The use of antiprogestogens in combination therapy

 

(57) Abstract:

The invention relates to medicine, in particular to the gynecologist, and can be used to hold a contraceptive or hormone replacement therapy in women. To do this in schemes involving participation of antiprogestogen, as a last offer to use antiprogestogen - Org 33245, entering it in the intermittent mode when the interval between each pair of sequentially input standard dose is more than 1 day. The invention minimizes uterine bleeding at high activity and selectivity impact antiprogestin. 6 N. and 3 C.p. f-crystals, 1 table.

The present invention relates to medicine, in particular to antiprogestogens the steroid 11-aryl, 17-spirometries type. These antiprogesterone compounds known from EP 549041 and EP 582338. As mentioned, therapeutic use of such compounds is determined by several advantages, including enhanced activity and a high selectivity than these compounds differ significantly from compounds of RU 486, which is provided as standard antiprogestogen, currently known in this area.

It was found that the above well-known group of 11-aryl, 17-spirometries steroids, one connection has significantly improved properties for introducing them to the intermittent mode than others. Such a compound described by the structural formula I below, then the description will appear as a Hen 33245:

See the description of the specific compound possesses in the highest degree useful property associated with the fact that it can be used in a specific embodiment, the combination therapy drugs only progestogenic actions.

Known drugs only progestogenic actions for contraception or for holding GST (HRT, hormone replacement therapy). Drugs of this type, used in contraceptive mode, commonly referred to as “pills Tooley to avoid the introduction of estrogen. Know the use of antiprogestogens to improve the effect of the introduction of drugs only progestogenic actions. This option applies in particular to improve the picture of the bleeding. Thus, in accordance with the main suggested improvement, periodically enter antiprogestogen that leads to the achievement of such a picture bleeding, which is quite closely reflects the natural menstrual cycle. One improvement of this kind was introduced by Hagena (Hodgen, WO 93/21927), who described the contraceptive rate that does not contain estrogen, while active, inhibiting ovulation ingredient was a progestogen, in the framework of this course antiprogestogen was administered in intermittent mode for best picture bleeding (including, by minimizing associated with progestogen excessive bleeding). Antiprogestogen is entered, for example, once in 30, 60, 90 or 120 days, and preferably once during each cycle of 30 days (most preferably on the 28th day of each cycle). Another this improvement is disclosed in WO 97/49407, which describes the introduction, in addition to the drug only progestogenic actions, from two to seven standard doses, and including the cloud (described as a period, constituting 20-32 days and preferably 28 days).

The concept of the above treatment only progestogenic actions” should not be confused with therapy or contraceptive methods by which and the progestogen, and antiprogestogen administered for several consecutive days in a single multi-phase multi-phase mode. This mode is known and described, for example, in the publication WO 94/04156, which reveals the contraceptive set capable of receiving in the first phase in the period from 5 to 20 days consecutive daily standard doses containing antiprogestogen, and receiving the second phase in the period from 10 to 25 days of consecutive daily standard doses containing progestogen.

It was found that When 33245 not only has significant activity and high selectivity, but shows strong binding to human orosomucoid, which is an indicator of a relatively long half-life (Steingold et al. 1990, American Journal of Obstetrics and Gynaecology 162, 532-524). This circumstance makes the connection extremely suitable for intermittent introduction and more convenient to use than the previously proposed antiprogestogen, such as RU 486 and Org 33628.

Should otmuchivanie close relative of the drug Org 33628, which was actually proposed for use in the course of treatment, are described in EP 549041 and EP 582338. Org 33628, being acceptable and promising drug from the point of view of its cost and activity, has the disadvantage, especially manifested when used in the intermittent mode of administration. This disadvantage is associated with its relatively fast metabolism, which can be seen from a short half-life from a human body (approximately 12 hours). This problem poses experts in this field, the need to find alternatives to such a connection, which would have advantages Org 33628, but would not have inherent drawbacks.

The specified invention overcomes the above disadvantage and enables you to use When 33245 upon receipt of contraceptive or means for GST, while the Hen 33245 is introduced intermittently, and the rest period between each pair of sequentially input standard doses of antiprogestogen is more than 1 day. The invention particularly relates to the use of the Hen 33245 to obtain the drug for its intermittent introduction to the course only progestogenic therapy (including contraception). On the other hand, the invention covers a method of loadee the invention also relates to the combination, including progestogen and antiprogestogen in which antiprogestogens is When 33245.

