per day in the human adult by the oral route.
The present estranes and pharmaceutically acceptable salts can be used to prepare pharmaceutical compositions containing, as active principle, at least one of the said compounds.
The present pharmaceutically acceptable compounds can be administered by the digestive, parenteral or local route.
The compositions can be solid or liquid and can be presented in the pharmaceutical forms currently used in human medicine such as plain or sugar-coated compressed tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams or gels. The pharmaceutical forms can be prepared by the usual methods.
The active principle is usually employed in admixture with a pharmaceutically acceptable excipient, which may be an excipient known for use in the formulation of pharmaceutical compositions. Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range or organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. the excipients may be compounded with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.
The compounds can be employed in the form of addition salts with pharmaceutically acceptable acids.
As addition salts with acids, there can be mentioned in particular hydrochlorides and methane-sulphonates.
The present compounds can be prepared by the general process described in European specification 57115, and the invention accordingly provides this process as applied to the present compounds.
The present compound which is an estrane of formula (A):
or a salt thereof, wherein Rq, represents a hydrogen atom or a methyl group can also be prepared by a process which comprises reacting a propyne of formula (C):
wherein R,1 is as defined above and K represents a protected ketone group in the ketal form, with a dehydrating agent able to free the ketone function.
The propyne of formula (C) can be prepared by a process comprising reacting an allylamine of formula (B):
wherein K is as defined above and R'" and R"" are such that either they each represent an allyl group or one represents an allyl group and the other a methyl group, with a de-allylation reagent so as to obtain the propyne of formula (C).
The allylamine of formula (B) can be prepared by a process comprising reacting, in the presence of cuprous chloride, an epoxide of formula (ills):
wherein K is as defined above, with an organo-magnesium halide of formula:
wherein R'" and R",1 are as defined above and X represents a halogen atom, so as to obtain the allyiamine of formula (B).
K preferably represents a dimethoxy or ethylenedioxy radical.
X preferably represents a chlorine or bromine atom.
The de-allylation reagent is preferably the Wilkinson reagent in the presence of diazabicyclo-octane.
The dehydrating agent able to free the ketone function is preferably dilute hydrochloric acid.
The present compound which is an estrane of formula (A,):
or a salt thereof, can also be prepared by a process which comprises reacting a carboxypropyne of formula (E):
wherein K rpersents a protected ketone group in the ketal form and T represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, with a dehydrating agent able to free the ketone function, to produce a ketone of formula (F):
which, when T represents an alkyl radical, is reacted with a saponification agent so as to produce the desired compound.
The carboxypropyne of formula (E) can be prepared by a process comprising reacting, in the presence of a strong base, an acetylenic derivative which has formula HC-C- CO3T wherein T is as defined above, with a keto derivative which has formula (D):
wherein K is as defined above, so as to obtain the carboxypropyne of formula (E).
The preferred strong base is butyl-lithium. When T represents a hydrogen atom, two equivalents of the base are used.
The saponification agent is preferably sodium hydroxide in an alcohol medium.
The present invention provides as a new chemical the allylamine of formula (B) described above or a salt thereof.
The invention also provides as a new chemical the ester of formula (F'):
wherein Alk represents an alkyl group having from 1 to 4 carbon atoms.
The epoxides of formula (ills) are described in European specification 57115 or can be prepared by the usual methods.
The invention is illustrated by the following Examples.
Example 1: 1 l-[4-(dimethylamlno)phen yll-1 7p- hydroxy- 1 7a-(3-hydroxyprop- l-ynyl)-estra-4,9-dien- 3- one.
3.1 g of the tetrahydropyranyl ether of propargyl alcohol in 6 cm3 of ether is introduced drop by drop under argon at between 10 and 15'C and under agitation to a 1.6M solution of methyl-lithium in ether.
