Derivatives of 1-arylsulfonyl, arylcarbamoyl or aristoteleion, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

The invention relates to derivatives of 1-arylsulfonyl, arylcarbamoyl or aristoteleion General formula I where L is selected from the group consisting of Co, CS and SO2; R1and R2independently selected from the group consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6), provided that when L - SO2, R1and R2at the same time do not represent hydrogen; R3independently represents 1 to 3 groups consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6); X is chosen from (CH2)nor Y(CH2)n-1where Y Is O or S, and n = 1, 2, 3. New derivatives are non-steroidal heterocyclic compounds that act as selective progestins and/or antiprogestin with high affinity in vitro in relation to the progestin receptor uterus, breast, or bone. As such, non-steroidal heterocyclic derivatives can be used for contraception, menopause, osteoporosis, or endometriosis. Also described is a method of obtaining and farmcampsite on the basis of the claimed compounds. 3 S. and 11 C.p. f-crystals, 3 PL.

for example, 3,4-diazo-1,2,3,9,10,10 and-hexahydrofuro-2-he (A) and 3,4,4 a,5,6,7 hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazin-2-he (B) described Holava and Partyka. 2,4,4 a,5-Tetrahydro-3H-indeno[1,2]pyridazin-3-one (C) described Toma, Cignarella, etc.

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Synthesis of 7-bromo-4-methyl-1-tetralone (E)-connection to the intermediate compounds used in this invention, 4-methyl-1-tetralone (D), described (verbally) Professor R. Danheiser from MIT. Although Danheiser describes the synthesis of compounds disclosed in the literature, its method similar to the method used in this case to obtain unknown first compounds used for the synthesis of compounds according to this invention.

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In the literature there is no description trihalomethane of benzocyclobutene.

From dihalogenoalkane known only 6,7-debtor - and 6,7-dichlorethylene, but get them in another way. W. M. Owton and M. Brunavs. Synthetic Communications, 21, 981 (1991).

No dibromoanthraquinone unknown.

All monobromomethane known, with the exception of 8-bromo-1-tetralone.

None of the claimed compounds according to this invention has not been described previously.

DESCRIPTION OF THE INVENTION

The present invention about and R2independently chosen from the group consisting of H, halogen, alkyl (C1-C6), haloalkyl (C1-C6), nitro, cyano, carboxyl and carbalkoxy(C1-C6); provided that when L is SO2, R1and R2cannot simultaneously represent hydrogen;

R3independently equal to 1, 2 or 3 in any model of substitution of the following substances: H, halogen, alkyl (C1-C6), haloalkyl (C1-C6), nitro, carboxyl or carbalkoxy(C1-C6);

X represents biradical formula (CH2)nor Y-(CH2)n-1where n is an integer from 1 to 3, a Y = O or s

In the framework of this invention, unless otherwise indicated, alone or together with another compound, the alkyl is defined as 1-6 carbon atoms and may be branched (in this case, he has at least 3 carbon atoms or unbranched. Halogen is defined as chlorine, bromine, fluorine or iodine. Alkoxy refers to groups derived from alcohols having 1-6 carbon atoms, and haloalkyl defined as a compound containing alkyl group having 1-3 carbon atoms, such as trifluoromethyl.

The compounds of this invention are non-steroidal Goethe is matter of great similarity in vitro with progestin receptor uterus, breast cancer or bone, as well as biological activity in the intravenous, subcutaneous and oral administration. Therefore, they can be used as a therapeutic agent in connection with contraception, menopause, endometriosis, breast cancer, synchronization of cycles, abortion, induction of labor or osteoporosis.

A DETAILED DESCRIPTION OF THE PREFERRED VARIANTS OF THE INVENTION

More specifically, the present invention relates to a series of non-steroidal heterocyclic compounds whose activity mimicries activity of progestins and/or of antiprogestins with great affinity (affinity) in vitro with the receptor, progestins uterus, breast, or bone.

The preferred compounds of this invention are such compounds where L = SO2at least one of R1and R2is a halogen, R3represents a halogen and/or CF3and X = (CH2)nwhere n = 1-3. Another preferred group of compounds according to this invention includes such compounds, where L = CO or CS, R1and R2represent hydrogen, R33,4 - dichloro, and X = (CH2)nwhere n = 1-3.

Connection Yes As can be seen from the Reaction scheme 1, appropriately substituted benzocyclobutene (II) is transformed into circular acylhydrazone (III) in a known manner, such as the way Holava and Partyka (J. Med. Chem, 14, 262 (1971)). In General, this method involves the conversion of II in unsaturated ketoacid using Glyoxylic acid and base, with subsequent restoration of ninasimone by heating zinc in acetic acid and treatment restored the keto acid with hydrazine to education III.

Then substituted cyclic acylhydrazone (III) is transformed into a cyclic hydrazone (IV) by reaction with a reducing agent, such as, for example, hydride or DIBORANE, lithium aluminum in a suitable solvent, such as tetrahydrofuran, in a known manner, for example, described J-L. Aubagnac, J. Elguero, R. Jacquier, R. Robert., Bull. Chem. Soc. France, 2859 (1972).

The obtained cyclic hydrazone (IV) acelerou with appropriately substituted benzoylchloride or sulphonylchloride in an appropriate solvent, such as tetrahydrofuran or toluene, with a base, such as triethylamine, to obtain a non-steroidal heterocyclic derivative (I).

The product is separated and purified, known in the art methods, for example by pouring the reaction mixture in razbunare or ethyl acetate. The organic layer is concentrated and the residue is subjected to crystallization or purification by chromatography on silica gel. The fractions containing the product are evaporated and the residue is subjected to recrystallization to obtain the desired compounds.

Amides derived in this way can be converted to thioamides (L = CS) reaction with the reagent Lawesons or P2S5in toluene.

