Novel derivatives of 11 beta, 19-[4-(cyanophenyl)-o-phenylene]- or 11beta, 19-[4-pyridinyl-3)-o-phenylene]-17 beta-hydroxy-17 alpha-(-3-hydroxypropen-1(z)-tl)-andosten-4-one-3

The subject of the invention is new derivatives of 1-, 19- [4- (cyanophenyl) -o-phenylene] or 1-, 1- [4- (pyridinyl-3) -o-phenylene] - ^ - hydroxy-17- (3- hydroxypropen-1 (Z) -yl) -androstene-4-one-3, useful as progesterone antagonists in a new way of contraception^-.

Through ham-ie -woreenias^{l7 -}Litter of Mycosis of uterus uozynnized n^-nesting ez^from-e^sschedule of^sajajaw mccicy (1ιαηκΜ & ηϊε with the capacity of pmyjwowanin wi ^ ^babout^ekancu^pIn females, competitive antagonists andprogns may be used^-cIΌnu.

RU ^uo6 (11 β1^dN, N- (^andwιm ^ cty^moaIraeo)^hym ^ yk) yl7i3-^cydr0ksye^and7 (yjpropyny^s> estyedien 4, ^sC^cO) -or] a3; op^-łanru^pfeminine selfishness no. EP-A-CK ^ III Syinna 110-anyly- ⁽°> 11 β^|l^ceιry¹ea (0i^cdeprotected steroids are compounds that can displace progesterone and glucocorticoids from their diphtheria necrophoresis. SiabsUm-U are different Eirmakelogkzniz nr⁽) 1xłs^about^^³m e m e rd ^ckie ^ it was an^Jagoy^andetyeona^cin the present ^]-ro^-Sn ^ s ^ 1 ^ i ^ ^^ uig^andabout^ataboutⁿβrtyko.dów. Włβśn^rbility^and U e^andI'cśla^WI1about^at call. Raktyanne Zart: Married¹aieuz^sEIP^fromaoiie. Rlo 4 ^j6 about it^-ancjaan^andfrom^andcn^andtangent to ρΐΌ ^ υ-Όηυηρ. jzrzAdatny^sTarapaui^ezone^abouty ^ break up about the nubuck-ic jo ontagnmst^andccna^JZaohm^atla^aboutuko0yko^-kat the dyteceema

173 337 Cushing's syndrome in stimulating the pathologically increased cortical secretion effect The dose for abortion in females is 200-600 mg.

It has also been known for a long time that competitive antagonists of progesterone are able to inhibit ovulation in various animal species and in women. (Collins et al., Blockade of the spontaneous mid-cycle gonadotropin surge in monkeys by Ru 486; A progesterone antagonist or agonist, J. Clin. Metab., 63, 1270-1276 (1986);

Croxatto HB Salvatierra 1990 Cyclic use of antigestagens for fertility control. IIIrd Internationa) Symposium of Contraconception, Heidelberg, june 19-23, 1990;

Danford et al., '' Contraceptive potential of RU 486 by ovulation inhibition. IIIrd. Preliminary observations on once weekly administration, Contraception 40: 195-200 (1989);

Kekkonen et al., Lahteoenmaki P 1990 Interference with ovulaton by sequential treatment with the antiprogesterone RU 486 and synthetic progestin, Fertil Steril [Fertilc Sterile] 53.4747;

Puri et al., Gonadal and pituitary response to progesterone antagonist ZK 98 299 during the follicular phase of the menstrual cycle in bonnet monkeys, Contraception 39, 2: 227-243 (1989);

Puri et al., Contraceptive potential of a progesterone antagonist ZK 98 734: Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeys. In Moudgal et al., (Eds) (1990).

U.S. Patent No. 4,764,513 states that the ability to receive uterine mucosa for implantation (nesting window) can be shifted (delayed) by giving a woman a competitive progesterone antagonist to increase the likelihood of successful implantation of an in vitro fertilized egg.