While maintaining the temperature below 15"C, one agitates for 10 minutes, and then adds over 15 minutes a solution of 2 g of 3,3-[1,2-ethanediyl-bis(oxy)]-11p- [4-(dimethylamino)phenyl]-5a-hydroxy-estra-9-en-17- one (prepared as described in Example 7 Stage A of European specification 57115) in 15cm3 of tetrahydrofuran. At the end of the addition, a further 15 cm3 of tetrahydrofuran is added and the agitation is continued for 30 minutes at ambient temperature. The medium is diluted with a solution of ammonium chloride and extracted with ethyl acetate; the extracts are washed with a solution of sodium chloride, dried and distilled to dryness. The oil obtained is dissolved in 20 cm3 of methanol. 5 cm3 of hydrochloric acid at 112 (or about 5 N) is added and the mixture is left for 2 hours at ambient temperature.Ice is added, then 5 cm3 of concentrated ammonia, and after extracting the medium with ethyl acetate, washing with water then with a solution of sodium chloride, drying, and distilling to dryness, the residue is crystallized from ethyl ether. isopropyl ether is added, then by filtering, washing, and drying at around 50"C, 1.42 g of the desired product is obtained, which is purified as follows: The product is dissolved in chloroform, and the solution is filtered and concentrated to dryness. 3 cm3 of chloroform is added to the residue, which is dissolved by heating, and 3 cm3 of isopropyl ether is added. Crystallization is started and the solution is left to cool slowly; 6 cm3 of isopropyl ether is added to it, and after leaving for two hours at ambient temperature, it is separated.The crystals are washed with a mixture of chloro formlisopropyl ether (1:3) and dried at about 50"C.
1.36 g of the product is obtained, which is dissolved in 4 cm3 of chloroform, and 4 cm3 of isopropyl ether is added twice.
1.3 g of the expected product is obtained.
M.P. = 229"C. [0!]D + 133 t 2.5 (c = 1 % CHCl3) Analysis : C29H3sNO3 Calculated C%: 76.45 Found C% : 76.8
H% : 7.57 H% : 8.0 N% 3.06 N% : 3.1 Example 2: 1 1p-(4-aminophenyl)- 17ss-hydroxy- 1 701- (prop- l-ynyl)-estra-4,9-dien-3-one.
Stage A : 3,3-dimethoxy-ll-[4-(diallylamino)phenyl]- -1 7a-(prop-1 -ynyl )-estra-9-en-5a,1 7ss-diol.
a) Preparation of N,N-dEallyl-4-bromoaniline.
At ambient temperature, a solution of 300 cm3 of benzene, 11.8 g of tetradecyl trimethyl ammonium bromide, 60.2 g of 4-bromoaniline and 60 cm3 of allyl bromide is added to 150 g of sodium hydroxide in tablet form dissolved in 300 cm3 of water.
After agitating for 87 hours at ambient temperature, extracting with ethyl acetate, washing in water, drying, and evaporating under reduced pressure, 89 g of an oil is obtained, which is purified by filtering on silica (eluent : cyclohexane). 81.7 g of yellow liquid is separated by distillation, and a pure compound is obtained. (B.P.
105 C/101 mmHg).
Analysis: C,2H,4BrN
Calculated C% :57.16 H% : 5.59 Br% 31.69 N% : 5.55
Found : 56.9 5.7 31.9 5.5 b) Preparation of magnesium compound.
5.25 g of magnesium in 10 cm3 of tetrahydrofuran is heated to 55"C under nitrogen, several drops of ethylene bromide are poured in and drop by drop a solution of 15.3 g of N,N-diallyl-4-bromoaniline in teterahydrofuran (sufficient quantity for 120 cm3) is added. The temperature is maintained at 55 C for 40 minutes and then allowed to return to ambient temperature.
c)Condensation.
5.6 g of 3,3-dimethoxy-5a,10a-epoxy-17a-(prop-l-ynyl)- estra-9(11)-en-17p-ol prepared according to
French patent 2,522,328 (preparation 4) is dissolved in 50 cm3 of tetrahydrofuran. 560 mg of cuprous chloride is added and the mixture is cooled under nitrogen to 0/-5"C. Drop by drop over 40 minutes, 125 cm3 of the magnesium compound prepared as described above is added. After leaving to react for 18 hours, the mixture is poured into a solution of ammonium chloride and extracted with ethyl acetate.