Some of the halogenated starting materials is unknown in the literature. These compounds can be obtained by the method shown in Reaction scheme 2 (see the end of the description).

As can be seen, the addition of 1.2 equivalents of halogenation agent in the presence of aluminum chloride results in two isomeric monohalobenzene, where the halogen is introduced into ketogroup in the meta-position. Adding more than 2 equivalents of halogenation agent in the presence of aluminum chloride results in dihalogenoalkane, as well as two isomeric trigonometrically. In addition, monohalobenzene can be galogenirovannyie other halogen to obtain a mixed substituents, such as, for example, 6-bromo-5-chloro-1-tetralone or 5-chloro-7-iodine-1-tetralone.

Activity sedimentrelated analysis "Ex Vivo".

The binding of progestin receptor

The procedure used is essentially the procedure described by J. L. McGuire, C. D. Bariso, A. P. Shroff. Biochemistry 13, 319 (1974).

Uterine new Zealand rabbits (1.5-2.5 kg) are placed in cold extraction buffer A (0.01 M Tris-HCl, pH 8.0, 0,001 ethylendiaminetetraacetic acid (EDTA), 0.25 M sucrose). The uterus is crushed, washed and homogenized in cold buffer solution A. the Homogenate (2 g wet tissue/ml buffer) and centrifuged at 220000 G for 1 hour at 4oC. high-Speed supernatant fraction is used as a drug receptor.

A comparative analysis of the binding of conduct, mixing3H-R5020 with drug receptor and adding a known amount of unlabeled compounds. The mixture is incubated at 4oC for 18 hours. Connection associated with the receptor is separated from the free compounds in solution, using loaded dextran coal dust, and determine the number of isotopes associated with the receptor. Suppression, constituting 20% or more from the reference binding isotope is considered to be significant.

A similar method can be used to determine the binding affinity with respect to d is doing3H-thymidine into cells of T47-D is used to determine the effect of compounds on cell proliferation T47-D. Compounds in this invention can be applied in vivo in biological terms, modulated progestin, where they show a significant impact on the growth of cells T47-D.

A similar method is used to determine the effects of test compounds on cells of the human bones THE.

T47-D line (human breast cancer) is used, applying the usual sterile techniques. Cells placed in a RPMI1640 medium containing fetal bovine serum (10%) and insulin (0.2 int. units/ml). Cells treated with trypsin and passedout using standard procedures.

Cells seeded in 96-well microtiter plates, incubare in RPMI medium (containing no phenol red and containing insulin and fetal bovine serum treated with 5% charcoal) at 37oC in an atmosphere consisting of 95% air and 5% CO2. After approximately 48 hours, used the medium replaced with fresh one containing the test compounds dissolved in dimethyl sulfoxide (final concentration of 0.1%), and cells incubated for approximately 22 hours. Add 3H-thymidine and continue inkubirovanii washed from soluble thymidine, treated with trypsin and harvested using standard procedures. The number of 3H-thymidine introduced into DNA was determined by counting in a liquid phase. Primary standards are promegestone, strong synthetic progestin, and RU486, antiprogestin. Test compounds are typically subjected to screening at a concentration of from 0.1 to 1000 nm. A compound is considered active if it stimulates or inhibits the introduction of thymidine. The results are expressed as the concentration of test compounds required to increase proliferation in 2 times in comparison with control (SC200), or the concentration required for inhibition of proliferation induced promegestone, 50% (EC50). A value less than 1000 nm is active.

Details of application procedures are described in the following sources: C. Christensen, D. Gunter, D. Saunders, V. Malviya, Gynecol. Oncol., 28, 25 (1987); J. Puzas, R. Drivdahl, G. Howard, D. Baylink, Proc. Soc. Exp. Biol. Med. , 166, 113 (1981); I. Keydar, L. Chen, S. Karby, F. Weiss, J. Delarea, M. Raduy, S. Chaitcik, H. Brenner, Eur. J. Cancer, 15, 659, (1979).

TABLE

Table 1 shows the examples of the invention with a molecular formula, melting point, binding affinity, expressed as concentration of the compound in nanomole per litre (x 10-9M), the required drobnosti to proliferate or to inhibit the proliferation of T47D, induced R5020, human cells, breast carcinoma (T47D). If in column T47D no value is specified, this means that a particular connection has not been checked.

Tables 2 and 3 show some examples of the invention with a molecular formula, melting and activity, expressed as the average increase cell proliferation in the bone at 5 concentrations (CP), or in the form of concentration of the compound in nanomole per litre (x 10-9M), necessary to displace 50% of vinylmation (VNT) type I125from progestin receptor human bones (BPR) (IC50). If in column CP no value is specified, this means that a particular connection has not been checked.

Pharmaceutical compositions containing as active ingredient the compound according to this invention in a homogeneous mixture with a pharmaceutical carrier can be obtained in accordance with conventional pharmaceutical methods of preparing mixtures. The media may have many different forms depending on the desired form of administration, for example, intravenous, oral or parenteral. In the preparation of oral dosage is Oli, oils, alcohols, corrigentov, preservatives, dyes, etc., for oral liquid preparations (such as, for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, sizing, binders, beam splitters, etc. for oral solid preparations (such as powders, capsules and tablets). Due to the ease of administration, tablets and capsules represent the most preferred oral unit dosage form. In this case, the use of solid pharmaceutical carriers are obviously. If desired, the tablets may be coated in sugar or intersolubility floor using standard methods. In the case of parenteral administration, the carrier typically includes sterile water, you can also use other ingredients, for example, to improve the solubility or preservation. Can also be prepared suspension for injection. In this case, you can use the appropriate liquid carriers, suspendresume agents, etc., Possible indications for the use of pharmaceutical compositions according to this invention are contraception, menopause, endometriosis, breast cancer, synchronizations. The drug is usually used in the form of the dosage unit, for example, tablets, capsules, powder, etc., in the amount of from about 1 to about 500 mg/kg/day, preferably from about 10 to about 100 mg/kg/day of the active ingredient. The exact dose may vary depending on the age and condition of the patient, and depending on the case.