The term “intermittent” is not to be confused with the term “volatile”. Regular consistent daily introduction (in which one introduction, for example daily administration of tablets, accompanied by the natural period of the 24-hour pause before the introduction of the following daily dosage) is not an intermittent introduction, defined in the context of the present invention. In the context of the present description, the term “intermittent” should be understood as referring to “a consistent, daily introduction” so that this introduction can be considered as “not consistent daily intermittent introduction”. In other words, when in the sequence of days of consecutive daily administration means the administration of a standard dose every day in this sequence (e.g., tablets), then the sequence is not a daily introduction means that for every introduction should pause, comprising at least one day in which do not enter antiprogestogen, and for the specified period, a pause, another introduction of antiprogestogen. In other sloovere introducing doses of antiprogestogen was more than 1 day. Of course, when a break of 2 days or more, the advantage of using the Hen 33245 becomes even more apparent, since the problem is only exacerbated when using Org 33628, using the Hen 33245 can be resolved.

As it is obvious to every expert with the average level of knowledge in this field, the present invention relates to a compound of formula I, as well as to its prodrugs and predecessors, i.e. close to those of related compounds, the substituents of which are easily metabolized to active compounds of the formula I or easy to split up such a connection during their introduction. In addition to the most common prodrugs, the present invention encompasses compounds of formula II and their pharmaceutically acceptable salts.

where X denotes the (N, N), (O) or (N-OH). Thus preferably 3-catasetinae, for example, the Hen 33245, in which X denotes (About). Other possible substitutions at the third carbon atom satisfy this requirement, according to which compounds of the present invention are precursors (prodrugs) preferred 3-ketose-organisations, which is one of the important properties of these compounds. For the purposes of clarity, the present invented what are the links to EP 549041 and EP 582338, more specifically, for example, 1 ER 549041. In the course of intermittent use according to the present invention Org 33245 mostly administered in a dose ranging from 0.1 to 300 mg, and preferably from 0.5 to 150 mg Dosage Org 33245 can be in each moment of time the same, but it may also be reduced, as described in WO 97/49407.

The type of introduction of the Hen 33245 can refer to any type of standard dosages, which are suitable for intermittent injection, which means may include an injection that can be administered once or several times per month or can include percutaneous patch, which is applied and removed again one or more times per month, and in each case, most of the days does not include the introduction of a Hen 33245. However, the most convenient and desirable form of intermittent introduction of the Hen 33245 is a standard oral dose, preferably tablet.

Intermittent introduction When 33245 particularly advantageous during the course of therapy only progestogenic actions (including contraception). Because antiprogestogen give in intermittent mode, i.e. only on certain days, preferably in such a day it was introduced, together with the dose of progestogen. While antiprogestogen characterized oceniania simultaneously with the progestogen, Org 33245 can be entered in the form, physically combined with a progestogen. Thus, the present invention also includes a combination of standard dose, including progestogen and antiprogestogen in which antiprogestogens is When 33245.

The invention also includes a delivery system for the drug for contraceptive use (contraceptive set), containing standard daily oral dose, with each standard dose contains progestogen and 1-7, preferably 1-4 units, including antiprogestogen, preferably combined with a progestogen. One of the standard doses of antiprogestogen introduced at the end (or in certain cases, at the beginning of the cycle). In fact, the dose of antiprogestogen, which is given once in the cycle, marks the transition from one cycle to the next (that is, the term “end of cycle” can also be interpreted as “start cycle”). Second antiprogestogen dose, in case of its use, enter in the middle of the cycle. If used by more than two standard doses of antiprogestogen, then one of them give at the end of the cycle, while others are distributed uniformly on the cycle. Preferred specific course entry dosages described in the documents WO 93/sa to the natural menstrual cycle, that is, the period of 28-32 days.

The present invention also includes a delivery system of a drug for holding GST (hormone replacement therapy), including daily standard dose, and each dose includes a progestogen in the presence of estrogen or without it, or just estrogen and 1-7, preferably 1-4 dosage, including antiprogestogen, one of which is preferably introduced in the beginning of the cycle and other distributed uniformly on the cycle (if there is one second dosage in the middle of the cycle).

In General, the invention relates to a contraceptive and/or set for GST (hormone replacement therapy), including consistently taken daily standard dose for oral administration, each containing as the only effective contraceptive respect ingredient progestogen or as an effective ingredient for GST progestogen in combination with estrogen or without one or estrogen, as well as two or more standard units, including antiprogestogen.

Optionally, the kits may contain pills with placebos to join the two periods of introduction of the active ingredients.

The present invented dose), a way to use that product and method for producing a pharmaceutical product.