After washing, drying and evaporation of the solvent, about 16 g of a yellow oil is obtained, which is chromatographed on silica by eluting with a benzene-ethyl acetate mixture 85:15 with 1% of triethylamine and 7.3 g of the product is separated. After crystallization from isopropyl ether of the 1.529 of the product obtained by chromatography, 1.049 of pure product is collected.
Stage B : 3,3-dimethoxy-1 1 p-(4-aminophenyl)-1 7p-(prop- I-ynyl )-estra-9-en-5cL,1 7p-diol.
4.3 g of product obtained at Stage A is dissolved in 80 cm3 of ethanol and 5 cm3 of water. 215 mg of diazabicyclo-octane and 430 mg of Wilkinson reagent [chlorotris(triphenylphosphine) rhodium] is added.
After heating for 30 minutes at reflux, cooling, diluting in water and extracting with ethyl acetate, the expected product is obtained after evaporation of the organic phase.
Stage C:11ss-(4-aminophenyl)-17ss-hydroxy-17α-(prop- l-ynyl)-estra-4,9-dien-3-one.
The product obtained at Stage B is dissolved in 50 cm3 of methanol and 15 cm3 of 2N hydrochloric acid.This is left for 1 hour 15 minutes at ambient temperature, and then the solution is poured into a solution of sodium bicarbonate and extracted with ethyl acetate. After washing, drying, and evaporating the organic phase, 4 g of crude product is obtained, which is dissolved in methylene chloride. This is purified by chromatography on silica by eluting at first with ethyl ether and then with an ether-ethyl acetate mixture (9:1), and 1.5 g of the expected product is collected.2.4 g of the product obtained in this manner is dissolved in methylene chloride, the filtered solution is diluted with isopropyl ether and then concentrated to expel the methylene chloride.
After cooling and separating, 2.18 g of crystallized product is obtained. A purified product is obtained by recrystallizing from a mixture of methylene chloride-ethanol and then triturating in ethanol at reflux.
M.P. = 286 C. [OI]D = + 112.5 + 1.5 (c = 1% CHCl3) Analysis : C27H31NO2
Calculated : C% : 80.76 H% : 7.78 N% : 3.49 Found : 80.6 8.1 3.3 Example 3: 17ss-hydroxy- 1 l ydroxy- Ip-[4-(methylamino)phenyl]- - 17a-(prop-l-ynyl)-estra-4,9-dien-3-one. Stage A
: 3,3-[ethanediyl-bis(oxy)l-l ss-[4(N-methyl- -N-allylamino)phenyl]-17ss-(prop-l-ynyl)-estra-9-en-5α,17ss- diol.
1) Preparation of 4-bromo-N-methyl-N-allylaniline.
a )N-methyl-4-bromoaniline.
Over 45 minutes and under an inert atmosphere, a solution containing 179 g of bromine in 120 cm3 of acetic acid is added over 45 minutes to a mixture of 120 g of N-methylaniline in 600 cm3 of acetic acid while the temperature is kept below 40"C.
After agitating for an hour and a quarter, letting the temperature return to ambient, then pouring over a mixture of water and ice, made alkaline by sodium carbonate to a pH of 10, extracting with methylene chloride, washing the methylene chloride phases with a saturated sodium chloride solution, drying, and concentrating to dryness under reduced pressure, 213 g of the expected product is collected.
b)4-bromo-N-methyl-N-allylaniline.
280 cm3 of an ethereal solution of ethyl magnesium bromide is added drop by drop under an inert atmosphere to 50.05 g of the product obtained at Stage a) while maintaining the temperature below 20"C.
After agitating for 30 minutes, 28 cm3 of allyl bromide is added over 15 minutes and the mixture heated at reflux for 40 minutes. The mixture is allowed to cool, and then drop by drop 25 cm3 of a N ethyl magnesium bromide solution is added, with agitation for 25 minutes. The resulting mixture is poured on to an iced solution of ammonium chloride; the aqueous phase is decanted and extracted with methylene chloride, the extracts are dried and concentrated to dryness, and 61.35 g of the expected product is collected.
2)Preparation of magnesium compound.
