JPS5842199B2 - ESTRIO-RUUUDOUTAINO - Google Patents

Description

Detailed Description of the Invention The present invention provides estriol derivatives of the formula (wherein OR represents an N-oxide nicotinoyloxy group, and R2O represents a methoxy group, a cyclopentyloxy group, or an N-oxide nicotinoyloxy group) Concerning the manufacturing method.

According to the invention, said estriol derivatives are capable of converting the corresponding hydroxyl compounds, i.e. estriol, its 3-methyl or 3-cyclopentyl ether, into nicotinic acid N-oxide in the form of a reactive derivative, e.g. nicotinoyl chloride N- Obtained by acylation with oxide in a conventional manner.

The following examples illustrate the invention.

Example 1 3.16α,17β-triN-oxidonicotinoyloxy-1,3,5(10)-estratriene (IB
Preparation of O56) In a 100 CC flask protected from light and moisture, 5.76 g (0.02 mol) of estriol are dissolved in 60 CC of anhydrous pyridine.

10 g of nicotinoyl chloride N-oxide are added and the entire contents are stirred at room temperature for 24 hours.

After adding cold water 11 and stirring for 30 minutes, extraction with chloroform, the solution was dried over sodium sulfate, and chloroform was distilled off under reduced pressure.

The crude product obtained is purified by silica gel chromatography by elution with chloroform and increasing amounts of methanol in chloroform.

m, p, 252°C Example 2 Production of 3-methoxy-16α,17β-di-N-oxide nicotinoyloxy-1,3,5(10)-estratriene (IBO80) 3-methoxy-1,3, 4 g of 5(10)-estratriene-16α,17β-diol in 60 CC of anhydrous pyridine in a 100 CC flask protected from water and moisture.
dissolve in

Next, 6 g of nicotinoyl chloride N-oxide was added to the
Add to this cooled solution.

The entire contents are stirred at room temperature overnight, then the reaction mixture is diluted with 11 parts of ice water and extracted with chloroform.

The crude product obtained is purified by silica gel chromatography, eluting with chloroform and increasing amounts of methanol in chloroform.

m, p, 152°C Example 3 Production of 3-cyclopentyloxy-16α,17β-di-N-oxide nicotinoyloxy-1,3,5(10)-estratriene (IB104) In Example 2, 3-methoxy- 1, 3, 5 (10)
-Estratriene-16α,17β-diol is replaced by 3-pentyloxy-1,3,5(10)-estratriene-16α,17β-diol to obtain the title compound.

m, p, 251°, by acylating two or three hydroxyl groups of estriol with N-oxide nicotinoyl groups, it is possible to reduce the estrogenic activity remaining after esterification by the oral route. It has been discovered that it has the ability to manifest or increase lipemic effects.

Therefore, for all the advantages of hypolipidemic activity, there is an additional increase in the therapeutic limits of these compounds.

The quantitative results shown in Table 1 are from a number of experiments with estriol and the compounds disclosed in the Examples.

Estrogen effects (keratinization of the intestinal epithelium) were measured on body weight tests of ovariected rats after a single dose (oral or subcutaneous) of the test compound (C,W).

Emmens, Strogens J, D, Dor
fman's "Methods in Hormone"
Re5earchJlind, vol.

Part A, Chapter 2, Academic Press (196
9) ).

Hypolipidemic activity was measured subcutaneously by hyperlipidemia induced in male rats by intravenous injection of Triton (WR1339) (7).

(S, Garattini et al., “Drugs Af
ffecting Lipid Metabolism
J, 144 pages, Elzevier publ 1ca
tion (1961)] All numbers in the first three columns are
It represents the percentage of the effect produced subcutaneously by the standard product (Estrone).

The numbers in the last column indicate the ratio between the hypolipidemic activity and the estrogenic activity of each compound.

The two numbers shown correspond to the lipid parameters corresponding to the minimum (minimum) or maximum (maximum) for the test compound.

Such a method of evaluating results makes it possible to foresee the practical interest of certain estrogen derivatives.

This interest is due to hypolipidemia effect (++) and hormonal activity (-
There is a conflicting relationship between the two.

Of the estrogens currently in therapeutic use, estriol has the most important dissociative effect.

(D.L., Cook et al., “Arch Int. Pha
rm, J 135, 91-1o4, 1962].