11β, 19-phenylene bridged steroids that exhibit a particularly strong competitive antagonist activity against progesterone in the case of significantly reduced anti-corticoid activity relative to the reference compound, namely to 11 P- (4-dimethylaminophenyl) -1 7p-hyd ^ <^ 1 ^^^^ 17α-propynyl-i) estradeno-4.9 (10) -onu-3 (with the trade name RU 486, European Patent Application No. EP-A-0057115) was first described in U.S. Patent No. 5,095,129. Although the new compounds of the invention (compounds I and II) fall within the scope of the general formula of U.S. Patent No. 5,095,129, they were not disclosed there by name or example.

The dose of a competitive progesterone antagonist with ovulation inhibition is highly dependent on the species in which it is being used. In the case of RU 486, it is 50-100 mg for women. (Croxatto et al .; Ledge et al. (1992) Inhibition of ovulation using very low dose mifepristone; Abstract: Second Congress of the European Society of Contraception. RU 486 shows little or no separation of central and endometrial effects in humans (Ledge WL et al., Terra Symposium on Progestrone Antagonists, May 25-29, 1992, Mohouk, N, Y.).

LH + 2 treatments for nesting inhibition have already been proposed (Swahn et al., The effect of RU 486 administration during the early luteal phase on bleeding pattern, hormonal parameters and endometrium, Human Reproduction 5.4: 402-408 (1990)): 2 days after the LH peak (LH = luteinizing hormone) in the menstrual cycle (the occurrence of the LH peak corresponds to the ovulation time) a woman (i.e. on days 14, 15 or 16) is dosed with a single ovulation-inhibiting dose of RU 486. Thus, the active compound is only administered after ovulation during the luteal phase of the menstrual cycle (luteal contraception).

It has only recently been reported that desynchronization of the endometrium in a woman can be achieved without hormonal changes (progesterone and estradiol levels) by means of a competitive antagonist to progesterone RU 486 when the latter is administered on the 5th day and on the 8th day after the occurrence of the LH peak in the menstrual cycle (10 mg in each case, orally) (Kettel et al., 1992). Some fertilization cannot be achieved without ovulation inhibition if a competitive progesterone antagonist is administered only after reaching LH peaks in the menstrual cycle.

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It has now been found that, according to the invention, competitive progesterone antagonists are, under a dosage regimen that does not inhibit ovulation or abortion, capable of inhibiting the formation of mucous glands, the uterus in the proliferative phase, and inhibiting the functioning of the glands in the luteal phase of the menstrual cycle, including contraception itself is achieved when the dose is administered at least once before and possibly also after the occurrence of the LH peak.

The object of the invention is to develop new compounds suitable for use in the method of preventing pregnancy in females, consisting in administering them during the follicular phase of their menstrual cycle and possibly also in the luteal phase of a new competitive progesterone antagonist in such an amount which is less than the inhibitory amount ovulation and less than the dose causing the abortion, which is effective in inhibiting the formation of the endometrium, which glands are needed to implant a fertilized egg into the womb.

This goal is achieved by means of the new 11,19-o-phenylene-17-x-hydroxy-17- (3-hydroxypropen-1 (Z) -yl) -androst.en-4-ones-3 of formula:

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The pharmaceutical composition may contain in admixture with a pharmaceutically acceptable carrier such a quantity of a new competitive antagonist substance against progesterone in a unit dose, which is less than the amount that inhibits ovulation and less than the dose that causes abortion, the actor is also effective in inhibiting the formation of mucous glands and the growth of endothelium.

In the phase of proliferation, in normśrś'ki- m (en ^^ a (^^at/ jn^t/ m us ^ re-ordered e ρύΌ ^ nrm is formed^and in the mucosa ^ crotów in'yίlfie^lI am watching when in the fictional hitaal and UU there was a phase in^bda^jElani)^andtoday dayin^gd^lThey are jovial in the West by the West. We hear a lot of competitive progesterone antagonists^FROMuntil^ande^crol^tfernnji,^jmark pgzf^bnot to be found in paraphernalia, are not found in the wild, breaking down post-one, mevation / proliferative adenomas. n^s es^jrogenu. Porntdt (vol. Erected in blood in Ishir^g^ ro^NLcreeps in the muro ^ croego is there¹sardzorn^UseeP^sthat I have a bad day! almek porvych komcistyczny śuⁿj¹an^sji^aboutnt according to oms¹the most famous landmarks^aboutychwnględnmpłygno^Lesonn^LROk cr smtelOvate with the use of pwmownma mw:^gny bm nieskody; ·ⁿin^sfywu cy^Oirnansttuznyjky and ^atLZ^k .awct from^cytmaⁿat eb^r causeⁿ abozcję, JESLE^l1 p⁰ ljt-st^yozygygokżyżynn