A suspension of 1.4 g of magnesium in 10 cm3 of tetrahydrofuran is heated to 40oC, and several drops of a solution of 9.4 g of 4-bromo-N-methyl-N-allylaniline in 26 cm3 of tetrahydrofuran are added.
The release of the magnesium compound is started by adding several drops of ethylene bromide, and then the addition of the solution of the bromide derivative is continued over 30 minutes so as to maintain the temperature at 60 C.
The temperature is maintained at 60 C in an oil bath for 30 minutes more, then the product is cooled and titrated with iodine = 0.93 M/litre.
3) Condensation.
A solution of 4.4 g of 5a, 100-epoxy-3,3-[1,2-ethanediyl- bis(oxy)]-17(Z-(prop-l-vnyl)-estra-9(11)en-17ss-ol (prepared as in Example 5 of European specification 57115) in 44 cm3 of tetrahydrofuran is cooled in a bath to OOC to which is added 450 mg of cuprous chloride, and then drop by drop over 40 minutes 34 cm3 of 0.93 M magnesium derivative prepared as described above is added. The mixture is left for an hour at 0 C, diluted with 50cm3 of tetrahydrofuran, and then poured into a solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed, dried and evaporated under reduced pressure, and 10.7 g of impure product is obtained.The product is filtered on silica (eluent : benzene-ethyl acetate 7:3). 5.2 g of the expected product is obtained, which is used as it is for the following Stage.
Stage B : 3,3-[ethanediyl-bis(oxy)]-11ss-[4-(methylamino)- phenyl]-17a-(prop-l-ynyl)-estra-9-en-5a,17ss-diol.
100 mg of Wilkinson reagent [chlorotris(triphenylphosphine) rhodium] is added to a solution of 1 g of the product obtained at Stage A in 10 cm3 of ethanol and heated to reflux. After 30 minutes at reflux, the mixture is evaporated under reduced pressure, and the product obtained is filtered on silica (eluent methylene chloride then ether). The eluents are united, brought to dryness and crystallized from isopropyl ether.After separating, washing and drying, 805 mg of crystals are obtained. M.P. = 225"C.
Analysis : C30H39NO4= 477.65
Calculated : C% : 75.44 H%: 8.23 N% :2.93
Found : 75.7 8.4 2.9 Stage C: 7p-hydroxy-1 1 ss-[4-methylamino)phenyl]-17a- -(prop-l-ynyl)-estra-4,9-dien-3-one.
770 mg of the product obtained at Stage B is dissolved in 7.7 cm3 of methanol and 7.7 cm3 of 2N hydrocloric acid. After an hour of reaction, the mixture is diluted with 10 cm3 of water, then filtered, diluted with a solution of sodium bicarbonate, precipitated and the precipitate is dried at 70"C under reduced pressure.
640 mg of crude product is obtained, which is crystallized from a mixture of methylene chloride-isopropyl ether. 567 mg of purified product is obtained.
An analytical sample is obtained by purifying by chromatography and recrystallizing from a chloroform-isopropyl ether mixture. M.P. = 238 C.
Analysis : C38H33N03 = 415.58
Calculated : C% : 79.96 H% : 7.9 N% : 3.32 Found: 80.1 3.3
8.1 [0']D = + 128.5 t 3Q (c = 1% CHC13) Example 4 : N-[4-[17ss-hydroxy-3-oxo- 17a-prop-l-ynyl)- -estra-4,9-dien- 11 p-yl]phenyl]acetamide.
1.42 g of 11ss-(4-aminophenyl)-17ss-hydroxy-17α-(prop- I-ynyl)-estra-4,9-dien-3-one are suspended in 14 cm3 of benzene and 3.5 cm3 of tetrahydrofuran. 0.37 cm3 of acetic anhydride is added, and the mixture is agitated at ambient temperature for an hour and then poured on to a saturated solution of sodium bicarbonate. After extracting with ethyl acetate, washing with a saturated aqueous solution of sodium chloride, drying, and evaporating the solvent, 1.62 g of crude product is obtained, which is purified by chromatography on silica, eluting with ethyl acetate. 1.524 g of purified product is obtained, which is dissolved in the minimum of methylene chloride and then precipitated by the addition of isopropyl ether.
