Method of producing 5,6-dihydro-4h-benzo[f]pyrrolo[1,2-α][1,4]diazepin-6-one

FIELD: chemistry.

SUBSTANCE: described is a method of producing 5,6-dihydro-4H-benzo[f]pyrrolo[ 1,2-α][1,4]diazepin-6-one 1, involving moulding a pyrrolodiazepine frame as a result of reduction of nitro-groups of N-(2,5-dioxoalkyl)-2-nitrobenzamides 4, in acetic acid in the presence of iron while carrying out the reaction until boiling and holding for 60 minutes at room temperature.

EFFECT: simultaneous formation of a pyrrole and a diazepine ring, and high output of end products owing to change in the sequence and conditions of the reaction.

 

The invention relates to the field of organic chemistry - synthesis of heterocyclic compounds - derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α] [1,4] diazepin-6-it.

The invention relates to a developing method of obtaining derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]diazepin-6-it General formula 1, which can be used as substances with high biological activity.

td align="center"> CH3
ConnectionRR1R2R3
1ACH3HHH
1Bt-BuHHH
1BCH3CH3HH
1GCH3C6H5HH
1DHCH3H
1stCH3Hp-ClC6H4H
1GCH3HHCH3

It is known that pyrrolo[1,2-α][1,4]benzodiazepines affect the Central nervous system [G.W..Cheeseman and S.G.Greenberg, Chem. Ind. (London), 1974, 916-917; (b) F.Corelli, S.Massa, G.C.Pantaleoni, G.Palumbo and D.Fanini, Farmaco, 1984, 39, 707-717; A.Mai, R.Di Santo, S.Massa, M.Artico, G.C.Pantaleoni, R.Giorgi, M.F.Coppolino and A.Barracchini, Eur. J. Med. Chem., 1995, 30, 593-601], showing sedative [S.Massa, F.Corelli, M.Artico, A.Mai, R.Silvestri, G.C.Pantaleoni, G.Palumbo, D.Fanini and R.Giorgi Farmaco, 1989, 44, 109-123], anticonvulsant, myorelaxant [Tyga, Y.Kayama, Tmog, .Itoh, H.Fujimori, .Sunami, Y.Hashimoto and S.Ishimoto, J.Med. Chem., 1978, 21, 263-268; S.Massa, M.Artico, A.Mai, F.Corelli, M.Botta, A.Tafi, G.C.Pantaleoni, R.Giorgi, M.F.Coppolino, A.Cagnotto and M.Skorupska, J. Med. Chem., 1992, 35, 4533-4541] and psychotropic properties [E.G.Glamkowski and Y.Chiang, J.Heterocycl. Chem., 1987, 24, 1599-1604; S.Massa, M.Artico, A.Mai, F.Corelli, G.C.Pantaleoni, R.Giorgi, D.Ottaviani and A.Cagnotto, Farmaco, 1990, 45, 1265-1281]. In addition, derivatives pyrrolo[1,2-α][1,4]benzodiazepine showed anti-inflammatory [F.Corelli, S.Massa, G.Stefancich, G.Ortenzi, M.Artico, G.C.Pantaleoni, G.Palumbo, D.Fanini and R.Giorgi, Eur. J. Med. Chem. - Chim. Ther., 1986, 21, 445-449], analgesic [S.Saito, H.Ummiya, Y.Suga, M.Sato and N.Kawashima, WO Pat., 2003, WO 2003095427; Chem. Abstr., 139, 395821] and fungicidal activity [.Gilkerson, R.J.Nash, J.F.E.Van Gestel and L.Meerpoel, WO Pat., 2002, WO 2002034752; Chem. Abstr., 136, 340708; (b) L.Meerpoel, J.Van Gestel, F.Van Gerven, F.Woestenborghs, P.Marichal, V.Sipido, G.Terence R., Nash, D.Corens and R.D.Richards, Bioorg. Med. Chem. Lett., 2005, 15, 3453-3458].