Over there^sżhwu^LN I am thinking of something that is less than crazy, it seems like a homosexual fabricate^ande1ezt^atnrdzp in ^ rnol-you are on weddings. which is the opposite of liitc will hang out^s long term π ^ ν coac^srr set the warnoi, and prm ζηο ^ ίjajudz^atowamu^,

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A definite advantage of the proposed use of the compounds according to the invention is the very high certainty of preventing pregnancy due to the use of the new progesterone antagonist, since the endometrium is not able to accept a fertilized egg if a relatively low dose of this competitive progesterone antagonist is given before and possibly after ovulation. . Nesting cannot also be ruled out during the proliferation phase of the normal menstrual cycle. Since endometrial glandular secretions are important for uterine absorption, successful implantation is not possible with atrophy of the endometrium and epithelium. As a result, the reliability of pregnancy prevention is also guaranteed in women with an irregular menstrual cycle.

New competitive progesterone antagonists, i.e. 11β, 19 [4- (4-cyanophenyl) -o-phenylene-17e-hydroxy-17- (3-hydroxypropen-1 (Z) -yl) androstene-4on-3 (compound I ) and 1ie, 19- [4- (pyridinyl-3) -o-phenylene-17e-hydroxy-17- (3-hydroxypropen-1 (Z) -yl) androstem4-one-3 (compound II) have an unexpectedly high selective peripheral effectiveness, i.e. the effect of compounds I and II on the endometrium is extremely pronounced, while at the same dose, only a slight central effect is seen on the pituitary-ovary axis.

These competitive progesterone antagonists may also be considered dissociated because at a certain threshold dose, although endometrial changes are observed, ovulation is not inhibited (central effects). As a measure of dissociation, the ratio of ovulation inhibiting dose to implantation inhibiting dose (dissociation rate) (determined after oral administration to rats) can be used. This ratio varies depending on the type of antagonist, but for dissociated and competitive progesterone antagonists is at least about 30 or more.

The advantage of dissociated and competitive progesterone antagonists is that they can be administered at sufficiently high doses to achieve effects on the endometrium without inhibiting ovulation. As a result, the normal menstrual cycle is preserved.

Competitive progesterone antagonists are preferably administered as individual discrete unit doses, e.g., preferably over 4-10 days at regular intervals, e.g., each week of the menstrual cycle, each time at a dose insufficient to inhibit ovulation or to induce an abortion. if nesting has already taken place. A similar effect on the ability to be absorbed by the endometrium can also be achieved with a much lower oral dose once daily. Slow-release systems (such as microcrystalline suspensions, transdermal patches and subcutaneous implants) may also be used if the amount of progesterone antagonist released from them is sufficient to inhibit implantation of the egg during the intended period of the system's operation, but lower than the dose that would interfere with any ovulation, which may occur during this time period. Compounds that have great affinity for the gestagen receptor (progesterone receptor) and which themselves do not exhibit any gestagen activity are suitable as competitive progesterone antagonists.

For pharmaceutical use, those competitive progesterone antagonists that have a selective peripheral effect, i.e. a pronounced effect on the endometrium, at a dose at which only at most only weak central activity on the pituitary-ovarian axis is observed, are particularly suitable.

These competitive progesterone antagonists can be called dissociated, because at a certain threshold dose there are changes in the endometrium, but ovulation (central effect) is not inhibited. As a measure of dissociation, the ratio of ovulation inhibiting dose to implantation inhibiting dose (dissociation rate) can be used. It varies depending on the species and is about 30 or more for the new dissociated competitive progesterone antagonists (in oral rats) according to the invention.

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The unexpected advantage of using the new dissociated competitive progesterone antagonists of the invention is that they can be administered at higher doses to provide the necessary effect on the endometrium without inhibiting ovulation; that is, maintaining the normal course of the menstrual cycle.

Competitive progesterone antagonists can be administered, e.g., locally, topically, enterally, transdermally or parenterally. Oral administration is preferred.