The precipitate is separated, washed with isopropyl ether and then dried under reduced pressure. 1.47 g of pure product is obtained.Rf 0.28 (pure ethyl acetate
N.M.R. : CDCI3 ppm 0.51(18-Me); 1.91 (CH3-C#C-); 2.16 (CH3CO); 4.4 (H at 11); 5.8 (H at 4).
Example 5: p-l4-(cimethylamino)phen yl]-l 17ss-hydroxy- 3-oxo- 19-nor- 17a-pregna-4,9-dien-20-yne-2 1-carboxylic acid. Stage A : 3,3-[ethanediyl-bis(oxy)l-5a,l -/P-dihydroxy- -11 P-[4-(dimethylamino)phenyl]-l 9- nor-17a-pregna-9-en-20- yne-21-ethyl carboxylate.
Over 30 minutes and at -70OC, 3 cm3 of a 1.68 M solution of n-butyl-lithium in hexane is added to a solution of 10 cm3 of tetrahydrofuran and 0.51 cm3 of ethyl propiolate.
The solution obtained is agitated for 10 minutes, and then over 15 minutes 452 mg of 3,3-[ethanediyl bis(oxy)]-5a-hydroxy- 11p-[4-dimethylamino)phenyl]-estra-9-en-i7-one (prepared as in Example 7 Stage A of European specification 57115) in solution in 4cm3 of tetrahydrofuran is introduced. The mixture is agitated for an hour at -70 C, and then 0.5 cm3 of acetic acid is added.The temperature is allowed to return to ambient, sodium bicarbonate is added, and extraction is carried out with ethyl acetate; the extracts are washed with water, dried and brought to dryness, and 750 mg of the product is obtained, which is chromatographed on silica by eluting with a benzene-ethyl acetate mixture, 3:2, with 1% of triethylamine. A pure product is obtained for analysis by dissolving 470 mg of the product in 8 cm3 of methylene chloride, filtering, adding 20 cm3 of isopropyl ether, concentrating until crystallization starts, cooling, separating, washing in isopropyl ether and then drying under reduced pressure. 370 mg of pure product is obtained. M.P. = 255 C.
Stage B: 11ss-[4-(dimethylamino)phenyl]-17ss-hydroxy- 3-oxo-1 9-nor-i 7a-pregna-4,9-dien-20-yne-2 1 - ethyl carboxylate.
360 mg of the product obtained at Stage A is suspended under nitrogen at ambient temperature in 7 cm3 of ethanol, and 0.7 cm3 of 0.5N hydrochloric acid is added. The solution obtained is heated for 1 hour at 50 C, the ethanol is distilled off, and sodium bicarbonate is added, then after agitation, extraction is carried out with ethyl acetate; the extracts are washed in water, dried then brought to dryness.300 mg of product is obtained, which is chromatographed on silica, eluting with a mixture of petroleum ether (B.P. = 60 -80 C)-ethyl acetate, 1:1. 190 mg of the expected product is obtained.
Analysis : C31H37NO4 Calculated : C% : 76.35 H% : 7.65 N% : 2.87 Found : 76.1 7.8 2.9 [OL]D = +78"C + 1.5 (c = 1% in chloroform)
Stage C 11 ss-[4-(dimethylamino)phenyl]-17ss-hydroxy- -3-oxo-19-nor-17α-pregna-4,9-dien-2O-yne-21- carboxylic acid.
0.4 cm3 of 2N sodium hydroxide is added to a solution of 350 mg of product prepared as at Stage B in 7 cm3 of ethanol. The mixture is heated to 60"C for 30 minutes, brought to ambient temperature, and neutralised with 0.4 cm3 of 2N hydrochloric acid. The ethanol is distilled off, the residue is taken up with 20 cm3 of methylene chloride, washed in water, dried then brought to dryness. 300 mg of product is obtained, which is chromatographed on silica (eluent : methylene chloride-methanol 8:2).
