Ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin e1 agent which exhibits uterotonic activity

FIELD: chemistry.

SUBSTANCE: invention relates to chemical and pharmaceutical industry and specifically to an agent which is ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1 of formula (I), which exhibits uterotonic activity. This compound relates to the family of 11-deoxyprostaglandines and has a chemical structure similar to misoprostol.

EFFECT: agent, which is more chemically stable and is twice less toxic, surpasses misoprostol on uterotonic activity which, along with synthetic availability and absence of side effects, makes it exceptionally promising in practical use for replacing misoprostol in gynaecological binary preparations.

2 tbl, 3 ex

 

The invention relates to pharmaceutical industry and relates to funds that represent ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1formula (I), showing uterotonic activity and low toxicity.

Previously described synthesis [1], antiulcer and a number of other types of activity of compound (I) [2-4].

Currently in obstetric practice is extremely urgent problem of labor activation and termination of pregnancy in I and II trimesters of pregnancy complications in pregnancy or extragenital diseases. There are 2 ways to solve this problem: instrumental and medication. The first approach, especially in case of early termination of pregnancy, it is extremely dangerous possible far-reaching consequences (childlessness). Of great importance is the choice of the most rational medical methods for early termination of pregnancy for medical reasons and in the interests of the fetus, for the accelerated ripening of the cervix, labor activation and agostinelli.

One of the most promising drugs in this direction are the prostaglandins (PG). They are able to stimulate contractions of the myometrium and can lead to maturation and disclosure of cervical match is, and the use of prostaglandins during therapeutic abortion in the third trimester of pregnancy may induce uterine activity. Prostaglandins can also promote the release of oxytocin from the pituitary gland of the mother and to create a low threshold of excitability in relation to oxytocin [5].

As is known, for early termination of pregnancy and childbirth in women apply PG E-type prostaglandin E1[6], sulfa-derived prostaglandin E2 - sulprostone, 9-methylene isaster PGE2- metropost [7], and in recent years became widely used misoprostol [5, 8].

However, these prostaglandins are characterized by a number of disadvantages, namely: low chemical and metabolicheskoi stability, relatively high toxicity, the presence of negative side-hypertensive and dialoging action and high cost drugs based on them. It should be noted that, although the production of prostaglandins is a complex and multistage process, however, it is economically advantageous, since prostaglandins are effective in very low doses.

Globally important achievement of recent years in the field of gynecology was the creation of the combined drugs (antigistaminny steroid + prostaglandin) for early termination of pregnancy and childbirth. As Stero the ne components used highly modified steroid Mifepristone (Mifegyne, RU 486), prostaglandin component is an analogue of prostaglandin E1- Misoprostol (II) [8].

The combination of steroid (600 mg) with a low dose (0.2 mg Misoprostol not only increases abortifacient efficacy (from 84% to 96%), but also reduces side effects (diarrhea, vomiting).

The closest analogue to the properties of the claimed object - ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1(11-desoximetasone) is a synthetic analogue of PGE1is misoprostol with uterotonic activity [8].

However, despite effectively, misoprostol has a number of side effects such as gastro-intestinal tract. In addition misoprostol relatively chemically unstable in the presence of the cyclic part of the misoprostol β-hydroxyketones groups capable of easy digitately with the formation of compounds cyclopentenone type, prone to subsequent reactions of isomerization and seals. In addition, the misoprostol is marked by a significant toxicity and high market value.

In view of the above shortcomings existing in gynecology and obstetrics GHGs, including misoprostol, remains an urgent search for new PG analogues with uterotonic action devoid of these shortcomings.

The problem to which direction is about the claimed technical solution, is to search among the derivatives of prostaglandins available compounds with high uterotonic activity and clinical acceptability (less toxic and devoid of unwanted side effects).

The problem is solved by means represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1(I)showing uterotonic activity.

The compound (I) was obtained according to the scheme [1] by processing at a temperature of -60°C readily available cyclopentenone (III) prepared in situ cuprate reagent (IV) (molar ratio 1:1.5) in tetrahydrofuran. After acid hydrolysis of the reaction mass and the HRO-

maturational purification on a column with SiO2isolated compound (I) with the release of 76%.