For preferred oral administration, especially tablets, coated tablets, capsules, pills, suspensions or solutions, which can be prepared in the usual way, with the additives and excipients usually used in galenical forms, are particularly suitable.

For local or topical administration, e.g. vaginal suppositories, vaginal gels, inserts, vaginal rings or transdermal systems such as patches for sticking to the skin are suitable. Vaginal rings are also possible and can be removed after a certain time of administration, e.g. after 14 days of administration, and placed again at the beginning of the next administration period.

If the administration of the pharmaceutical composition according to the invention takes place by means of an insert, vaginal ring or transdermal system, these administration systems must be designed so that the released single dose of the competitive progesterone antagonist is within 0.5-50 mg, because the substances with selective peripheral action allow for a much higher dosage without causing ovulation inhibition. The term single dose or administration includes an application system that continuously releases a competitive progesterone antagonist at a rate corresponding to a single dose of 0.5-50 mg.

For the use of the pharmaceutical composition containing the new compounds, it is limiting that at least one unit dose be administered in the follicle phase of the menstrual cycle (before ovulation) and optionally at least one unit dose be administered in the luteal phase of the menstrual cycle (after ovulation).

This pharmaceutical agent is preferably administered in individual unit doses every 4-10 days, preferably one week or on the same day, starting from any day before ovulation occurs in the first menstrual cycle during administration. The time intervals between administration of individual unit doses are preferably constant.

Preferably, the pharmaceutical composition containing the new compound of the invention is subjected once every week, on the same day of the week, e.g. on Monday (Monday pill). With a weekly delivery rhythm, always on the same day of the week, this ensures a high degree of reliability. However, the unit dose may also be administered daily, every 2 days or every 3 days, or only during the folliculam phase, or in addition in the luteal phase of the menstrual cycle. It is also possible to vary the time intervals between the administration of individual unit doses of this pharmaceutical agent or it can be administered continuously from a nested carrier that slowly releases this agent.

To determine ovulation-inhibiting dose of competitive progesterone antagonists, ovulation inhibition tests in rats discussed below were performed; suitable doses for effective abortion are derived from known rat abortion trials (e.g., U.S. Patent No. 5,095,129).

Determined dissociation coefficients for compounds I, II and the comparative compound called RU 486 dissociation:

Relationship: dissociation factor:

I&gt; 100

Π&gt; 30

RU 486 &lt;10

For both compounds I and II, it was also found that next to the extremely strong anti-implantation effect in the womb (compound I is completely effective

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Ί to inhibit implantation in rats at a daily dose of only 0.1 mg and compound II at a daily dose of 0.3 mg), they also exhibit anti-glucocorticoid effects. This is evident from an attempt to freeze the thymus to the anti-glucocorticoid effect (European Patent No. EP-A-0283428).

The preparation of compounds I and II is carried out analogously to the synthesis discussed in EP-A-0283428, as in the examples below.

In the examples given below, the temperature is given in degrees Celsius and, unless otherwise indicated, all parts and percentages relate to parts and percent by weight.

Example 1. 11β.19- [4- (4-Cyanophenyl) -o-phenylene] -17β-hydroxy-17α- (3-hydroxypropen-1 (Z) -yl) -andro-steno-4-one-3.

a) 3,3-Dimethyltrimethylenedioxy-11β, 19- (4-nine-fluorobutylsulfonyloxy-phenylene) androstanediol-5a, 17p.

g 3,3-dwumett ^ 'lotr (eighth ^ tt ^^and lenodio kί ^} ^^ 11 β, 19- (4-hydroxy-o-phenylene) androstanediol -5α, 17β (see example 18a application PCT / dE 88/00150) was dissolved in a protective gas atmosphere in 1.75 liters of tetrahydrofuran (slightly cloudy solution) and stirred at 0 ° C with 71.3 ml of n-butyllithium solution (1.6 m in hexane). After stirring for 30 minutes, added dropwise

22.8 ml of 1,1,2, -22,3,3,4,4,4-nine-fluorobutanesulfonyl-1 fluoride (~ 90%). After one hour of stirring with cooling in an ice bath, the reaction mixture was stirred into saturated sodium bicarbonate solution and stirred vigorously for a further hour. Then, after adding ethyl acetate, the aqueous phase was separated and extracted several times with ethyl acetate. The combined organic phases were washed to neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation under reduced pressure. 90.9 g of the title compound were obtained as a crude product. The nonaflate (C4F9SO3) thus obtained was chromatographed on silica gel with an ethyl acetate / hexane mixture. 1.27 g of pure title compound was obtained in the form of a white foam.