The fractions of Rf = 0.15 are brought to dryness, 200 mg of the expected amorphous product is obtained.
Claims (26)
1. A compound which is an estrane of formula (X):
or a salt thereof, wherein
R"'represents -CH2OH, -COOH or -CH,; and when R"' represents -CH2OH or -COOH, R' and R" each represent a methyl group; and
when R"' represents -CH3, R' and R" each represent a hydrogen atom, or one represents a hydrogen atom and the other a methyl group or an acetyl group.
2. A compound which is an estrane of formula (A):
or a salt thereof, wherein R11 represents a hydrogen atom or a methyl group.
3. 11 p-[-(dimethylamino)phenyl]-l 7p-hydroxy-170(-(3- hydroxyprop-l-ynyl)-estra-4,9-dien-3-one.
4. 11 p-(4-aminophenyl)-17p-hydroxy-1 70'-(prnp-l-ynyl)- estra-4,9-dien-3-one.
5. 11 ss[4-(methylamino)phenyl]-17ss-hydroxy-17α-(prop- I-ynyl)-estra-4,9-dien-3-one.
6. N-[4-[1 7p-hydroxy-3-oxo-1 7a(prop-l-ynyl)-estra-4,9- dien-1 1 ss-yl]phenyl]acetamide.
7. 11 p-[4-(dimethylamino)phenyl]-l 7p-hydroxy-3-oxo-l 9- nor-17α-pregna-4,9-dien-20-yne-21-carboxylic acid.
8. A Pharmaceutically acceptable addition salt of a compound claimed in any one of claims 3-7 with an acid.
9. A process for preparing a compound claimed in claim 2, which process comprises reacting a propyne of formula (C):
wherein R,1 is as defined in claim 2 and K represents a protected ketone group in the ketal form, with a dehydrating agent able to free the ketone function.
10. A process for preparing an estrane claimed in claim 7 or a salt thereof, which process comprises reacting a carboxypropyne of formul (E):
wherein K represents a protected ketone group in the ketal form and T represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, with a dehydrating agent able to free the ketone funtion, to produce a ketone of formula (F):
which, when T represents an alkyl radical, is reacted with a saponification agent so as to product the desired compound.
11. A process for preparing a compound claimed in any one of claims 1-8, which process is performed substantially as described wherein.
12. A process for preparing a compound claimed in any one of claims 1-8, which process is performed substantially as described herein in any one of the Examples.
13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient together with a compound which is an estrane claimed in any one of claims 1-7 or a pharmaceutically acceptable salt thereof.
14. A composition according to claim 13 which is solid.
15. A composition according to claim 13 in the form of compressed tablets, gelatin capsules, gran uies, suppositories, injectable preparations, ointments, creams or gels.
16. A composition according to claim 13 wherein the excipient is talc, gum arabic, lactose, starch, magnesium stearate, a fatty substance of animal or vegetable origin, a parafin derivative or a glycol.
17. A composition according to claim 13 which contains a wetting, dispersing or emulsifying agent or a preservative.
18. A composition according to claim 13 substantially as described herein.
19. For use in a method of treatment of the human or animal body by therapy, a compound which is an estrane claimed in any one of claims 1-7 or a pharmaceutically acceptable salt thereof.
20. A compound claimed in claim 19 substantially as described herein.
21. A compound claimed in claim 19 substantially as described herein in any one of the Examples.
22. An allylamine of formula (B):
or a salt thereof, wherein K represents a protected ketone group in the ketal form and R',1 and R",1 either each represent an allyl group or one represents an allyl group and the other a methyl radical.
23. An ester of formula (F'):
or a salt thereof, wherein Alk represents an alkyl group containing from 1 to 4 carbon atoms.
24. A process for preparing an allylamine or salt thereof claimed in claim 22 or an ester or salt thereof claimed in claim 23, which process is performed substantially as described herein.
25. A process for preparing an allylamine or salt thereof claimed in claim 22 or an ester or salt thereof claimed in claim 23, which process is perfdrmed substantially as described herein in any one of the Examples.