, the compounds according to the invention significantly improve the action of estriol in this respect.

Thus, for a similar hypolipidemic effect, for example, the estrogenic activity of compound lBO30 is 20 to 100 times weaker than that of estriol with respect to various parameters (see Table 1).

The hypolipidemic activity of the compounds according to this invention is considerably different from conventional estrogens from both quantitative and qualitative points of view.

Estrone, estradiol and premarin are 7
It is effective against the hyperlipidemia induced in rats by Triton at a dose of 5 μg/Kt/day, whereas the compounds according to the invention (e.g. lBO30) are already highly active at a dose of 3 μg/KP/day. It is.

(Thus, when used in the same manner, the effective dose of clofibrate is 300■,/υ, so 100,0
00 times bigger.

) Another method uses plasma lipid fluctuations in healthy, intact rats treated daily (orally or subcutaneously) with the test product for several weeks.

A certain number of animals from each batch are sacrificed each week.

Plasma total lipids, cholesterol, triglycerides and phospholipids are measured (K, Uchida et al., “E
ndocrinol J (Japan), vol. 16, p. 211, 1969, and R. There-not and M.
C-Hazard, fi-C,R,5olc,Bio
l, J (Paris), vol. 167, p. 509, 197:3
J.

As can be seen from Tables 2A and 2B below, the activity of compound lBO30, similar to estriol, becomes significant from a dosage of 0.6 μg/Ky/day, compared to 75 μg and above for estrone and estradiol. .

Furthermore, contrary to what happens with the two substances mentioned below, lBO30
or continued treatment with estriol does not result in attenuation or reversal of the effect.

Table 3 below confirms the quantitative and qualitative differences existing between estriol and the series of its derivatives disclosed in this invention (IBOSO here) on the one hand and traditional estrogens on the other hand, Even after 6 weeks of treatment at a daily dose of Ky1 (thus more than 100 times the effective dose), the effects of lBO30 (and estriol) remain unchanged, whereas the effects of Premarin and estradiol remain unchanged at the effective dose. decreased and/or reversed in the second or fourth week at doses not exceeded.

The interest of the above table in therapy is the considerable reversal of the effects of estrone and estradiol, their derivatives and Premarin, whose negative consequences on arteriosclerosis are well known.

This risk does not exist with estriol and its derivatives obtained according to the present invention, and furthermore, the superiority of the latter over the original Nistrokene results in a considerably expanded therapeutic limit with the same antilipid effect (see Table 1). be.

Therefore, all these compounds have a greater hypolipidemic effect than estriol.

N-oxidized nicotinic acid diesters have a stronger hypolipidemic effect, which has not only absolute but also relative value since the estrogenic effect is selectively reduced by N-oxidation.

They maintain all the unique properties of estriol with no reversal of action even after high doses and long treatments.

Therapeutic applications of the compounds according to the invention can be achieved by various conventional routes, such as oral or lingual, transdermal (e.g. intramuscular),
A transcutaneous route can be taken.

The excipient is selected depending on the route of administration, and the excipient must be pharmaceutically satisfactory, for example in sterile injectable solutions or suspensions, or in tablets, capsules,
adsorption onto or admixture with a satisfactory vehicle in the form of suppositories, lipids or volatile solutions, creams, ointments, gels, etc.

The units cited above as examples contain between 1 and 10 mL of product, depending on the compound and the associated therapeutic index (see below).

Therefore, (1) it is preferable to use lB104 (by oral or translingual route) as an estrogen replacement in women with a history of hyperlipidemia or high vascular risk, with a daily dose of 1 to 8 days. Change depending on the situation.

(2) As an estrogen substitute for women with obvious hyperlipidemia, it is preferable to use the compound 1BO36, whatever route is chosen, and the -day dosage varies from 2 to 10 μm.

(3) As a hypolipidemia and anti-arteriosclerotic treatment in men and women, whichever route is chosen, the compound lBO30
It is preferable to use
Change with 1011III.

Claims (1)

[Claims] 1 Estriol, or its 3-methyl or 3
- a formula characterized by reacting a reactive derivative of nicotinic acid N-oxide with cyclopentyl ether (in the formula, OR represents an N-oxide nicotinoyloxy group, and R'0 is a methoxy group, a cyclopentyloxy group, or -representing an oxidonicotinoyloxy group) A method for producing an estriol derivative.