Melting temperature; 132-133 ° C;

[«] D = + 15.4 (CHCl3; c = 0.525)

b) 3.3-Dimethyltrimethylenedioxy-5a-hydroxy-11e, 19- (4-fluorobutylsulfonyloxy-o-phenylene) androstanone-17

63 g of chromium trioxide was added portionwise at a temperature of 0 ° C to a mixture of 210 ml of pyridine and 600 ml of methylene chloride. Then, at the same temperature, 89 g of nonaflate, obtained as described in a), dissolved in 250 ml of methylene chloride were added dropwise. Then, the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After stirring, the upper phase was decanted and the residue was washed several times thoroughly with methylene chloride. The combined organic phases essentially freed of residual inorganic components by washing with a 0.5 m sodium hydroxide solution, washed with water to neutral, dried over sodium sulfate and concentrated by evaporation under reduced pressure (removal of pyridine by azeotropic distillation with toluene). Chromatography of the alumina residue (neutral, step ID) with an ethyl acetate / hexane mixture gave 61.9 g of the title compound as a yellowish foam. Crystallization from ethyl acetate gave 55.7 g of product.

Melting temperature; 176-177 ° C;

[a] o = + 25.3 ° (CHCl3; c = 0.520)

c) 3,3-Dimethyltrimethylenedioxy-11 e ^ - ^ - nine-fluorobutylsulfonyloxy-phenylene) - 17a-1,3- (tetrahydrocarbyl] and tetrahydrocarbamic acid ;; ^ y ^ - ^ 1-yl) just night overnight, 17β

At 0 ° C and under protective gas, 1 liter of absolute tetrahydrofuran was mixed with 73.5 ml of 2- (2-propynyloxy) tetrahydro-2H-pyran. Then 328 ml of a 1.6 m solution of n-butyllithium (in hexane) was slowly added dropwise to this solution without a clear increase in temperature. After 30 minutes of stirring, while cooling the reaction mixture in an ice bath, 50 g of ketone, prepared as described in b), dissolved in 500 ml of absolute tetrahydrofuran, were slowly added dropwise to it and stirred for a further 30 minutes. The reaction mixture was then stirred with saturated ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with sodium chloride solution, dried over sodium sulfate and concentrated by evaporation under reduced pressure

173 337 pressure. The residue was chromatographed on alumina (neutral, step III). 50.3 g of the title compound were obtained as a white foam.

d) 11β, 19 | 4- (4-cyanophenyl) -phenylene] - 3,3-dimethyltrimethylenedioxy-17- [3-tetrahydropyranyl-2-oxy) propin-1-yl) androstanediol-5a, 17

In a mixture of 400 ml of toluene and 155 ml of ethanol, 50 g of the nonaflate obtained as described in c) were dissolved and mixed successively in a protective gas atmosphere with 1.44 g of tetrakis (triphenylphosphine) palladium (0), 5.33 g of lithium chloride, 78 ml 2 m sodium carbonate solution and 13.1 g 4- (1,3,2-dioxaborinanyl-2) benzonitrile. S, Takahashi et al., Bul. Chem. Soc. Jpn., 62, 3896 (1989). The reaction mixture was then stirred for 3 hours in an oil bath at 95 ° C, cooled to room temperature and mixed with water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel with an ethyl acetate / hexane mixture. 38 g of the title compound were obtained in the form of a yellowish foam.