26. A method of contraception, which method comprises administering to a human or animal female an effective amount of an estrane claimed in any one of claims 1-7 or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8410304A FR2566779B2 (en) | 1984-06-29 | 1984-06-29 | NOVEL 11B SUBSTITUTED STEROID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8516387D0 GB8516387D0 (en) | 1985-07-31 |
| GB2160873A true GB2160873A (en) | 1986-01-02 |
| GB2160873B GB2160873B (en) | 1988-03-09 |
Family
ID=9305596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08516387A Expired GB2160873B (en) | 1984-06-29 | 1985-06-28 | 11b-(4-aminophenyl) estra-4,9-dienes |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS6118798A (en) |
| CH (1) | CH666277A5 (en) |
| DE (1) | DE3523297A1 (en) |
| FR (1) | FR2566779B2 (en) |
| GB (1) | GB2160873B (en) |
| IT (1) | IT1184285B (en) |
| NL (1) | NL8501868A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0411733A2 (en) * | 1989-08-04 | 1991-02-06 | Schering Aktiengesellschaft | 11-Beta-aryle-gona-4,9-dien-3-ones |
| EP0414606A2 (en) * | 1989-08-23 | 1991-02-27 | Roussel-Uclaf | Omega-phenyl amino alkanoic acids, substituted on the phenyl ring by a 19-nor steroid group, their salts, a process for their preparation and intermediates of this process, their use as medicines and pharmaceutical compositions thereof |
| FR2654337A1 (en) * | 1989-11-15 | 1991-05-17 | Roussel Uclaf | NOVEL BIODEGRADABLE INJECTABLE MICROSPHERES PREPARATION METHOD AND INJECTABLE SUSPENSIONS CONTAINING THEM. |
| US5407928A (en) * | 1990-08-15 | 1995-04-18 | Schering Aktiengesellschaft | 11β-aryl-gona-4,9-dien-3-ones |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3619413C2 (en) * | 1986-06-10 | 2000-04-06 | Schering Ag | 9alpha, 10alpha-methylene-estrene, their preparation and pharmaceutical preparations containing them |
| DE3621024C2 (en) * | 1986-06-20 | 1999-10-28 | Schering Ag | 11beta-phenylestradienes, their preparation and pharmaceutical preparations containing them |
| BE1004905A4 (en) * | 1987-12-30 | 1993-02-23 | Roussel Uclaf | NOVEL 17BETA-OH 19-NOR DERIVATIVES SUBSTITUTED IN 17ALPHA, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2651435A1 (en) * | 1989-09-07 | 1991-03-08 | Roussel Uclaf | NEW USE OF ANTI-PROGESTOMIMETIC COMPOUNDS. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0057115A2 (en) * | 1981-01-09 | 1982-08-04 | Roussel-Uclaf | Steroid derivatives substituted in the 11-beta position, process for their preparation, their utilization as medicaments and compositions containing them |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2377418A1 (en) * | 1977-01-13 | 1978-08-11 | Roussel Uclaf | NEW 4,9-DIENIC 11B-SUBSTITUTE STEROID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| FR2528434B1 (en) * | 1982-06-11 | 1985-07-19 | Roussel Uclaf | NOVEL 19-NOR STEROIDS SUBSTITUTED IN 11B AND POSSIBLY IN 2, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS A MEDICAMENT |
| DE3321826A1 (en) * | 1983-06-15 | 1984-12-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | 13 alpha -Alkylgonanes, the preparation thereof and pharmaceutical products containing these |
-
1984
- 1984-06-29 FR FR8410304A patent/FR2566779B2/en not_active Expired
-
1985
- 1985-06-28 NL NL8501868A patent/NL8501868A/en not_active Application Discontinuation
- 1985-06-28 GB GB08516387A patent/GB2160873B/en not_active Expired
- 1985-06-28 IT IT48298/85A patent/IT1184285B/en active