The present invention also relates to a method of contraception and/or holding GST in women before menopause, during or after menopause, which include the holding of a woman above courses of treatment. Thus, the invention also covers a method of contraception comprising daily administration in a woman of childbearing effective contraceptive ratio of the number of progestogen and intermittent introduction of antiprogestogen, with antiprogestogen is a Hen 33245. Another object of the invention is a method of treating irregular or heavy bleeding in women using the drug only progestogenic actions, which includes intermittent introduction When 33245. In these ways it is preferable that When 33245 was administered in 1-4 days 28-32 day cycle, when divided into the period specified cycle, when an injection is usually carried out at the end (or, depending on the consideration, in the beginning of the cycle).

Progestogens used in the framework of the present invention are 3-ketodesogestrel (etonogestrel), desogestrel, gestodene, leonieke 13-ethyl-11-methylene-18,19-di-nor-17-pregn-4-EN-20-in-17-ol and is preferred progestogen. It is believed that desogestrel metabolized in the body to 3-ketodesogestrel. Preferably, the standard dose contains 75 micrograms of desogestrel or 3-ketodesogestrel, or a number of other POCs, equivalent in effect 75 mcg of desogestrel. From the point of view of almost the injected doses, levonorgestrel, desogestrel and 3-ketodesogestrel are relatively equal in strength progestogenic activity. Gestodene about 1.5 times more active than the specified connection. Norgestrel has activity equal to approximately half of the activity levonoguestrela. Another preferred progestogen represents Org 30659, see EP 897927.

Below the present invention is described with reference to examples.

Example 1

Org 33245 ((11, 17)-17, 23-epoxy-11-[(4-dimethylamino)phenyl]-19, 24-Generala-4, 9, 20-trien-3-one) is synthesized in accordance with the procedure of example 1 of EP 549041.

Example 2

Get a number of pharmaceutical compositions containing the steroid in accordance with the present invention. Org 33245 stirred in a standard way with the other ingredients and mix granularit.

The composition has the following structure:

Org 33245 (active ingredient) 1-10 wt.%

Lactose 200 M (diluent) To 100 wt.%

The resulting granules can be used for tabletting after the procedure, commonly used in the art, and thus receive standard doses suitable for use within the present invention.

Example 3

Define linking multiple antiprogestogens with orosomucoid, as described in the literature (Philibert et al., Antihormones in Health and Disease (M. K. Agarwal, ed.), 1991, 19, 1-17). The results are shown in the table below. The results show that binding of other studied antiprogestogens lower than the value obtained for RU 486 (100%), whereas When 33245 demonstrates a significant improvement.

Example 4

Antiprogesterone activity determined by test anti-Mac-File (anti-McPhail test), known to specialists in this field and are described, for example, Kloosterboer et al., Humah Reproduction (1994), Volume 9, Supplement q, p.47-52. The following table shows the results, expressed as the minimum active dose (MAD).

1. Application When 33245 for the manufacture of a contraceptive or as a means for GST, characterized in that the Hen 33245 administered in an intermittent mode, and the interval between each pair of sequentially wadima fact, that intermittent introduction When 33245 carry out in addition to only progestogenic therapy.

3. Application When 33245 for the manufacture of a medicinal product to minimize uterine bleeding in women, which uses pharmaceutical drug only progestogenic actions, characterized in that antiprogestogens is When 33245, which must be administered intermittently, with a break between each pair of sequentially input standard doses of antiprogestogen more than one day.

4. The use according to any one of the preceding paragraphs, characterized in that the dosage Org 33245 administered during the period 1-7 days 28-32 day cycle, and acceptance of one dosage marks the end of the cycle, and optional other dosage administered evenly divided over the remaining days of the cycle.

5. Contraceptive kit containing tool that provides daily administration of progestogen, and means providing intermittent introduction of antiprogestogen, the latter is a connection When 33245.

6. The combined means for the dosage of the progestin and antiprogestogen, characterized in that antiprogestogens is When 33245, which must be administered intermittently, with the

7. The method includes daily administration to a woman of childbearing age contraceptive effective amount of a progestagen and intermittent introduction of antiprogestogen, while antiprogestogens is When 33245 with a break between each pair of sequentially input standard doses of antiprogestogen more than one day.

8. A method for the treatment of irregular or heavy uterine bleeding in women, which uses the drug progestogenic actions, including intermittent introduction of antiprogestogen, while antiprogestogens is When 33245, which must be administered intermittently, with a break between each pair of sequentially input standard doses of antiprogestogen more than one day.

9. The method according to p. 7 or 8, characterized in that the specified antiprogestogen administered during the period of 1-4 days 28-32 day cycle.

 

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