Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-07-16
2003-03-04
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C552S548000, C552S552000, C552S556000
Reexamination Certificate
active
06528501
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to 22S-hydroxycholesta-8,14-diene derivatives, to pharmaceutical compositions containing the same, as well as to the use of these 22S-hydroxycholesta-8,14-diene derivatives for the preparation of a medicament for the control of fertility.
BACKGROUND OF THE INVENTION
Sexual reproduction involves a cyclic alternation of diploid and haploid states: diploid cells divide by the process of meiosis to form haploid cells, and the haploid cells fuse in pairs at fertilization to form new diploid cells. The process of meiosis is characterized by two meiotic divisions, unique to both male and female germ cells. During the process two cell divisions, following one round of DNA replication, give rise to four haploid cells from one single diploid cell. Chromosomal crossover events, during which paternal and maternal genetic material is exchanged, occur during the prophase of the first meiotic division. At the end of the first meiotic division one member of each chromosome pair, composed of two sister chromatids is distributed to each daughter cell. The second meiotic division segregates each sister chromatide into a separate haploid cell. Male and female germ cells are subject to similar meiotic divisions but differ in the regulation of these processes. In the male meiosis is a continuous process in germ cells derived from a population of immature germ cells, the stem cell spermatogonia. After sexual maturation of the male, spermatogonia from this stem cell population embark on meiosis. The first and second meiotic division proceed without interruption and eventually give rise to four mature spermatozoa.
In the female, primary oocytes start the first meiotic division already during the embryonic stage but they remain arrested in the prophase (dictyate stage) until the female becomes sexually mature. Meiosis resumes at the time of ovulation (egg maturation) after which the first meiotic division is completed and the second meiotic division is initiated. In most vertebrates the second meiotic division is arrested at the metaphase and only completed after fertilization. At the end of the first and of the second meiotic division the cytoplasm divides asymmetrically to produce two secondary oocytes, each with a haploid number of single chromosomes, but greatly differing in size: one is a small polar body, which eventually degenerates, and the other is a large cell containing all the developmental potential. Finally one mature ovum is produced.
The stage at which the developing oocyte is released from the ovary and is ready for fertilization differs in different species. In both invertebrates and vertebrates ovarian accessory cells respond to polypeptides (gonadotropins) produced elsewhere in the body so as to control the maturation of the oocyte and eventually (in most species) ovulation. In humans the primary oocytes of the newborn female are arrested in prophase of meiotic division I and most are surrounded by a single layer of follicle cells; such an oocyte with its surrounding cells constitute the primordial follicle. A small portion of primordial follicles sequentially begins to grow to become developing follicles: the follicle cells enlarge and proliferate to form a multilayered envelope around the primary oocyte; the oocyte itself enlarges and develops the zona pellucida, an extracellular matrix consisting largely of glycoproteins, and cortical granules, specialized secretory vesicles just under the plasma membrane in the outer region, the cortex, of the egg cytoplasm [when the egg is activated by a sperm, these cortical granules release their contents by exocytosis; the contents of the granules act to alter the egg coat so as to prevent other sperms from fusing with the egg].
The developing follicles grow continuously and some of them develop a fluid-filled cavity, or antrum, to become antral follicles. Development of such follicles is dependent on gonadotropins (mainly follicle stimulating hormone -FSH) secreted by the pituitary gland and on estrogens secreted by the follicle cells themselves. Starting at puberty, a surge of secretion by the pituitary of another gonadotropin, luteinizing hormone (LH), activates a single antral follicle to complete its development: the enclosed primary oocyte matures to complete the meiotic division I as the stimulated follicle rapidly enlarges and ruptures at the surface of the ovary, releasing the secondary oocyte within. As is the case with most mammals, the secondary oocyte is triggered to undergo division II of meiosis only if it is fertilized by a sperm.
Studies on the mechanisms controlling initiation and regulation of the meiotic process in male and female germ cells suggest a role for cyclic nucleotides in mediating meiotic arrest. Spontaneous maturation of oocytes can be prevented by compounds that maintain elevated cAMP levels [Eppig, J. and Downs, S. (1984)
Biol. Reprod.
30: 1-11]. Purines, like adenosine or hypoxanthine, are thought to be involved in the cAMP mediated maintenance of meiotic arrest [Eppig, J., Ward-Bailey, P. and Coleman, D. (1985) Biol. Reprod. 33: 1041-1049]. The presence of a meiosis regulating substance in a culture system of fetal mouse gonads was first described by Byskov, A. et al (1976) Dev. Biol. 52: 193-200. It was suggested that the concentrations of a meiosis activating substance (MAS) and a meiosis preventing substance (MPS) regulate the meiotic process in concert [Byskov, A. et al. (1994). In “
The physiology of reproduction
”, Eds. Knobil, E. and Neill, J., Raven Press, New York]. More recently (3&bgr;,5&agr;,20R)-4,4-dimethylcholesta-8,14,24-trien-3-ol (FF-MAS), isolated from human follicular fluid, and (3&bgr;,5&agr;,20R)-4,4-dimethylcholesta-8,24-dien-3-ol, isolated from bull testes, were identified by Byskov, A. et al [(1995),
Nature
374: 559-562] as endogenous meiosis activating substances in human and bovine, respectively. These sterols proved to be able to activate the resumption of meiosis in cultured cumulus enclosed and naked mouse oocytes.
Derivatives of the endogenous sterols, having either a saturated or an unsaturated cholestane side chain, have been disclosed in the international patent applications WO 96/00235, WO97/00884 and WO98/28323 (NOVO NORDISK A/S) as meiosis regulating substances. Meiosis regulating substances are compounds that are agonists or antagonists of a naturally occurring meiosis activating substance. Thus, they might be used in the treatment of infertility or for contraception.
A drawback of the compounds described in the first two patent applications mentioned above is their restricted membrane penetration, which results in accumulation in cell membranes or fatty tissues, thereby restricting their therapeutic potential as fertility control agents. This unwanted accumulation is most probably due to the fysico-chemical properties of these compounds, which resemble those of cholesterol, an important constituent of cell membranes [Norum, K. R. et al (1983)
Physiological Rev.
63: 1343; Babiker, A. et al (1998)
Biochimica
&
Biophysica Acta
1392: 333].
BRIEF SUMMARY OF THE INVENTION
We have now found, that certain 22S-hydroxy substituted cholestane derivatives, i.e. the 22S-hydroxycholesta-8,14-diene derivatives of formula I given below, are highly active as meiosis activating compounds.
DETAILED DESCRIPTION OF THE INVENTION
wherein
R
1
is OR, OSO
3
H or ═NOR; with R being H, (C
1-6
)alkyl or (C
1-6
)acyl;
each of R
2
and R
3
is independently hydrogen or (C
1-6
)alkyl;
R
4
is hydrogen, (C
1-6
)alkyl or (C
1-6
)acyl;
R
5
is hydrogen; or R
5
designates, together with R
6
, an additional bond between the carbon atoms at which R
5
and R
6
are placed;
R
6
is hydrogen, hydroxy or halogen; or R
6
designates, together with R
5
, an additional bond between the carbon atoms at which R
6
and R
5
are placed;
each of R
7
and R
8
is independently hydrogen or (C
1-4
)alkyl, optionally substituted with OH, (C
1-4
)alkoxy, or halogen;
or a pharmaceutically acceptable
Hanssen Robert Gerard Jules Marie
J. van der Louw Jaap
Leysen Dirk D.
Wiersma A. Anja
Akzo Nobel N.V.
Blackstone William M
Milstead Mark W.
Qazi Sabiha
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