Currently known methods of synthesis pyrrolo[1,2-α][1,4]benzodiazepines, based on the use of 1-[2-(aminomethyl)phenyl]pyrrole, which is introduced into the acid-catalyzed condensation with aldehydes, proceeding analogously to the reaction Pictet-Spengler [a) S.Raines, S.Y.Chai and F.P.Palopoli, J.Heterocycl. Chem., 1976, 13, 711-716; (b) G.W.H.Cheeseman and S.G.Greenberg, J. Heterocycl. Chem., 1979, 16, 241-244; (c) S.Massa, A.Mai, M.Artico, F.Corelli and M. Botta, Tetrahedron, 1989, 45, 2763-2772; (d) S.Massa, A.Mai and M.Artico, Synth. Commun., 1990, 20, 3537-3545; (e) S.Vega and M.S.Gil, J.Heterocycl. Chem., 1991, 28, 945-950] or subjected to acylation followed by cyclization under the action of POCl3(bischler-Napieralski) [(a) S.Vomero, R.Giuliano, .Artico and G.Stefancich, Farmaco, 1980, 35, 110-119; (b) S.Massa, A.Mai, R.Di Santo and M.Artico, J.Heterocycl. Chem., 1993, 30, 897-903; (d) F.Esser, K.-H.Pook, A.Carpy and J.-M. Leger, Synthesis, 1994, 77-82; (e) S.Massa, R.Di Santo, R.Costi and M.Artico, J. Heterocycl. Chem., 1993, 30, 749-753]. Aromatic aminomethyl group can also nucleophile to attack the carbonyl function in position 2 of the pyrrole ring with the formation of diazepinones fragment [(a) G.De Martino, .Scalzo, S.Massa, R.Giuliano and M.Artico, Farmaco, 1972, 27, 980-989; (b) S.Rault, M.Cugnon de Sevricourt M. and M.Robba, Compt. Rend. Acad. Sc., 1978, 287C, 117-120]. Instead of aminomethyl groups in these reactions, the use of which ovale appropriate imine [I.Rault, S.Rault and .Robba, Tetrahedron Lett., 1993, 34, 1929-1930; (b) I.Rault, M.-P.Foloppe, S.Rault and M.Robba Heterocycles 1993, 36, 2059-2066], oximes [E.E.Garcia, J.G.Riley and R.I.Fryer, J. Org. Chem., 1968, 33, 1359-1363] and amides [(a) M.Boulouard, S.Rault, A.Alsaidi, P.Dallemagne and M.Robba, J. Heterocycl. Chem., 1995, 32, 1719-1724; (b) M.Boulouard, S.Rault, P.Dallemagne, A.Alsaidi and M.Robba, J. Heterocycl. Chem., 1996, 33, 87-91].

The main disadvantage of the methods described here refers to either the use of remote agents, or a multi-stage process that reduces the total yield of the target product.

A method of obtaining derivatives pyrrolo[1,2-α][1,4]diazepine, annulirovano with aromatic and heteroaromatic ring [RF patent №2323939 Way to obtain derivatives pyrrolo[1,2-α][1,4]diazepine // Butin AV, Stroganova T.A., Basil VK, Krapivin GD, Nevolin T.A.]. The basis of this method lies acid-catalyzed management furan ring furfurylamine aromatic or heteroaromatic carboxylic acids containing in ortho-position to the amino group, which can simultaneously generate both diazepinones and pyrrole cycle.

In particular, to obtain 1-methyl-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]-diazepin-6-it 1A as starting compound used is 5-methylpyrrolidone 2-aminobenzoic acid 3A, which was obtained from 5-methylpentylamino 2-nitrobenzoic acid 2A during the recovery of hydrazine hydrate in the presence of Raney Nickel. When is provedenii reaction recyclization in acetic acid in the presence of conc. hydrochloric acid at 60-70°C for 10-15 minutes yield of the target product was 47% [RF patent №2323939 Way to obtain derivatives pyrrolo[1,2-α][1,4]diazepine // Butin AV, Stroganova T.A., Basil VK, Krapivin GD, Nevolin T.A.].

The main disadvantage of this method is the impossibility of obtaining derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]diazepin-6-it 1, containing substituents R1, R2or R=t-Bu, and low output 1 containing substituent R3.

ConnectionRR1R2R3
andCH3HHH
bt-BuHHH
inCH3CH3HH
gCH3C6H5 HH
dCH3HCH3H
eCH3Hp-ClC6H4H
WCH3HHCH3

Thus, the reaction of recyclization of furfurylamine I (R3=Me) in these conditions leads to a significant reduction of the output pyrrolobenzoxazepine 1G to 11%. When using as a substrate of N-furfurylamine 3b-e, the formation of the corresponding target products was not observed.

The objective of the invention is to develop a new method of obtaining derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]diazepin-6-it 1, containing different substituents R, R1, R2, R3.

The technical result is to ensure the simultaneous formation of pyrrole and diazepinones rings and increase the yield of the final products due to a change in the sequence of reactions and conditions.

The technical result is achieved by the fact that in the process for manufacturing adnych 5,6-dihydro-4H-benzo [f]pyrrolo [1,2-α] [1,4] diazepin-6-it 1, including the formation of pyrrolidinedione frame in the reduction reaction of the nitro N-(2,5-DIOXOLANYL)-2-nitrobenzamide 4, the reaction is brought to a boil in acetic acid in the presence of iron and incubated for 60 minutes at room temperature.

