Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-01-28
2004-06-22
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C540S008000
Reexamination Certificate
active
06753326
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel equilenin derivatives, methods for producing the same and medicaments containing them.
2. Description of the Related Art
Equilenin itself is an estrogenic steroid obtainable from the urine of pregnant mares.
The novel equilenin derivatives of the invention have an oxygen function on carbon atom 11 and an &agr;-methylene bridge between carbon atoms 14 and 15. Equilenin derivatives with an oxygen function on carbon atom 11 are known. Thus, the racemic 11-oxoequilenin methyl ether was obtained by total synthesis [Tetrahedron Lett. 2763 (1967); Austr. J. Chem. 23, 547 (1970); J. Org. Chem. 39, 2193 (1974)]. A total synthetic route was also used to obtain racemic 11-oxo-3-methoxyestra-1,3,5(10),-6,8,14-hexaen-17&bgr;-ylcarboxylic acid [Tetrahedron Lett. 479 (1968)]. 14&agr;,17&agr;-Bridged equilenin derivatives with an 11-oxygen function were obtained by partial synthesis. The introduction of the 11-oxygen function into the molecule was achieved with Ce(IV) ammonium nitrate [Tetrahedron Lett. 35, 8599 (1994)]. Equilenin derivatives with an &agr;- or &bgr;-methylene bridge between carbon atoms 14 and 15 have also been prepared by partial synthesis whereby the B ring was dehydrogenated with dichlorodicyanobenzoquinone (DDO) [Tetrahedron Lett. 35, 2329 (1994)].
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel equilenin derivatives and a method for producing the same.
According to the invention, this objective is attained by forming equilenin derivatives of general formula (I)
wherein
R
1
denotes a hydrogen atom, a C
1
-C
5
-alkyl group, a C
1
-C
5
-acyl group or a benzoyl group,
R
2
denotes a hydrogen atom and R′
2
denotes a fluorine atom, a hydroxyl group or a C
1
-C
5
-acyloxy group or R
2
and R′
2
together denote an oxo group,
R
3
denotes a hydrogen atom or a methyl group,
R
4
denotes a hydrogen atom and R′
4
denotes a hydroxyl group or a C
1
-C
11
-acyloxy group or R
4
and R′
4
together denote an oxo group, a methylene group, a halomethylene group or a dihalomethylene group and
R
5
denotes a hydrogen atom or a methyl group.
According to the invention, R
6
is preferably a hydrogen atom.
According to the invention, particularly preferred equilenin derivatives are for example:
1) 14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaene-3,11&bgr;,17&bgr;-triol,
2) 11&bgr;,17&bgr;-dihydroxy-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-3-yl benzoate,
3) 11&bgr;,17&bgr;-dihydroxy-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-3-yl propionate,
4) 3,11&bgr;-dihydroxy-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-17&bgr;-yl decanoate,
5) 3,11&bgr;-dihydroxy-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-17-one,
6) 3-methoxy-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-11&agr;,17&bgr;-diyl diacetate,
7) 15&bgr;-methyl-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaene-3,11&bgr;,17&bgr;-triol,
8) 11&bgr;-fluoro-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaene-3,17&bgr;-diol,
9) 3,17&bgr;-dihydroxy-14&agr;,15&agr;-methylene-1,3,5(10),6,8-pentaen-11-one,
10) 3-methoxy-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-11&agr;,17&agr;-diyl diacetate,
11) 3-methoxy-14&agr;,15&agr;-methylene-11-oxoestra-1,3,5(10),6,8-pentaen-17&agr;-yl acetate,
12) 11&bgr;-hydroxy-17,17-difluoromethylene-14&agr;,15&agr;-methylenestra-1,3,5(10),6,8-pentaen-3-yl benzoate, and
13) 14&agr;,15&agr;-17,17-bis-methylenestra-1,3,5(10),6,8-pentaene-3,11&agr;-diol.
For purposes of the present invention, “C
1
-C
6
-alkyl” means a branched or straight-chain alkyl group. Examples are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.butyl, n-pentyl or isopentyl groups.