- 1985-06-28 JP JP60140687A patent/JPS6118798A/en active Pending
- 1985-06-28 DE DE19853523297 patent/DE3523297A1/en not_active Ceased
- 1985-06-28 CH CH2772/85A patent/CH666277A5/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0057115A2 (en) * | 1981-01-09 | 1982-08-04 | Roussel-Uclaf | Steroid derivatives substituted in the 11-beta position, process for their preparation, their utilization as medicaments and compositions containing them |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991001958A3 (en) * | 1989-08-04 | 1991-12-12 | Schering Ag | 11β-ARYL-GONA-4,9-DIEN-3-ONES |
| WO1991001958A2 (en) * | 1989-08-04 | 1991-02-21 | Schering Aktiengesellschaft Berlin Und Bergkamen | 11β-ARYL-GONA-4,9-DIEN-3-ONES |
| EP0411733A3 (en) * | 1989-08-04 | 1992-01-22 | Schering Aktiengesellschaft Berlin Und Bergkamen | 11-beta-aryle-gona-4,9-dien-3-ones |
| EP0411733A2 (en) * | 1989-08-04 | 1991-02-06 | Schering Aktiengesellschaft | 11-Beta-aryle-gona-4,9-dien-3-ones |
| FR2651233A1 (en) * | 1989-08-23 | 1991-03-01 | Roussel Uclaf | NOVEL OMEGA-PHENYLAMINO ALKANOUIC ACIDS SUBSTITUTED ON THE AROMATIC CORE BY A RADICAL DERIVED FROM 19-NORTHERNIDES, PROCESS FOR PREPARING THEM, THEIR APPLICATION AS DRUGS AND COMPOSITIONS COMPRISING THE SAME. |
| EP0414606A3 (en) * | 1989-08-23 | 1991-07-24 | Roussel-Uclaf | Omega-phenyl amino alkanoic acids, substituted on the phenyl ring by a 19-nor steroid group, their salts, a process for their preparation and intermediates of this process, their use as medicines and pharmaceutical compositions thereof |
| EP0414606A2 (en) * | 1989-08-23 | 1991-02-27 | Roussel-Uclaf | Omega-phenyl amino alkanoic acids, substituted on the phenyl ring by a 19-nor steroid group, their salts, a process for their preparation and intermediates of this process, their use as medicines and pharmaceutical compositions thereof |
| AU634569B2 (en) * | 1989-08-23 | 1993-02-25 | Hoechst Marion Roussel | New omegaphenylamino alkanoic acids substituted on the aromatic nucleus by a radical derived from 19-nor steroids, their salts, their preparation process and the new intermediates of this process, their use as medicaments and the compositions containing them |
| FR2654337A1 (en) * | 1989-11-15 | 1991-05-17 | Roussel Uclaf | NOVEL BIODEGRADABLE INJECTABLE MICROSPHERES PREPARATION METHOD AND INJECTABLE SUSPENSIONS CONTAINING THEM. |
| BE1005511A4 (en) * | 1989-11-15 | 1993-08-31 | Roussel Uclaf | Use of new injectable biodegradable microspheres, microspheres of these new method of preparation and injection suspensions containing. |
| AT400298B (en) * | 1989-11-15 | 1995-11-27 | Roussel Uclaf | USE OF INJECTABLE, BIODEGRADABLE MICROBALLS, METHOD FOR THEIR PRODUCTION AND INJECTABLE SUSPENSIONS CONTAINING THE SAME |
| US5407928A (en) * | 1990-08-15 | 1995-04-18 | Schering Aktiengesellschaft | 11β-aryl-gona-4,9-dien-3-ones |
| US5739125A (en) * | 1990-08-15 | 1998-04-14 | Schering Aktiengesellschaft | 11 Beta-aryl-gona-4, 9-dien-3-ones |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2566779A2 (en) | 1986-01-03 |
| CH666277A5 (en) | 1988-07-15 |
| DE3523297A1 (en) | 1986-01-09 |
| NL8501868A (en) | 1986-01-16 |
| GB8516387D0 (en) | 1985-07-31 |
| FR2566779B2 (en) | 1987-03-06 |
| IT8548298A0 (en) | 1985-06-28 |
| GB2160873B (en) | 1988-03-09 |
| JPS6118798A (en) | 1986-01-27 |
| IT1184285B (en) | 1987-10-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20010628 |