EXAMPLES

1. Obtaining raw materials and intermediates used to produce the final products of this invention

Subsequent Sections A, B and C contain a description of the receipt of certain starting materials and intermediates used to produce compounds according to this invention.

A. Obtaining halobenzene

In the following examples, N-bromosuccinimide can be substituted by bromine and N-chlorosuccinimide, or to obtain chlorine compounds can be used chlorine. N-iodosuccinimide gives iodine analogues.

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1-indanone (VI) VIIa, X=Br; VIIb, Y=Br: VIIc. X=Y=Br

6-Bromantan-1-he (VIIb) and 4-bromantan-1-he (VIIa)

250-Ml triggerlevel flask with a round bottom equipped with water-cooled refrigerator Liebig, mechanical stirrer, and retrieve the hydrated aluminium chloride (16.6 g, a 0.125 mol) and stirring the two portions over 3 minutes, add 1-indanone (VI) (6.60 g, 0,05 mol), ground to fine powder using mortar and pestle. Rapid separation of gaseous HCl is accompanied by a moderate exothermic reaction, the mixture quickly turns into a dark brown homogeneous suspension, stir for another 10 minutes.

To a well stirred mixture for 10 minutes, added dropwise bromine (3.1 ml of 0.06 mol). After the addition of bromine, the molten mixture is heated in a water bath to 80oC for 5 minutes. The hot mixture was poured into 100 g of crushed ice and 20 ml of concentrated hydrochloric acid. Then ice the mixture is stirred for 10 minutes, diluted with 100 ml of water and extracted with ether (2 x 200 ml). The combined ether extracts washed with water (2 x 100 ml), dried over anhydrous sodium sulfate and concentrated, gaining 10.6 g of a red oil that crystallized upon storage at room temperature.

Analysis of the product by gas chromatography and mass spectroscopy shows a mixture of 1: 1 monitorov. Material chromatographic on a column of silica gel (45 x 10 cm) using n-hexane/tetrahydrofuran (8:1) for section a is-bromantan-1-it (VIIb).

VIIa: the output of 37.7%; so pl. 108-109oC, light yellow prisms; IR (KBr) 1712 cm-1;1H NMR (CDCl3) 2,70-to 2.74 (m, 2H), is 3.08-of 3.12 (m, 2H), 7,35-7,38 (d, 1H), 7,66-of 7.70 (DD, 1H), 7,87-7,88 (d, 1H); MS m/z 211;

Elemental analysis for C9H7BrO:

Calculated: C 51,22; H 3,34.

Found: C 51,10, H 3,25.

VIIIb: output 35.8 per cent; so pl. 90-92oC, light yellow prisms; IR (KBr) 1709 cm-1;1H NMR (CDCl3) 2,71 is 2.75 (m, 2H), 3,06-to 3.09 (m, 2H), 7,25-7,30 (DD, 1H), 7,69-7,71 (d, 1H), 7,74-7,76 (DD, 1H); MS m/z 211;

Elemental analysis for C9H7BrO:

Calculated: C 51,22; H 3,34.

Found: C 50,38, H 3,24.

7-Bromo-1-tetralone (IXa) and 5-1-tetralone (IXb)

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1-Tetralone (VIII)

1-Tetralone (VIII) (7,3 g of 0.05 mol) is added dropwise to the anhydrous aluminium chloride (16.6 g, a 0.125 mol) with vigorous stirring for 3 minutes. To the resulting suspension is added bromine (3,71 ml of 0.06 mol) over 10 minutes. After the addition of bromine, the mixture is heated to 80oC for 5 minutes and in the molten state is poured into 150 g of crushed ice containing 20 ml of 12 N HCl. After the same processing as in example 1, get 10,85 g of brown oil. Oil chromatographic on a column of silica gel (45 x 10 cm) using hexane:tetrahydrofuran (8:1). Separated isomers paracrystals. 74-75oC, light yellow prisms; IR (KBr) 1676 cm-1;1H NMR (CDCl3) 2,09-to 2.18 (m, 2H), 2,63-to 2.67 (t, 2H), 2,89-of 2.93 (t, 2H), 7,13-7,16 (d, 1H), 7,55-7,58 (DD, 1H), 8,14-of 8.15 (d, 1H); MS m/z 225;

Elemental analysis for C10H9BrO:

Calculated: C 53,36; H Is 4.03.

Found: C 53,14; H 3,96.

IXb: output of 39.8%; so pl. 45-46oC, light yellow prisms; IR (KBr) 1679 cm-1; 1H NMR (CDCl3) 2,11-of 2.20 (m, 2H), 2,62-to 2.67 (t, 2H), 2,94-3,03 (t, 2H), 7,15-7,21 (DD, 1H), 7,71-7,74 (DD, 2H), 7,99-8,02 (DD, 2H), MS m/z 225;

Elemental analysis for C10H9BrO:

Calculated: C 53,36; H Is 4.03.

Found: C 52,97; H 3,94.