For purposes of the present patent application, “C
1-6
-acyl or C
1-11
-acyl” means a radical of a straight-chain or branched alkanecarboxylic acid with 1 to 5 or with 1 to 11 carbon atoms, for example a radical of formic, acetic, propionic, butanoic, isobutanoic, heptanoic or undecanoic acid.
For purposes of the present invention, “halogen” means an atom of fluorine, chlorine, bromine or iodine.
The equilenin derivatives of the invention are new. Thus far, they have neither been prepared nor have their properties been described. The equilenin derivatives of the invention exhibit antioxidative activity and minor systemic hormonal action. The antioxidative activity was determined by, among other things, inhibition of iron(II)-catalyzed lipid peroxidation in synaptosomal membrane fractions of rats, by inhibition of copper(II) sulfate-induced LDL cholesterol oxidation and by inhibition of xanthine oxidase and of various other monooxygenases. The systemic estrogen action was evaluated by the Allen-Doisy test in rats. The spectrum of activity of the equilenin derivatives of the invention makes them potentially suitable for therapeutic use in all those cases in which oxygen radicals are in a causal relationship with diseases of organs or tissues, for example in brain or spinal column injuries, states of shock, emphysema, acute respiratory distress syndrome (ARDS), ageing processes, tissue injuries after a myocardial infarction, injuries caused by intoxication or irradiation, burns and transplantation-related immune reactions, such as organ injuries in the reperfusion phase following transplantations, in spinal trauma, stroke, arteriosclerosis, ischemia, chronic-degenerative diseases of the CNS, senile dementia of the Alzheimer type (SDAT), asthma, muscular dystrophy and degenerative neurological diseases, among others, in the form of CNS intoxication or degeneration states. A preferred field of application is geroprophylaxis in women and—because the compounds of the invention exert only minor feminization action—also in men.
The compounds of the invention can be administered orally as well as parenterally. For oral administration, prodrugs in the form of carboxylate esters are particularly advantageous, because they provide active substance levels that remain constant for a long time.
Another object of the present invention is a method for producing the equilenin derivatives of the invention of general formula (I)
wherein R
1
, R
2
, R
2
′, R
3
, R
4
, R
4
′ and R
6
have the afore-indicated meaning, by making a compound of general formula (II)
wherein R
1
, R
2
, R
2
′, R
3
, R
4
, R
4
′ and R
5
have the afore-indicated meaning, react with diphosphorus tetraiodide in the presence of pyridine, and then converting the resulting compound into a compound of general formula (I) in a manner which in itself is known.
It is known that diphosphorus tetraiodide reacts with epoxides and alcohols. Thus, epoxides can be reduced to olefins with diphosphorus tetraiodide [Synthesis 905 (1978); Nouv. J. Chem. 3, 745 (1979)]. Alcohols react with diphosphorus tetraiodide forming iodides [Tetrahedron Letters 1801 (1979); J.C.S. Chem. Commun. 229 (1983)] or with elimination to give olefins [Helv. Chim. Acta 11, 106 (1928)] or to give cumulenes. [Ber. 71, 1899 (1938)]; ibid. 85, 386 (1952); ibid. 87, 598 (1954); J.C.S. Chem. Commun. 885 (1975)]. An outstanding feature of the method of the invention is that the action of diphosphorus tetraiodide on compounds of general formula (II) eliminates the 8,9-oxido group and at the same time introduces an additional double bond between carbon atoms 6 and 7. In this manner, it is possible to produce the equilenin derivatives of the invention having general formula (I) from compounds of general formula II in one step, and to avoid an additional reaction step to introduce the 6,7-double bond [Tetrahedron Letters 35, 2329 (1994)]. Another outstanding feature of the method of the invention—provided that compounds of general formula 11 are used wherein R
2
denotes hydrogen and R
2
′ stands for a hydroxyl group— is that neither elimination of the unprotected hydroxyl group to the corresponding olefin nor substitution of
Kaufmann Guenter
Roemer Wolfgang
Schwarz Sigfrid
Thieme Ina
Undeutsch Bernd
Jenapharm GmbH & Co. KG
Rao Deepak
Striker Michael J.
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