Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-11
2003-11-11
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S177000, C514S178000, C514S179000, C514S182000, C514S841000, C514S842000, C514S843000
Reexamination Certificate
active
06645953
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmacologically active compounds and to their use as medicaments. More particularly it has been found that the sterol derivatives of the invention are useful for regulating meiosis.
BACKGROUND
Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1n) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1c DNA.
The meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly. All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty. Thus, from early life the female has a stock of oocytes which is drawn upon until the stock is exhausted. Meiosis in females is not completed until after fertilization, and results in only one ovum and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces four spermatozoa.
Only little is known about the mechanisms which control the initiation of meiosis in the male and in the female. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, could be responsible for meiotic arrest (Downs, S M et al.
Dev Biol
82 (1985) 454-458; Eppig, J J et al.
Dev Biol
119 (1986) 313-321; and Downs, S M
Mol Reprod Dev
35(1993) 82-94).
SUMMARY OF THE INVENTION
The instant invention provides compounds and methods useful for relieving infertility in females and males, particularly in mammals, more particularly in humans. These compounds and methods are useful as contraceptives in females and males, particularly in mammals, more particularly in humans. Further, methods are described for using the instant compounds for regulating meiosis in oocytes and in male germ cells.
In its broadest aspect, the present invention relates to compounds of formula (I)
wherein R
1
and R
2
, independently, are selected from the group consisting of hydrogen and branched or unbranched C
1
-C
6
alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R
1
and R
2
together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R
3
is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR
26
wherein R
26
is hydrogen or C
1
-C
3
alkyl, halogen, and hydroxy and C
1
-C
4
alkyl bound to the same carbon atom of the sterol skeleton, or designates, together with R
9
or R
14
, an additional bond between the carbon atoms to which R
3
and R
9
or R
14
are bound; R
4
is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR
27
wherein R
27
is hydrogen or C
1
-C
3
alkyl, halogen, and hydroxy and C
1
-C
4
alkyl bound to the same carbon atom of the sterol skeleton, or R
4
designates, together with R
13
or R
15
, an additional bond between the carbon atoms to which R
4
and R
13
or R
15
are bound; R
5
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, methylene, hydroxy, methoxy, oxo, and ═NOR
22
wherein R
22
is hydrogen or C
1
-C
3
alkyl, or R
5
designates, together with R
6
, an additional bond between the carbon atoms to which R
5
and R
6
are bound; R
6
is hydrogen or R
6
designates, together with R
5
, an additional bond between the carbon atoms to which R
5
and R
6
are bound; R
9
is hydrogen or R
9
designates, together with R
3
or R
10
, an additional bond between the carbon atoms to which R
9
and R
3
or R
10
are bound; R
10
is hydrogen or R
10
designates, together with R
9
, an additional bond between the carbon atoms to which R
10
and R
9
are bound; R
11
is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR
28
wherein R
28
is hydrogen or C
1
-C
3
alkyl, halogen and hydroxy and C
1
-C
4
alkyl bound to the same carbon atom of the sterol skeleton, or R
11
designates, together with R
12
, an additional bond between the carbon atoms to which R
11
and R
12
are bound; R
12
is selected from the group consisting of hydrogen, C
1
-C
3
alkyl, vinyl, C
1
-C
3
alkoxy and halogen, or R
12
designates, together with R
11
, an additional bond between the carbon atoms to which R
12
and R
11
are bound; R
13
is hydrogen or R
13
designates, together with R
4
or R
14
, an additional bond between the carbon atoms to which R
13
and R
4
or R
14
are bound; R
14
is hydrogen or R
14
designates, together with R
3
, R
6
or R
13
, an additional bond between the carbon atoms to which R
14
and R
3
or R
6
or R
13
are bound; R
15
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR
23
wherein R
23
is hydrogen or C
1
-C
3
alkyl, or R
15
designates, together with R
4
, an additional bond between the carbon atoms to which R
15
and R
4
are bound; R
16
is selected from the group consisting of hydrogen, C
1
-C
3
alkyl, methylene, hydroxy, methoxy, oxo and ═NOR
24
wherein R
24
is hydrogen or C
1
-C
3
alkyl, or R
16
designates, together with R
17
, an additional bond between the carbon atoms to which R
16
and R
17
are bound; R
17
is hydrogen or R
17
designates, together with R
16
, an additional bond between the carbon atoms to which R
17
and R
16
are bound; R
18
and R
19
are independently hydrogen or fluoro; R
25
is selected from the group consisting of C
1-4
alkyl, methylene, hydroxy and oxo; A is a carbon atom or a nitrogen atom; when A is a carbon atom, R
7
is selected from the group consisting of hydrogen, hydroxy and fluoro, and R
8
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, methylene and halogen, or R
7
designates, together with R
8
, an additional bond between the carbon atoms to which R
7
and R
8
are bound; R
20
is selected from the group consisting of C
1
-C
4
alkyl, trifluoromethyl and C
3
-C
6
cycloalkyl and R
21
is selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
hydroxyalkyl, C
1
-C
4
haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C
3
-C
6
cycloalkyl, or R
20
and R
21
, together with the carbon atom to which they are bound, form a C
3
-C
6
cycloalkyl ring; and when A is a nitrogen atom, R
7
designates a lone pair of electrons and R
8
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl and oxo; R
20
and R
21
are, independently, C
1
-C
4
alkyl or C
3
-C
6
cycloalkyl; provided that the compound of formula (I) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
Cholest-7-ene-3&bgr;-ol;
4-Methylcholest-7-ene-3&bgr;-ol;
4-Ethylcholest-7-ene-3&bgr;-ol;
4,4-Dimethylcholest-7-ene-3&bgr;-ol;
4&agr;-Methyl-4&bgr;-ethylcholest-7-ene-3&bgr;-ol;
4&agr;-Ethyl-4&bgr;-methylcholest-7-ene-3&bgr;-ol;
4,4-Diethylcholest-7-ene-3&bgr;-ol;
4-Propylcholest-7-ene-3&bgr;-ol;
4-Butylcholest-7-ene-3&bgr;-ol;
4-Isobutylcholest-7-ene-3&bgr;-ol;
4,4-Tetramethylenecholest-7-ene-3&bgr;-ol;
4,4-Pentamethylenecholest-7-ene-3&bgr;-ol;
Cholest-8-ene-3&bgr;-ol;
4-Methylcholest-8-ene-3&bgr;-ol;
4-Ethylcholest-8-ene-3&bgr;-ol;
4,4-Dimethylcholest-8-ene-3&bgr;-ol;
4&agr;-Methyl-4&bgr;-ethylcholest-8-ene-3&bgr;-ol;
4&agr;-Ethyl-4&bgr;-methylcholest-8-ene-3&bgr;-ol;
4,4-Diethylcholest-8-ene-3&bgr;
Faarup Peter
Gronvald Frederik Christian
Guddal Erling
Badio Barbara P.
Began, Esq. Marc A.
Book, Esq. Richard W.
Green, Esq. Reza
Novo Nordisk A S
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