5,7-dibromo-1-tetralone (IXc), 5,6,7-tribromo-1-tetralone (IXd) and 5,7,8-tribromo-1-tetralone (IXe)

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IXc, X=Y=Br, W=Z=H

IXd. X=Y=W=Br, Z=H; IXe, X=Y=Z=Br, W=H

Bromine (7,42 r of 0.12 mol) is added dropwise to the suspension obtained from anhydrous aluminium chloride (16.6 g, a 0.125 mol) and 1-tetralone (VIII) (0,05 mol) as in Example 1. As a result, after processing gain of 15.0 g of a brown oil that crystallized during storage. Analysis using gas chromatography and mass spectroscopy shows a mixture consisting of 87% dibromononane product and 13% 1:1 mixture tribromopropane isomers. After chromatography and recrystallization from hexane get 7,7,

IXc: yield 51%; so pl. 60-61oC, CBE is H, J = 2 Hz), 8,13 (d, 1H, J = 2 Hz); MS m/z 304;

Elemental analysis for C10H8Br2O:

Calculated: C 39,51; H 2,65.

Found: C 39,41, H 2,49.

8-Bromo-1-benzocoumarin (XIa) and 6-bromo-1-benzocoumarin (XIb)

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XIa, X=Br, XIb, Y=Br; XIc, X=Y=Br

Following the General procedures described above to obtain tetralone, after conventional treatment mixture benzocoumarin (X) (8,01 g of 0.05 mol), aluminum chloride (16.6 g, a 0.125 mol.) and bromine (3,07 ml of 0.06 mol) get 11.87 per g of brown oil. Analysis using gas chromatography and mass spectroscopy shows a 1:1 mixture of monitorov containing 2% dibromsalan.

XIa: yield 30%; so pl. 38-38,5oC, whitish powder; MS m/z 239;

Elemental analysis for C11H11BrO:

Calculated: C 55,25, With 4.64 H.

Found: C 54,83, H 4,62.

XIb: yield 32%; clear oil, temp. boil 101-105o@ 0.12 mm Hg; MS m/z = 239;

Elemental analysis for C11H11BrO:

Calculated: C 55,25, With 4.64 H.

Found: C 55,32, H 4,59.

5,6-Dibromo-1-tetralone (XIIa) and 6,7-dibromo-1-tetralone (XIIb)

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XIIa, Y=Br, X=H

XIIb, X=Br, Y=H

Using the methods described above, the synthesized tetralone, after conventional treatment of a mixture of 6-bromo-1-tetralone (XII) (2 g, mmol), aluminum chloride (16.6 g, a 0.125 mol) and bro-Diazo-1,2,3,9,9 and-tetrahydrofuran-2-he (XIII)

The target connection receive in accordance with the description of L. Toma, G. Cignarella, D. Barlocco, F. Ronchetti, J. Med. Chem., 33, 1591-4, 1990.

3,4-Diazo-1,2,3,9,10,10 and-hexahydrofuro-2-he (XIV)

The target connection receive in accordance with the description of N. M. Holava, R. A. Partyka, J. Med. Chem., 14, 262 (1971).

3,4,4 a, 5,6,7-Hexahydro-2H-benzo[6,7] cyclohepta [1,2] pyridazin-2-he (XV)

The target connection receive in accordance with the description of N. M. Holava, R. A. Partyka, J. Med. Chem. 14, 262 (1971).

8-Bromo-3,4-diazo-1,2,3,9,10,10 and-hexahydrofuro-2-he (XVI)

The target compound is obtained by treatment of 5-bromo-1-tetralone (IXb) (20 mmol) of Glyoxylic acid (20 mmol); product restore an excess of zinc in acetic acid and treated with excess hydrazine by known methods, as described N. M. Holava, R. A. Partyka, J. Med. Chem. 14, 262 (1971), to obtain the target compound.

7,8-Dibromo-3,4-diazo-1,2,3,9,10,10 and-hexahydrofuro-2-he (XVII)

The target compound is obtained by treatment of 5,6-dibromo-1-tetralone (XIIa) (10 mmol) of Glyoxylic acid (10 mmol); product restore an excess of zinc in acetic acid, and then treated with an excess of hydrazine, as described N. M Holava, R. A. Partyka, J. Med. Chem. 14, 262 (1971), to obtain the target compound.

7-Chloro-3,4-diazo-1,2,3,9,10,10 and-t. Chem. 8, 809 (1971)) (50 mmol) and Glyoxylic acid (50 mmol) and the base, then restore the excess zinc in acetic acid, and then treated with an excess of hydrazine, as described N. M.Holava, R. A. Partyka, J. Med. Chem. 14, 262 (1971), to obtain the target compound.

8-Bromo-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7] cyclohepta-[1,2] pyridazin-2-he (XIX)

The target compound is obtained by treatment of 6-bromo-1-benzocoumarin XIb Glyoxylic acid, then restore the excess zinc in acetic acid, and then treated with an excess of hydrazine, as described N. M.Holava and R. A. Partyka, J. Med. Chem. 14, 262 (1971), to obtain the target compound.

C. Receiving cyclic hydrazones

3,4-Diazo-1,2,3,9,10,10 a-hexahydrofuro (XX)

3,4-Diazo-1,2,3,9,10,10 a-hexahydrofuro-2-she (XIV) (2.5 g, 12.5 mmol) is dissolved in tetrahydrofuran and added dropwise 1 equivalent of lithium-aluminiumhydride (21 ml, 1 M aq in THF). After 30 minutes at 22oC added dropwise to a 15% NaOH solution, and glutinously precipitate filtered. The filtrate is dried over magnesium sulfate, filtered and evaporated to dryness, obtaining oil used as starting material without further purification.

7-Chloro-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro (XXI)

7-Chloro-3,4-diazo-1,2,3,9 is Nigeria (1 M solution in tetrahydrofuran). After 30 minutes at 22oC added dropwise to a 15% NaOH solution, and the precipitate filtered. The filtrate is dried over magnesium sulfate, filtered and evaporated to dryness, obtaining oil used as starting material without further purification.