Source derivatives of N-(2,5-DIOXOLANYL)-2-nitrobenzamide 4 (table 1) were obtained from 2-(2-nitrophenylacetonitrile)furan-2 in the acid-catalyzed reaction of opening the furan cycle [A.V.Butin, S.K.Smirnov, F.A.Tsiunchik, M.G.Uchuskin and I.V.Trushkov, Synthesis, 2008, No. 18, 2943-2952; T.A.Stroganova, A.V.Butin, V.K.Vasilin, T.A.Nevolina and G.D.Krapivin, Synlett, 2007, 1106-1108].

Experimentally it was found that the optimum condition for the simultaneous formation of pyrrolidinedione framework is to bring the reaction to boiling in acetic acid in the presence of iron and keeping at room temperature for 60 minutes. In this case it is possible not only to increase the outputs of compounds 1A, W to 81% and 80%, respectively, but also to find the derivatives of 5,6-dihydro-4H-benzo [f]pyrrolo[1,2-α] [1,4]diazepin-6-it with different substituents R, R1, R2, R3.

The technical result allows to expand the number of derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α] [1,4]diazepin-6-it.

Thus, the set of essential features set forth in the claims, allowed yet to achieve the desired technical result.

The identity and structure of the synthesized compounds 1 confirmed1H,13C NMR spectroscopy and elemental analysis (table 2).

Examples of the implementation of the proposed method obtain 1-methyl-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α] [1,4]-diazepin-6-it 1A:

Example 1

1-methyl-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]-diazepin-6-he (1A)

To a solution of the compound (4A) (1 g, 3.6 mmol) in glacial acetic acid (20 ml) was added iron (3 g) and bring to a boil, then incubated 60 min at room temperature. The reaction mixture was poured into water (100 ml) and neutralized with sodium bicarbonate to pH~7. The precipitation is filtered off and thoroughly washed with hot ethyl acetate (5×30 ml), not mixed with mother liquor. The combined organic extracts are dried and evaporated to dryness under reduced pressure; the residue is dissolved in a mixture of ethyl acetate-petroleum ether (1:2) and passed through a layer of silica gel. The purified solution is evaporated under reduced pressure to 1/3 the original volume and left to crystallize. Yield 81% (0.62 g).

TPL=235-236°C.

Found for C13H12N2O, %: C, 73.52; H, 5.45; N, 13.19.

Calculated: C, 73.57; H, 5.70; N, 13.20.

Range1H NMR (CDCl 3), (δ, m D. and coupling constants, J, Hz): 2.30 (s, 3H, Me), 4.09 (d,3J=6.0 Hz, 2H, CH2), 5.98-6.02 (m, 2H, HPyr), 7.26 (DD,3J=8.1 Hz,4J=1.2 Hz, 1H, HAr), 7.38 (DDD,3J=7.5 Hz,3J=7.8 Hz,4J=1.2 Hz, 1H, HAr), 7.54 (DDD,3J=7.5 Hz,3J=8.1 Hz,4J=1.5 Hz, 1H, HAr), 7.92 (Ust,3J=6.0 Hz, 1H, NH), 7.95 (DD,3J=7.8 Hz,4J=1.5 Hz, 1H, HAr).

Range13With NMR (CDCl3), (δ, m D.): 14.0, 38.0, 104.9, 109.5, 124.9, 126.2, 129.4 (2C), 131.2, 131.4, 132.7, 135.8, 170.7.

Example 2

To a solution of the compound (4A) (1 g, 3.6 mmol) in glacial acetic acid (20 ml) was added iron (1 g) and incubated for 60 hours at room temperature. The reaction mixture was poured into water (100 ml) and neutralized with sodium bicarbonate to pH~7. The precipitation is filtered off and thoroughly washed with hot ethyl acetate (5×30 ml), not mixed with mother liquor. The combined organic extracts are dried and evaporated to dryness under reduced pressure; the residue is dissolved in a mixture of ethyl acetate-petroleum ether (1:2) and passed through a layer of silica gel. The purified solution is evaporated under reduced pressure to 1/3 the original volume and left to crystallize. Yield 70% (0.53 g).

Example 3

To a solution of the compound (4A) (1 g, 3.6 mmol) in glacial acetic acid (20 ml) was added iron (3 g) and incubated for 48 hours at room temperature. The reaction mixture was poured into water (100 ml) and neutralize hydroc what rebonato sodium to pH~7. The precipitation is filtered off and thoroughly washed with hot ethyl acetate (5x30 ml), not mixed with mother liquor. The combined organic extracts are dried and evaporated to dryness under reduced pressure; the residue is dissolved in a mixture of ethyl acetate-petroleum ether (1:2) and passed through a layer of silica gel. The purified solution is evaporated under reduced pressure to 1/3 the original volume and left to crystallize. A 75% yield (0.57 g).

