Steroids, their preparation, pharmaceutical compositions...

Details Steroids, their preparation, pharmaceutical compositions... Steroids, their preparation, pharmaceutical compositions...

2001-08-01

2003-02-04

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S557000, C552S582000, C552S592000, C552S598000

Reexamination Certificate

active

06514956

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to steroid compounds and pharmaceutical acceptable salts thereof, a method for preparation thereof, pharmaceutical compositions containing the same as active component, and their use in the preparation of medicines for treating diseases associated with progestogen dependence and for fertility control, abortion or contraception and for anticancer use.
BACKGROUND OF THE INVENTION
Mifepristone (11&bgr;-[4-(N,N-dimethylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene -3-one) is a steroid compound which is disclosed in French Patent No. 2, 497, 807 to Rousell-Uclaf, published May 31, 1983. It is the first progesterone receptor antagonist put into clinical application and is a new type of anti-progestin. It binds to progesterone receptor and glucocorticoid receptor, having an affinity with progesterone receptor in rabbit endometrium five-fold higher than that of progesterone and thereby having strong anti-progesterone effect. It causes degeneration of pregnant villus tissue and decidual tissue, endogenous prostaglandin (PG) release, luteinizing hormone decrease, corpus luteum dissolution, and necrosis of embryo sac whose development depends on corpus luteum, leading to abortion. Therefore, it can be used as a non-surgical medicine for stopping early pregnancy. It can also be used, inter alia, in contraception and as an antineoplastic. (The Antiprogestin Steroid Ru486 and Human Fertility Control, 1985, New York: Plenum Press).
Onapristone (11&bgr;-[4-(N,N-dimethylamino)phenyl]-17&agr;-hydroxy-17&bgr;-(3-hydroxypropyl)-13&agr;-4,9-estradiene-3-one), is a steroid compound which is disclosed in German Patent No. 3, 321, 826 to Schering A G, published Dec. 20, 1984. It has a strong antiprogestin activity and can be used in abortion (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), anticancer (Breast Cancer Research and Treatment, 1989, 14:275-288), etc. It was reported that onapristone had toxicity to human liver (European Journal of Cancer, 1999, 35(2): 214-218).
Lilopristone (11&bgr;-[4-(N,N-dimethylamino)phenyl]-17&agr;-[3-hydroxy-1(Z)-propenyl]-17&bgr;-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3, 347, 126 to Schering A G, published Jul. 11, 1985. It has a strong antiprogestin activity and can be used in abortion, contraception (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), etc. It was reported that the clinical effect of lilopristone in stopping early pregnancy was only equivalent to that of mifepristone (Human Reproduction, 1994, 9(1): 57-63).
ZK112993 (11&bgr;-(4acetylphenyl)-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3, 504, 421 to Schering A G, published Aug. 7, 1986. It has a potent antiprogestin activity and can be used in, inter alia, anticancer (Anticancer Res., 1990, 10: 683-688).
In European Patent No. 321, 010 to Akzo N V, The Netherland published Jun. 21, 1989 are disclosed “11-arylsteroid compounds” having a strong antiprogestin activity.
OBJECT OF THE INVENTION
An object of the invention is to provide a class of steroid compounds of pharmaceutical value, especially having antiprogestin effect.
Another object of the invention is to provide a method for preparation of the steroid compounds.
Still another object of the invention is to provide pharmaceutical compositions for treating diseases associated with progestin dependence, and for fertility control, abortion or contraception and neoplasm control.
A further object of the invention is to provide use of said steroid compounds and pharmaceutical compositions in the preparation of medicines for treating diseases associated with progestin dependence, and for fertility control, abortion or contraception and neoplasm control.
DETAILED DESCRIPTION OF THE INVENTION
The steroid compounds of the present invention has the following general formula (I):
wherein R
1
is cyclohexyl or cycloheptyl, R
2
is hydrogen or C
1
-C
6
alkyl, R
3
is hydrogen, C
1
-C
6
alkyl or methylol, R
4
is hydrogen or hydroxymethylene (═CHOH).
The compounds of the present invention can be existed in the form of their salts. Also, due to multiple asymmetric carbon atoms contained therein, there may be many isomers of the compounds. These salts and isomers all fall within the scope of compounds of the present invention sought for protection.
The compounds of formula (I) of this invention are preferably those wherein R
2
is hydrogen or methyl and R
3
is methyl or methylol.
More preferred compounds of the invention include:
11&bgr;-[4-(N-methyl-N-cyclohexylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-cyclohexylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
2-hydroxymethylene-11&bgr;-[4-(N-methyl-N-cyclohexylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-methyl-N-cyclohexylamino)phenyl]-17&agr;-(3-hydroxy-1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-cyclohexylamino)phenyl]-17&agr;-(3-hydroxy-1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-methyl-N-cycloheptylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-cycloheptylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
2-hydroxymethylene-11&bgr;-[4-(N-methyl-N-cycloheptylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-methyl-N-cycloheptylamino)phenyl]-17&agr;-(3-hydroxy-1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one,
11&bgr;-[4-(N-cycloheptylamino)phenyl]-17&agr;-(3-hydroxy-1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one.
The preparation method of the present invention includes the following single- or multi-step procedures:
1. Method for the preparation of 11&bgr;-[4-(N-methyl-N-cyclohexylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one (VI) which includes the following steps:
(1) Preparation of Grignard Reagent (III)
4-bromo-N-methyl-N-cyclohexylaniline (II) is reacted with magnesium in tetrahydrofuran (THF) to obtain Grignard reagent of formula (III).
(2) C
11
Additive Reaction
Compound of formula (IV) and the Grignard reagent of formula (III) prepared in step (1) are brought to an additive reaction to obtain compound of formula (V).
(3) Hydrolytic Reaction
The compound of formula (V) prepared in step (2) is subjected to a Hydrolytic reaction to obtain compound of form (VI).
2. Method for preparation of 11&bgr;-[4-(N-cyclohexylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one (XI) which includes the following steps:
(1) Preparation of Grignard Reagent of Formula (IX)
4-bromo-N-cyclohexylaniline (VII) is first protected by trimethylchlorosilane, then reacted with magnesium in THF to obtain Grignard reagent of formula (IX).
(2) C
11
Additive Reaction
Compound of formula (IV) and the Grignard reagent of formula (IX) prepared in step (1) are brought to an additive reaction to obtain compound of formula (X).
(3) Hydrolytic Reaction
The compound of formula (X) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of formula (XI).
3. Method for preparation of 2-hydroxymethylene-11&bgr;-[4-(N-methyl-N-cyclohexylamino)phenyl]-17&agr;-(1-propinyl)-17&bgr;-hydroxy4,9-estradiene-3-one (XII) which includes a formylation reaction as follows:
Compound of formula (VI) is subjected to a formylation reaction to obtain compound of formula (XII).
4. Method for preparation of 11&bgr;-[4-(N-methyl-N-cyclohexylamino)phenyl)]-17&agr;-(3-hydroxy-1-propinyl)-17&bgr;-hydroxy-4,9-estradiene-3-one (XVII) which includes the following steps:
(1) C
11
Additive Reaction
Compound of formula (XIII) and the Grignard reagent of formula (III) prepared in step (1) according to claim 13 are brought to an additive reac

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