8-Bromo-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7] cyclohepta[1,2]of pyridazine (XXII)

8-Bromo-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7] cyclohepta[1,2] pyridazin-2-he (XIX) (1 g, 3.4 mmol) dissolved in tetrahydrofuran and added dropwise to 2 equivalents of DIBORANE (1m solution in tetrahydrofuran). After 2 hours at 22oC the reaction is strongly cooled and 1 ml of 6 M HCl and neutralized with 50% NaOH solution, then dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness, obtaining oil, used without further purification.

8-Bromo-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro (XXIII)

8-Bromo-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro-2-he (XVI) (1.0 g, 3.6 mmol) dissolved in tetrahydrofuran (100 ml) and added dropwise to 2 equivalents of DIBORANE (1m solution in tetrahydrofuran). After 1 hour the reaction is heated on the steam bath in the 22oC for 5 minutes, then cooled rapidly to 1 ml of 6 M HCl and neutralized with 15% NaOH solution, and then dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness, V)

7,8-Dibromo-3,4-diazo-1,2,3,9,10,10 and-hexahydrofuro-2-he (XVII) (0.71 g, to 1.98 mmol) suspended in tetrahydrofuran and at the 22oC added dropwise to 2 equivalents of DIBORANE (3,96 ml of 1 M solution in tetrahydrofuran). The mixture is briefly heated to 45oC to dissolve all solids, then stirred at room temperature for 60 hours. The reaction is strongly cooled and 1 ml of 6 M HCl and neutralized with 50% NaOH solution, and then dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness, obtaining oil used as starting material without further purification.

3,4-Diazo-1,2,3,9,9 and-tetrahydrofluorene (XXV)

3,4-Diazo-1,2,3,9,9 and-tetrahydrofuran-2-he (XIII) (3.5 g, 17.5 mmol) is dissolved in tetrahydrofuran and added dropwise 1 equivalent of lithium-aluminiumhydride (1 M solution in tetrahydrofuran). After 30 minutes at 22oC added dropwise to a 15% NaOH solution, and glutinously precipitate filtered. The filtrate is dried over magnesium sulfate, filtered and evaporated to dryness, obtaining oil used as starting material without further purification.

3,4-Diazo-9-oxa-1,2,3,9,10,10 a-hexahydrofuro (XXVI)

3,4-Diazo-9-oxa-1,2,3,9,10,10 a-hexahydrofuro-2-he (15 mmol), obtained as the above, 2 equivalents of DIBORANE.

3,4-Diazo-9-thia-1,2,3,9,10,10 a-hexahydrofuro (XXVII)

3,4-Diazo-9-thia-1,2,3,9,10,10 a-hexahydrofuro-2-he (10 mmol), obtained as described in Tohru Nakao, Hiroshi Tanaka, Yasuto Motitomo, Shuzo Takehara, Kenichi Demizu, Tetsuya Tahara, Yakugaku Zasshi, 110(12), 922-31 (1990), restore, as described above, two equivalents of DIBORANE.

The following examples serve to illustrate the present invention and not to limit its scope.

EXAMPLES

Example 1: 8-Bromo-3,4,4 a,5,6,7 hexahydro-2-(4-identicality)-2H-benzo[6,7]cyclohepta[1,2]pyridazin

8-Bromo-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7] cyclohepta[1,2] pyridazin (XIX) (1.0 g, 3.6 mmol) and 4-identicality chloride (1.1 g, 3.6 mmol) are combined in a solution of 50 ml of dichloromethane and 50 ml of pyridine. The mixture was stirred at 22oC for 64 hours, while it acquires a dark red colour. The mixture is concentrated under reduced pressure, a solution of pyridine is then poured into 6 M HCl and ice and then extracted with dichloromethane. The organic layer is concentrated under reduced pressure and filtered through silica gel, elwira dichloromethane, obtaining 1.3 g of solid whitish substance, which is recrystallized from a mixture of isopropanol/chloroform to obtain a white solid, iluv>S:

Calculated: C 41,85, H Of 3.33, N 5,14.

Found: C 41,68, H Is 3.27, N 5,03.

Example 2: 8-Bromo-3,4-diazo-1,2,3,9,10,10 a-hexahydro-3-(4-identicality)phenanthrene

8-Bromo-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro (XXI) (1.0 g, of 3.77 mmol) and 4-identicality chloride (1,14 g of 3.77 mmol) are combined in 100 ml of pyridine. The mixture was stirred at 22oC for 16 hours, while it acquires a dark red colour. The mixture is then poured into 6 M HCl and ice and extracted with dichloromethane. The organic layer is concentrated under reduced pressure and filtered through silica gel, elwira dichloromethane, receiving 0.3 g crude material, which was recrystallized from hexane to obtain 0.28 g of solid whitish substance having a melting point of 197-198oC.

Elemental analysis for C18H16BrIN2O2S:

Calculated: C 40,76, H 3.04 From, N 5,27.

Found: C 40,59, H 2,89, N Is 5.06.

Example 3: 7,8-Dibromo-3,4-diazo-1,2,3,9,10,10 a-hexahydro-3-(4-identicality)phenanthrene

7,8-Dibromo-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro (XVII) (0.7 g, 1.9 mmol) and 4-identicality chloride (0.65 g, 2.1 mmol) are combined in 100 ml of pyridine. The mixture was stirred at 22oC for 16 hours, while it acquires a dark red colour. CME is AI and filtered through silica gel, elwira dichloromethane give crude material, which was recrystallized from hexane to obtain 0.1 g of white solid, having a melting point 202-203oC.

Elemental analysis for C18H15Br2IN2O2S:

Calculated: C 35,44, H 2,48, N 4,59.

Found: C 35,54, H 2,47, N Br4.61.