In the study of biological activity of compound (I) as the reference drug used synthetic PG - Misoprostol. Acute toxicity of the compound (I) was determined on outbred mice weighing 18-20 g at single intraperitoneal route of administration. It is established that the compound (I) is low toxic substance (LD5075 mg/kg)and 2 times less toxic than misoprostol, LD5035 mg/kg

Uterotonic activity of compound (I) was studied in outbred rats according to the method of Magna is and [9]. Conducted in vivo tests on pregnant female rats showed that the compound (I) has a high uterotonic activity and surpass those of misoprostol. The research results are summarized in table 1.

Table 1
The influence of the 11-desoximetasone and misoprostol on the contractile activity of the uterus in rats
ConnectionBreeding, g/mlThe number of animalsThe amplitude of uterine contractions %The tone of the uterus, %
11 dioximes-prostol2×10-615of 98.2±2,915,9±1,3
P1<0,01
P2<0,01
misoprostol2×10-615of 74.3±5,914,3±1,
P1<0,02
P1- significantly in relation to spontaneous contractions
P2- significantly towards misoprostol

Study of the influence of the 11-desoximetasone on the motility of the gastrointestinal tract hungry rats showed that the compound (I) does not increase evacuation capacity of the small intestine (table 2), i.e. does not show side dialoging dasve characteristic misoprostol [10].

Table 2
The influence of the 11-desoximetasone and misoprostol in evacuation capacity of the small intestine of rats (n=15)
ConnectionDose, mg/kgThe length of the small intestine, cmDistance traveled label, cmEvacuation capacity, %
11-deoxy-misoprostol0.0493.8±2.8918,4±3.6819.5±3,3
P1-3<0,05
misoprostol0.0491.4±2.7319.0±3,9925.8±3,34
P1>0,05
control-91.2±3.3624.8±2.6327.48±1.11

Thus, the proposed remedy represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1(11-desoxypipradrol) (I)related to certain 11-deoxyprostaglandin, and similar in chemical structure with misoprostol, but more stable and with less 2 times the toxicity, surpassing its uterotonic activity. In addition, synthetic accessibility, combined with the above makes it extremely promising for implementation in practice with the aim of replacing misoprostol in gynecology binary products.

The invention is illustrated by the following examples.

Example 1. Determination of acute toxicity.

Acute toxicity 11-desoximetasone of whom were on outbred mice weighing 18-20 g at single intraperitoneal route of administration. The compound (I) and misoprostol was dissolved in vegetable oil. Observation of the animals was carried out for 10 days. The clinical picture of poisoning animals with the introduction of the studied compounds was expressed in the lateral position of the body, slow breathing and convulsions.

Parameters of acute toxicity was evaluated according to the method of Litchfield and Wilcoxon signed [11]. LD5011-Desoximetasone equal to 75 mg/kg LD50misoprostol - 35 mg/kg classification GOST 12.1.007.76, 11-desoxypipradrol belongs to the class of non-lethal substances and misoprostol belongs to the class of srednetonnazhnyh connections.

Example 2. The study of the uterotonic activity of compound (I).

Uterotonic activity of compound (I) was studied in outbred rats according to the method of Magnus [9]. With this purpose an isolated segment of the uterus was placed in aerated by air a solution of ringer-Locke (composition of solution of NaCl (9 g/l; KCl - 200 mg/l; NaHCO3200 mg/l; CaCl2200 mg/l; glucose, 1 g/l) with temperature of 37°C and was attached to the recorder. The effect of compound (I) on uterine contractions was investigated in a dilution of 2×10-6g/ml. About uterotonic activity was judged by the percentage increase in the amplitude reduction relative to the original (inotropic effect) and by the percentage change in uterine tone (donotreply effect). Uterotonic activity was compared with that of misoprostol in the same breeding.