[and]_D²² = -36.5 ° (CHCls, c = 0.515)

e) 11 β, 19- [4- (4-cyanophenyl) -o-phenylene] -ue-hydrolosy-17- (3-hydroxypropin-1-yl) androstene-4-one-3

In 950 ml of acetone, 37 g of ketone acetal prepared as described in d) were dissolved and mixed under a protective gas atmosphere with 95 ml of 4 N aqueous hydrochloric acid solution. After stirring for 2 hours at 50 ° C, the reaction mixture was poured into cold saturated sodium bicarbonate solution (basic pH) and most of the acetone was distilled off. Methylene chloride was added, the aqueous phase separated and extracted several times with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel with an ethyl acetate / hexane mixture. 23.8 g of the title compound were obtained in the form of a yellowish foam.

f) 1β, 19- [4- (4-digitanophenyl) -o-phenylene] -17β-hydroxy-17α- (3-hydroxypropen-1 (Z) yl) androste n-4-one-3.

g of propargia alcohol, prepared as described in e), was dissolved in a protective gas atmosphere in 825 ml of tetrahydrofuran, mixed with 23 ml of pyridine and hydrogenated using 2.3 g of palladium (10%) supported on barium sulfate under standard pressure as a catalyst. After absorbing an equivalent amount of hydrogen (as controlled by TLC!), The reaction mixture was filtered through Celite, the filter residue was again washed with tetrahydrofuran and the filtrate was concentrated by evaporation under reduced pressure. Pyridine was removed by azeotropic distillation with toluene. The residue was recrystallized from an acetone / tetrahydrofuran mixture and the crystalline product thus obtained was again recrystallized from a methylene chloride / methanol mixture. 19.3 g of the title compound were obtained in the form of white crystals.

Melting point: 265-266 ° (with decomposition);

[α] ο = +117.8 (CHCb, C = 0.500)

Example 2. 11e, 19- [4- (4-pyridinyl) -o-phenylene] -17e-hydroxy-17a, - (3-hydroxypropen-1 (Z) -yl) -androstene-4-one-3.

a) IIβ, 19-14-p1-pyridinyl-3) -y-phenylene] -3,3-d] yumethylϋ · dimethoxodioxo-17α- [3-tetrahydropyran-2-oxy) propin-1-yl) androstanediol-5a, 17 β.

In a mixture of 140 ml of toluene and 70 ml of ethanol, 13.7 g of nonaflate obtained as described in point 1c) were dissolved and mixed successively in a protective gas atmosphere with 877 mg of tetrίαds (triphenylphosphine) palladium (0), 1.29 g lithium chloride, 19 ml 2 m sodium carbonate solution and 2.46 g diethyl (pyridinyl-3 ') borate. The reaction mixture was then stirred for 2 hours in an oil bath at 95 ° C, cooled to room temperature and stirred with water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel with an ethyl acetate / hexane mixture. 8.8 g of the title compound were obtained in the form of a yellowish foam.

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b) 11β, 19- (4- (pyridinyl-3) -o-phenylene) -17f3-hydroxy - 17α- (3-hydroxypropin-1-yl) androstene-4-one-3

8.8 g of ketone acetal prepared as described in a) were dissolved in 250 ml of acetone and mixed under a protective gas atmosphere with 5 ml of 4 N aqueous hydrochloric acid solution. After stirring for 2 hours at 50 ° C, the reaction mixture was poured into cold saturated sodium bicarbonate solution (basic pH) and most of the acetone was distilled off. Addition of methylene chloride, the aqueous phase separated and extracted several times with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel with an ethyl acetate / hexane mixture. 5 g of the title compound were obtained as yellowish foam.

[and]_D²² = + 48.6 ° (CHCb; c = 0.530)

c) 1 ie, 19- [4- (pyridinyl-3) -o-phenylene] -17e-hydroxy-17- (3-hydroxypropen-1 (Z) -yl) androstene-4-one-3.

g of propargia alcohol prepared as described in b) was dissolved in a protective gas atmosphere in 200 ml tetrahydrofuran, mixed with 5 ml pyridine and hydrogenated using 500 mg palladium (10%) supported on barium sulfate under standard pressure as a catalyst. After absorbing an equivalent amount of hydrogen (as controlled by TLC!), The reaction mixture was filtered through Celite, the filter residue was again washed with tetrahydrofuran and the filtrate was concentrated by evaporation under reduced pressure. Pyridine was removed by azeotropic distillation with toluene. The residue was chromatographed on silica gel with an ethyl acetate / hexane mixture. received

3.4 g of the title compound in the form of a yellowish foam. Crystallization from ethyl acetate gave 3.12 g of white crystals.

Melting temperature; 219-221 ° C;

[Α] ο ² = +72.2 (CHCb; c = 0.505).

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