Example 4: 7-Chloro-3,4-diazo-1,2,3,9,10,10 and hexahydro-3- (4-identicality)phenanthrene

7-Chloro-3,4-diazo-1,2,3,9,10,10 and-hexahydrofuro (XXI) (1.1 g, 5.0 mmol) and 4-identicality chloride (1.2 g, 3.9 mmol) are combined in a solution of 50 ml of dichloromethane and 50 ml of pyridine. The mixture was stirred at 22oC for 20 hours, while it acquires a dark red colour. The mixture is concentrated under reduced pressure, and a solution of pyridine is then poured into 6 M HCl and ice and extracted with dichloromethane. The organic layer is concentrated under reduced pressure and filtered through silica gel, elwira dichloromethane, getting a solid whitish substance, which is recrystallized from hexane to obtain 0.5 g of white solid, having a melting point 194-196oC.

Elemental analysis for C18H10ClIN2O2S:

Calculated: C 44,42, H 3,31, N 5,76.

Found: C 44,73, H is PR-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro (XXI) (1.0 g, 4.7 mmol) and 2,5-dichlorobenzenesulfonyl chloride (1.2 g, 4.9 mmol) are combined in 100 ml of pyridine. The mixture was stirred at 22oC for 16 hours, while it acquires a dark red colour. The mixture is then poured into 6 M HCl and ice and extracted with dichloromethane. The organic layer is concentrated under reduced pressure and filtered through silica gel, elwira dichloromethane, receiving 0.5 g of crude material, which was recrystallized twice from a mixture of hexane/chloroform to obtain 0.25 g of solid whitish substance having a melting point of 186-187oC.

Elemental analysis for C18H15Cl3N2O2S:

Calculated: C 50,31, H 3.52, The N 6,52.

Found: C 50,23, H 3,45, N 6,44.

Example 6: 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 a - hexahydrofuro

3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro (XXI) (2.67 g, and 14.3 mmol) and 3,4-dichlorobenzophenone (3.0 g) are combined in 100 ml of pyridine and stirred at 22oC for 16 hours. The mixture is then poured into dichloromethane and washed twice with 2 M HCl, then dried over magnesium sulfate and filtered. The filtrate is concentrated and filtered through silica gel, elwira dichloromethane, gaining 3.7 g of solid whitish substance, having a melting point 154-155oC.

Example 7: 2-(3,5-dichlorobenzoyl)-3,4,4 a,5,6,7 hexahydro-2H-benzo[6,7] cyclohepta[1,2]pyridazin

3,4,4 a,5,6,7 Hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazin (XV) (2.0 g, 10 mmol) and 3,5-dichlorobenzophenone (2.1 g, 10 mmol) are combined in 75 ml of dichloromethane and add 5 ml of triethylamine. The mixture was stirred at 22oC for 16 hours and evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane and washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira dichloromethane, receiving 2.5 g of white solid, having a melting point 115-116oC.

Elemental analysis for C20H18Cl2N2O:

Calculated: C 64,35, H A 4.86, N 7,50.

Found: C 64,38, H 4,56, N 7,56.

Example 8: 2-(3,4-divertimenti)-3,4,4 a,5,6,7 hexahydro-2H-benzo[6,7] cyclohepta[1,2]pyridazin

3,4,4 a, 5,6,7-Hexahydro-2H-benzo[6,7] cyclohepta[1,2] pyridazin (XV) (2.0 g, 10 mmol) and 3,4-differentiald (2.1 g, 10 mmol) are combined in 75 ml of dichloromethane and add 5 ml of triethylamine. The mixture was stirred at 22oC for 16 hours and dried to dryness under reduced pressure. The residue is dissolved in dichloromethane and washed with diluted HCl, dried over su is on solids, having a melting point 117-118oC.

Elemental analysis for C20H18F2N2O:

Calculated: C 70,58, H 5,33, N 8,23.

Found: C 70,59, H 5,26, N 8,35.

Example 9: 2-(3,4-dichlorobenzoyl)-3,4,4 and,5,6,7 hexahydro-2H-benzo[6,7] cyclohepta[1,2]pyridazin

3,4,4 a, 5,6,7-Hexahydro-2H-benzo[6,7] cyclohepta[1,2] pyridazin (XV) (2.24 g, and 11.2 mmol) and 3,4-dichlorobenzophenone (2,34 g, and 11.2 mmol) are combined in 100 ml of dichloromethane and add 10 ml of triethylamine. The mixture was stirred at 22oC for 16 hours and evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane and washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira dichloromethane, obtaining 2.0 g of light yellow solid having a melting point of 136-137oC.

Elemental analysis for C20H18Cl2N2O:

Calculated: C 64,35, H A 4.86, N 7,50.

Found: C 64,29, H 4,80, N 7,39.

Example 10: 3-(3,4-differentail)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro

3,4-Diazo-1,2,3,9,10,10 and-hexahydrofuro (XIV) (1,83 g, 9,82 mmol) and 3,4-differentiald (1.73 g, 9,82 mmol) are combined in 75 ml of dichloromethane and add 5 ml of triethylamine. The mixture was stirred at washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira dichloromethane, gaining 1.4 g white solid, having a melting point 146-147oC.

Elemental analysis for C19H16F2N2O:

Calculated: C 69,93, H 4,94, N 8,58.

Found: C 69,78, H 4,72, N 8,79.

Example 11: 3-(3,5-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro

3,4-Diazo-1,2,3,9,10,10 and-hexahydrofuro (XIV) (2.67 g, and 14.3 mmol) and 3,5-dichlorobenzophenone (3.0 g) are combined in 250 ml of dichloromethane and add 10 ml of triethylamine. The mixture was stirred at 22oC for 1 hour and evaporated to dryness under reduced pressure. The yellow residue is dissolved in dichloromethane and washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira a mixture of ether/dichloromethane (2:1) to give 3.0 g white solid, having a melting point 141-142oC.