In a dilution of 2×10-6g/ml of compound (I) increased the amplitude of uterine contractions on to 98.2% (P1<0,01), whereas misoprostol - by 74.3% (P1<0,02) in relation to spontaneous contractions. This 11-desoxypipradrol and misoprostol slightly changed the tone of the uterus (table 1).

Thus, 11-desoxypipradrol has a more pronounced uterotonic properties (P2<0.01) compared with misoprostol.

Example 3. Study of the influence of the 11-desoximetasone on the motility of the gastrointestinal tract.

To study side dialoging effect of compound (I) investigated the effect on the motility (evacuation ability of the small intestine) of the gastrointestinal tract to the hungry rats [10]. The compound (I) and misoprostol was administered 5 min prior to the introduction of coal labels (1 ml of 5%coal usesi in starch). About dialogando activity was judged based on distance traveled coal label 30 minutes from the pyloric part of the stomach through the intestines. Evacuation capacity of the small intestine expressed in percent as the ratio of the distance that the main part of the label, to the whole length of the intestine.

The rat 11-desoximetasone slowed peristalsis. After 30 minutes the distance traveled main part of the label, in the experimental animals of both groups was less than that of the control. 11-Deso seminoprotein significantly decreased evacuation ability of the small intestine compared with the control group. In the group of animals treated with misoprostol in the same dose, the evacuation capacity of the small intestine was lower than the control, and the results unreliable (table 2).

Thus, the tool that represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1has a more pronounced uterotonic activity than misoprostol and 2 times less toxic than he, and does not cause side dialoging actions.

Literature

1. Ivanova N.A., Shainurova A.M., Miftakhov MS Prostanoids. LXIX. Synthesis of ethyl ester of (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1. // Chem.-Pharm. Log. - 1998. No.. 6. - P.39-40.

2. Sapozhnikova T.A., Saudi FS, Karachurina LT, Makar NS, khisamutdinova HE, Ivanov N.A., Shainurova A.M., Miftakhov MS Pharmacological properties 11-desoximetasone. // Experimental. and clinically. pharmacology. - 2003. - So 66. No. 1. - P.34-36.

3. Ivanova N.A., Sapozhnikova T.A.; Saudi F.S.; Maschenko NJ; Makar NS; khisamutdinova RU; Gabdrakhmanova SF; Nazarov, V.S. Hepatoprotective activity 2-demethoxycurcumin-2-etoxycarbonyl-11-desoximetasone. // Experimental. and clinically. pharmacology. - 2007. - So 70. No. 4. - P.30-31.

4. Sapozhnikova T.A.; Saudi F.S.; Maschenko NJ; Gabdrakhmanova SF; Makar NS; khisamutdinova RU; Nazarov, V.S. Choleretic activity 2-demethoxycurcumin-2-ethoxycarbonyl the-11-desoximetasone on the model of hepatitis, caused by CCL. // Bulletin of experimental biology and medicine. - 2008. - 145 so. No. 2. - .183-184.

5. Abramenko CENTURIES Prostaglandins and antigestagen in obstetrics and gynecology. - Petrozavodsk: Intelteck. - 2003. - 208 S.

6. Mashkovsky PPM Medicines. - M.: New wave. - 2005. - 535 S.

7. Collins P.W., Stevan W.D. Synthesis of therapeutically useful prostaglandin and prostacyclin analogs. // Chem. Rev. - 1993. - V.93. - P.1533-1564.

8. Abramenko B.B., Abrahamian P.A., Abrahamian LR Induction birth and their regulation by prostaglandins. SPb.: ALBI-SPb. - 2005. - 288 S.

9. George VI a Practical guide to the physiology of farm animals. M: High school in 1976. - S-273.

10. Belyaev O.A., A. Fedin. Evaluation of the effects of microbial enzymes on the motility of the small intestine of rats // Exp. and the wedge. Pharm. - 1998. - T. No. 5. - P.24-26.

11. Belenky, M. elements of a quantitative evaluation of the pharmacological effect. L., Medgiz. - 1963. - 152 C.

The tool represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1formula (I)

showing uterotonic activity.



 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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