Example 4

To a solution of the compound (4A) (1 g, 3.6 mmol) in glacial acetic acid (20 ml) was added iron (5 g) and incubated for 48 hours at room temperature. The reaction mixture was poured into water (100 ml) and neutralized with sodium bicarbonate to pH~7. The precipitation is filtered off and thoroughly washed with hot ethyl acetate (5×30 ml), not mixed with mother liquor. The combined organic extracts are dried and evaporated to dryness under reduced pressure; the residue is dissolved in a mixture of ethyl acetate-petroleum ether (1:2) and passed through a layer of silica gel. The purified solution is evaporated under reduced pressure to 1/3 the original volume and left to crystallize. A 75% yield (0.57 g).

Example 5

To a solution of the compound (4A) (1 g, 3.6 mmol) in glacial acetic acid (20 ml) was added iron (1 g) and boiled for 60 minutes, the Reaction mixture was poured into water (100 ml) and neutralized with sodium bicarbonate to pH~7. Dropped out OS the iPod is filtered off and thoroughly washed with hot ethyl acetate (5x30 ml), not mixing with the mother liquor. The combined organic extracts are dried and evaporated to dryness under reduced pressure; the residue is dissolved in a mixture of ethyl acetate-petroleum ether (1:2) and passed through a layer of silica gel. The purified solution is evaporated under reduced pressure to 1/3 the original volume and left to crystallize. Yield 65% (0.49 g).

Example 6

To a solution of the compound (4A) (1 g, 3.6 mmol) in glacial acetic acid (20 ml) was added iron (3 g) and boil for 30 minutes. The reaction mixture was poured into water (100 ml) and neutralized with sodium bicarbonate to pH~7. The precipitation is filtered off and thoroughly washed with hot ethyl acetate (5×30 ml), not mixed with mother liquor. The combined organic extracts are dried and evaporated to dryness under reduced pressure; the residue is dissolved in a mixture of ethyl acetate-petroleum ether (1:2) and passed through a layer of silica gel. The purified solution is evaporated under reduced pressure to 1/3 the original volume and left to crystallize. Yield 76% (0.58 g).

As follows from the above examples, conducting the reaction at room temperature using different amounts of iron causes an increase in the duration of the process from 48 to 60 hours.

Boiling of the reaction mixture with 1 g of iron within 60 minutes leads to greater resinification of the reaction mixture and, as consequence, to decrease in the course of the target product. Less resinification and increased output pyrrolobenzoxazepine was observed by boiling the reaction mixture for 20-30 minutes using 3 g of iron. The best option is the use of iron in the amount of 3 g, bringing the reaction mixture to boiling and curing for 60 minutes at room temperature. In this case, the output of 1-methyl-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]-diazepin-6-he (1A) reaches 81%.

The claimed method received a number of derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]diazepin-6-it 1-W.

The method of obtaining derivatives of 5,6-dihydro-4H-benzo[f]pyrrolo[1,2-α][1,4]diazepin-6-it General formula 1,

ConnectionRR1R2R3
1ACH-HNN
16t-BuHHH
1BCH3CH3H H
1 gCH3With6H5HH
1DCH3HCH3H
1stCH3HR-l6H4H
1GCH3HHCH3

characterized in that the formation of pyrrolidinedione frame is the result of the reaction of the nitrogroup reduction of N-(2,5-DIOXOLANYL)-2-nitrobenzamide 4 in acetic acid in the presence of iron, the reaction is brought to a boil and incubated for 60 min at room temperature.



 

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55 cl, 19 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 5,6-dihydro-4H-benzo[f]pyrrolo[ 1,2-α][1,4]diazepin-6-one 1, involving moulding a pyrrolodiazepine frame as a result of reduction of nitro-groups of N-(2,5-dioxoalkyl)-2-nitrobenzamides 4, in acetic acid in the presence of iron while carrying out the reaction until boiling and holding for 60 minutes at room temperature.

EFFECT: simultaneous formation of a pyrrole and a diazepine ring, and high output of end products owing to change in the sequence and conditions of the reaction.

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and synthesis of heterocyclic compounds - 5,6-dihydro-7H-pyrrolo[1,2-d][1,4]benzodiazepin-6-one derivatives of formula 1a-e by boiling 2-amino-N-(2-furan-2-yl-phenyl)-acetamides in a mixture of glacial acetic acid and concentrated hydrochloric acid with subsequent treatment with sodium bicarbonate while boiling.

EFFECT: method is characterised by simple execution.

2 tbl, 5 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

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