Elemental analysis for C19H16Cl2N2O:

Calculated: C 63,52, H 4,49, N 7,84.

Found: C 63,45, H 4,14, N 7,70.

Example 12: 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-oxa-1,2,3,9,10,10 a-hexahydrofuro

3,4-Diazo-9-oxa-1,2,3,9,10,10 a-hexahydrofuro (XXVI) (1.73 g, 9.2 mmol) and the when the 22oC for 14 hours and evaporated to dryness under reduced pressure. The yellow residue is dissolved in dichloromethane and washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira dichloromethane, receiving 1.2 g of solid whitish substance having a melting point of 166-167oC.

Elemental analysis for C18H14Cl2N2O2:

Calculated: C 59,85, H 3,91, N 7,75.

Found: C 59,83, H 3,86, N 7,73.

Example 13: 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-thia-1,2,3,9,10,10 a-hexahydrofuro

3,4-Diazo-9-thia-1,2,3,9,10,10 a-hexahydrofuro (XXVII) (1,33 g, 6.6 mmol) and 3,4-dichlorobenzophenone (1,38 g, 6.6 mmol) are combined in 100 ml of dichloromethane and add 100 ml of triethylamine. The mixture was stirred at 22oC for 48 hours and evaporated to dryness under reduced pressure. The yellow residue is dissolved in dichloromethane and washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira ether:dichloromethane (2:1) to give 1.0 g of solid whitish substance, which is recrystallized from benzohexone to obtain 0.84 g white solid, having a melting point 145-146oC.

Element and the 3.

Example 14: 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,9 a-tetrahydrofluorene

3,4-Diazo-1,2,3,9,9 and-tetrahydrofluorene (XXV) (1.6 g, 9.3 mmol) and 3,4-dichlorobenzophenone (1,95 g, 9.3 mmol) are combined in 100 ml of dichloromethane and add 10 ml of triethylamine. The mixture was stirred at 22oC for 16 hours and evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane and washed with diluted HCl, dried over magnesium sulfate, filtered and chromatographic on silica gel, elwira dichloromethane, obtaining 1.1 g of solid whitish substance having a melting point of 122-124oC.

Elemental analysis for C18H14Cl2N2O:

Calculated: C 62,60, H 4.09 To, N 8,12.

Found: C 62,50, H 4,11, N Of 7.90.

Example 15: 2-(3,5-dichlorobenzoyl)-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazin

2-(3,5-dichlorobenzoyl)-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7] cyclohepta[1,2] pyridazine from Example 7 (1.22 g, with 3.27 mmol) and pentasulfide phosphorus (2.14 g, 3.9 mmol) are combined in 200 ml of toluene and heated to 100oC for 1 hour. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, receiving 1.2 g twardego melting point 149-150oC.

Elemental analysis for C20H18Cl2N2S:

Calculated: C 61,40, H 4,66, N 7,19.

Found: C 61,67, H 4,65, N 7,06.

Example 16: 2-(3,4-divertimenti)-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazin

2-(3,4-Divertimenti)-3,4,4 a,5,6,7 hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazine from Example 8 (1.5 g, 4.4 mmol) and pentasulfide phosphorus (1,74 g, 5.3 mmol) are combined in 200 ml of toluene and heated to boiling under reflux for 1 hour. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, obtaining 1.3 g of solid yellow substance, which is recrystallized from ether to obtain the desired compound (0,83 g) having a melting point 134-136oC.

Elemental analysis for C20H18F2N2S:

Calculated: C 67,40, H 5,09, N 7,86.

Found: C 67,28, H 5,03, N 7,94.

Example 17: 2-(3,4-dichlorobenzoyl)-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazin

2-(3,4-dichlorobenzoyl)-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7] cyclohepta[1,2]pyridazine from Example 9 (1.5 g, 4.0 mmol) and pentasulfide (paternity) phosphorus (2.7 g, 6 moku of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, obtaining 1.3 g of solid yellow substance, which is recrystallized from ether to obtain the desired compound (1.0 g) having a melting point of 140-141oC.

Elemental analysis for C20H18Cl2N2S:

Calculated: C 61,40, H 4,66, N 7,19.

Found: C 61,78, H 4,69, N 7,09.

Example 18: 3-(3,4-divertimenti)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro

3-(3,4-differentail)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro from Example 10 (1.0 g, a 3.06 mmol) and pentasulfide phosphorus (2,05 g, 4.6 mmol) are combined in 150 ml of toluene and heated to boiling under reflux for 1.5 hours. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, obtaining 0.8 g of yellow solid substance having a melting point 170-171oC.

Elemental analysis for C19H16F2N2S:

Calculated: C 66,65, H 4,71, N 8,18.

Found: C 66,32, H 4,76, N 8,19.

Example 19: 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro

3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3, is wala and heated to boiling under reflux for 1.5 hours. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, obtaining 0.8 g of yellow solid substance having a melting point 110-111oC.

Elemental analysis for C19H16Cl2N2S:

Calculated: C 60,80, 4,30 H, N 7,46.

Found: C 60,74, H 4,11, N 7,47.

Example 20: 3-(3,5-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro

3-(3,5-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 a-hexahydrofuro from Example 11 (1.5 g, 4.2 mmol) and pentasulfide phosphorus (1,69 g, 4.2 mmol) are combined in 150 ml of toluene and heated to 80oC for 1 hour. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, and recrystallized from ether/hexane, obtaining 1.1 g yellow solid substance having a melting point of 162-163oC.

Elemental analysis for C19H16Cl2N2S:

Calculated: C 60,80, 4,30 H, N 7,46.

Found: C 60,78, H 4.26 Deaths, N 7,22.

