Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-09-06
2003-01-28
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
active
06512130
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel analogue 11&bgr;-[4-(N,N-dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(3-methyl-1-butynyl)-estra-4,9-dien-3-one of the structural formula 1,
of Mifepristone of the structural formula 6
The present invention also relates to a process for the preparation of the novel analogue 11&bgr;-[4(N,N-dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(3-methyl-1-butynyl)-estra-4,9-dien-3-one from estra-5(10), 9(11)-diene-3,17-dione-cyclic-3-(1,2-ethanediylacetal) of the structural formula 2.
The present invention also relates to the use of the compound of formula 1 as a progesterone receptor.
BACKGROUND OF THE INVENTION
Mifeprestone (RU-486) of structural formula 6 above is an important antiprogestin that effectively and safely terminates early pregnancy and also has a wide range of other clinical features such as antiglucocorticold and anti-cancer properties. It has also shown promising activity in the treatment of estrogen dependent gynaecological disorders and hormone deficient tumours.
The compound of structural formula 2 can be prepared from (+)-estrone in seven steps. Methylation of hydroxy group at C-3 in (+)-estrone, reduction of 17-ketone to 17&bgr;-alcohol followed by Birch reduction of ring A and mild hydrolysis of the enol ether to afford estra-17&bgr;-hydroxy-5(10)-en-3-one in four steps (Ref: Wilds, A. L. and Nelson, N. A.
J. Am. Chem. Soc
. 1953, 75, 5365-5369). This compound in another three steps, namely bromination and dehydrobrominatlon, ketalisation followed by Oppenauer oxidation yield compound having structural formula 2 (Ref: Perelman, M; Farkas, E.; Fornefield, E. J.; Kraay, R. J. and Rapala, B. T.
J. Am. Chem. Soc
. 1960, 82, 2402-2403).
U.S. Pat. No. 4,386,085 describes the synthesis of steroids of the general formula mentioned therein and exemplifies as many as 319 compounds covered by the said general formula. However, the analog of the invention is not mentioned at all in the said patent, nor is there any guidance towards the compound of formula 6 of the invention or its enhanced activity as a progesterone receptor.
OBJECTS OF THE INVENTION
It is an object of the invention to provide novel steroids with enhanced progesterone receptor activity.
It is another object of the invention to provide processes for the preparation of such novel steroids.
Accordingly, the present invention relates to a novel analog 11&bgr;-[4-(N,N-dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(3-methyl-1-butynyl)-estra 4,9-dien-3-one of the structural formula 1,
of Mifepristone of the structural formula 6.
SUMMARY OF THE INVENTION
The present invention also relates to a process for the preparation of 11&bgr;-[4-(N,N-dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(3-methyl-1-butnyl)-estra-4,9-dien-3-one of the structural formula 1,
said process comprising,
i. generating 3-methyl-1-butynyl lithium in situ by the addition of butyl lithium to a solution of 1,1-dibromo-3-methyl-1-butene in an organic solvent at a temperature in the range of −50° C. to −60° C., maintaining the reaction mixture at a temperature of −45° C. to −40° C. for a period in the range of 1 to 2 hours;
ii. adding to this resultant mixture a solution of compound of the structural formula 2 at a temperature in the range of −40° C. to 0° C., stirring the reaction mixture for a period ranging between 1 to 2 hours at a temperature in the range of from −10° C. to 0° C., quenching the reaction mixture with a quenching agent, extracting the crude product having a structural formula 3 in an organic layer removing the solvent under vacuum, further purifying the crude compound 3 by any conventional method;
iii. converting the compound of structural formula 3 into a compound of the structural formula 4
by preparing a solution of the compound having structural formula 3 in an organic solvent and adding drop wise an oxidising agent to this solution in the presence of a catalyst and buffer of pH 10 under constant stirring, maintaining the reaction temperature below 5° C.; bringing the temperature to ambient and continuing the stirring for 4 to 6 hours; extracting the crude compound 4 in a chlorinated solvent, separating the organic layer and quenching it with reducing agent, removing the solvent under vacuum and further purifying the crude product to obtain pure compound having the structural formula 4;
iv. converting the compound of formula 4 into a compound of formula 5
by preparing 4-(N,N-dimethylamino)phenyl magnesium bromide reagent; adding the solution of the above reagent to a mixture of a compound of formula 4 and a catalyst in an organic solvent at a temperature below −10° C., stirring the mixture for a period of 2 to 24 hours at a temperature in the range of −10° C. to 25° C., quenching the reaction mixture, extracting the compound 5 in an organic solvent, removing the solvent at a temperature below 20° C. under vacuum, further purifying the crude product to obtain the pure compound having the structural formula 5;
v. converting the compound of formula 5 to compound of formula 1 by treating the compound of formula 5 with an acid (60 to 70%) at a temperature in the range of 50° C. to 55° C. for 2 to 3 hours, neutralising with a base, extracting the crude product in organic solvent, separating the organic layer, removing the solvent under vacuum, further purifying the crude product by any conventional method to obtain the pure compound of formula 1.
In one embodiment of the invention, the organic solvent used in step i. for lithlation of 1,1-dibromo-3-methyl-1-butene is selected from the group comprising of dietylether, tetrahydrofuran, and dimethoxyethane.
In another embodiment of the invention, the quenching agent used in step ii may be selected from NH
4
Cl and HCl.
In another embodiment of the invention, the organic solvent used in step ii for the extraction of the compound of formula 3 may be selected from diethylether, ethyl acetate, chloroform, and dichloromethane.
In a further embodiment of the invention, the organic solvent used in step iii for preparing the solution of the compound of formula 3 may be selected from dichloromethane, chloroform and dichloroethane.
In yet another embodiment of the invention, the oxidising agent used in step iii may be selected from hydrogen peroxide, t-butyl hydroperoxide and 3-chloro perbenzoic acid.
In another embodiment of the invention, the catalyst used in step iii may be selected from hexahaloacetone, preferably hexafluoroacetone.
In still another embodiment of the invention, the reducing agent used in step iii for quenching the organic layer may be selected from sodium thiosulphate, sodium bisulphite, and sodium sulphide, preferably sodium thiosulphate.
In yet another embodiment of the invention, the catalyst used in step iv may be cuprous halide preferably cuprous iodide.
In a further embodiment of the invention, the organic used in the reaction may be selected from tetahydrofuran and diethyl ether.
In another embodiment of the invention, the organic solvent used in step iv for extracting the compound of formula 4 may be selected from the group consisting of diethyl ether, ethyl acetate, chloroform, and dichloromethane.
In another embodiment of the invention, the acid used in step v for treating the compound of formula 5 may be selected from the group consisting of acetic acid, hydrochloric acid, p-toluene sulphonic acid, and chloroacetic acid.
In a further embodiment of the invention, the base used for neutralisation in step v may be selected from sodium bicarbonate and potassium bicarbonate.
In another embodiment of the invention, the solvent used for extraction of compound of formula 1 in step v may be selected from the group consisting of diethyl ether, ethyl acetate, chloroform and dichloromethane.
REFERENCES:
Hazra et al., Steroids, vol. 65, pp. 157-162, Mar. 2000.
Basu Sourav
Dwivedi Anila
Hazra Braja Gopal
Joshi Padmakar Laxman
Pore Vandana Sudhir
Badio Barbara P.
Council of Scientific and Industrial Research
Ladas & Parry
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