Example 21: 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-oxa-1,2,3,9,10,10 a-hexahydrofuro

3-(3,3-Dichloro) are combined in 100 ml of toluene and heated to boiling under reflux for 1.5 hours. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, receiving 0.5 g of yellow solid substance having a melting point of 187-188oC.

Elemental analysis for C18H14Cl2N2OS:

Calculated: C 57,30, H 3,74, N 7,43.

Found: C 57,09, 3,75 H, N 7,29.

Example 22: 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,9 a-tetrahydrofluorene

3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,9 and-tetrahydrofluorene from Example 14 (0,63 g, 1.8 mmol) and pentasulfide phosphorus (1,05 g, 2.3 mmol) are combined in 100 ml of toluene and heated to boiling under reflux for 1.5 hours. The mixture is cooled, filtered through a pad of silica gel and washed with dichloromethane. The filtrate is evaporated to dryness and purified column chromatography, elwira dichloromethane, receiving 0.5 g of yellow solid substance having a melting point of 138-140oC.

Elemental analysis for C18H14Cl2N2S:

Calculated: C 59,84, H 3,91, N 7,76.

Found: C 59,77, H 3,97, N 7,76.

1. Derivatives of 1-arylsulfonyl, arylcarbamoyl or aristochromis-pyridazine formula

< / BR>
where L is selected Gorod, halogen, alkyl (C1-C6and haloalkyl (C1-C6), provided that when L - SO2, R1and R2at the same time do not represent hydrogen;

R3independently selected from 1-3 members of the group consisting of hydrogen, halogen, alkyl (C1-C6and haloalkyl (C1-C6);

X is chosen from (CH2)nor Y(CH2)n-1where Y Is O or S, a n = 1, 2, 3.

2. Connection on p. 1, where L IS the SO2at least one of R1and R2- halogen, R3independently selected from halogen or CF3and X represents (CH2)nwhere n=1-3.

3. Connection on p. 1, where L IS CO or CS, each of R1and R2is hydrogen, R33,4 - dichloro, and X - (CH2)nwhere n=1-3.

4. Connection on p. 1, selected from the group comprising of 8-bromo-3,4,4 a, 5,6,7-hexahydro-2-(4-iodobenzenesulfonyl)- 2H-benzo[6,7] cyclohepta[1,2] pyridazin; 8-bromo-3,4-diazo-1,2,3,9,10,10 and hexahydro-3-(4-iodobenzenesulfonyl)phenanthrene; 7,8-dibromo-3,4-diazo-1,2,3,9,10,10 and hexahydro-3-(4-iodobenzenesulfonyl)phenanthrene; 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 and-hexahydrofuro and 2-(3,5-dichlorobenzoyl)-3,4,4 a, 5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2]pyridazin.

5. Connection on p. 1, selected from the gr is oil)-3,4,4 and, 5,6,7-hexahydro-2H-benzo[6,7]cyclohepta[1,2] pyridazine; 3-(3,4-differentail)-3,4-diazo-1,2,3,9,10,10 and-hexahydrobenzene; 3-(3,5-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 and-hexahydrobenzene; and 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-oxa-1,2,3,9,10,10 and-hexahydrofuro.

6. Connection on p. 1, selected from the group comprising 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-thia-1,2,3,9,10,10 and-hexahydrobenzene; 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,9 and-tetrahydrofluorene; 2-(3,5-dichlorobenzoyl)-3,4,4 and,5,6,7 hexahydro - 2H-benzo[6,7]cyclohepta[1,2]pyridazine; 2-(3,4-divertimenti)-3,4,4 a, 5,6,7-hexahydro - 2H-benzo[6,7]cyclohepta[1,2]pyridazin; and 2-(3,4-dichlorobenzoyl)-3,4,4 and,5,6,7 hexahydro - 2H-benzo[6,7] cyclohepta[1,2]pyridazin.

7. Connection on p. 1, selected from the group comprising 3-(3,4-divertimenti)-3,4-diazo-1,2,3,9,10,10 and-hexahydrobenzene; 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 and-hexahydrobenzene; 3-(3,5-dichlorobenzoyl)-3,4-diazo-1,2,3,9,10,10 and-hexahydrobenzene; 3-(3,4-dichlorobenzoyl)-3,4-diazo-9-oxa-1,2,3,9,10,10 and-hexahydrobenzene; 7-chloro-3,4-diazo-1,2,3,9,10,10 a-hexahydro-3-(4-iodobenzenesulfonyl)phenanthrene; 7-chloro-3,4-diazo-1,2,3,9,10,10 and hexahydro-3-(2,5-dichlorobenzenesulfonyl)phenanthrene and 3-(3,4-dichlorobenzoyl)-3,4-diazo-1,2,3,9,9 and-tetrahydrofluorene.

8. The method of obtaining coedine) reaction benzocyclobutene formula

< / BR>
with Glyoxylic acid, and recovering the resulting product of the first reducing agent and processing of the resulting reduction product with hydrazine to obtain the cyclic acylhydrazone formula

< / BR>
the reaction of cyclic acylhydrazone with a second reducing agent to obtain a cyclic hydrazone of the formula

< / BR>
and the reaction of the cyclic hydrazone with allermuir agent, and, when L is CS, (b) reaction of the resulting amide with a reagent Lawesons or P2S5.

9. The method according to p. 8, wherein the first reducing agent is zinc in acetic acid.

10. The method according to p. 8, wherein the second reducing agent selected from lithium aluminum hydride and DIBORANE.

11. The method according to p. 8, characterized in that allerease agent selected from benzoylchloride and sulphonylchloride.

12. The method according to p. 8, characterized in that allerease agent is benzosulphochloride.

13. The method according to p. 8, characterized in that allerease agent represents benzoyl chloride.

14. Pharmaceutical composition which acts as a selective progestins and/or antiprogestin, characterized in that it includes those who

 

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