Method of obtaining derivatives of 8h-thieno[2,3-b]indole

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of obtaining derivatives of 8-thieno[2,3-b]indole of general formula I and can be used for obtaining biologically active substances. Method is characterised by the fact that derivatives of 2-alkyl-5-(2-isothiocyanoaryl)furanes are mixed in 1,2-dichloroethane in presence of aluminium chloride with molar ratio of initial substance and aluminium chloride 1:1÷1:2 at temperature from room temperature to temperature of 1,2-dichloroethane boiling for from 30 min to 48 hours. I a-e, Ia R1 = H, R2 = CH3, b R1 = H, R2 = CH2CH3, c R1 = CI, R2 = CH3, d R1 = CH3, R2 = CH3, e R1 = OCH3, R2 = CH3.

EFFECT: extension of series of potentially biologically active derivatives of the said agent.

1 cl, 6 ex, 3 tbl

 

The invention relates to the field of organic chemistry - synthesis of heterocyclic compounds - derivatives of 8H-thieno[2,3-b]indole of interest to obtain new drugs for agricultural purposes.

The invention relates to a developing method of obtaining derivatives 8H-thieno[2,3-b]indole of General formula I, which can be used in the synthesis of analogues of natural plant growth regulator - teodelina [Kanbe, K.; Okamura, M.; Hattori, S.; Naganawa, H.; Hamada, M.; Okami, Y.; Takeuchi, T. Biosci. Biotech. Biochem. 1993, 57, 632; Kanbe, K.; Naganawa, H.; Nakamura, K.T.; Okami, Y.; Takeuchi, T. Biosci. Biotech. Biochem. 1993, 57, 636].

Ia R1=H, R2=CH3b R1=H, R2=CH2CH3; R1=CI, R2=CH3d R1=CH3, R2=CH3; d R1=OCH3, R2=CH3.

Heterocyclic system 8H-thieno[2,3-b]indole is poorly studied to date are only a few methods available for its synthesis. However, compounds containing in their structure the frame, perspective from the point of view of their practical application. In particular, 6-chloro-8H-thieno[2,3-b]indol-2-carboxamid - natural alkaloid teodorin with astragalina activity for plants, was isolated from Streptomyces albogriseolus and fully characterized a group of Japanese researchers in the early 1990-ies [Kanbe, K.; Okamur, M.; Hattori, S.; Naganawa, H.; Hamada, M.; Okami, Y.; Takeuchi, T. Biosci. Biotech. Biochem. 1993, 57, 632; Kanbe, K.; Naganawa, H.; Nakamura, K.T.; Okami, Y.; Takeuchi, T. Biosci. Biotech. Biochem. 1993, 57, 636]. It is known also that he himself 8H-thieno[2,3-b]indole shows antifungal activity [Pedras, M. S.; Suchy, M. Bioorg. Med. Chem. 2006, 14, 714].

As mentioned above, information about the synthesis of derivatives of 8H-thieno[2,3-b]indole is very limited, and existing methods are divided into two groups. The first group includes the synthesis, in which the source are compounds comprising in their structure indole fragment, and completed thiophene nucleus [Levy, J.; Royer, D.; Guilhem, J.; Cesario, M.; Pascard, C. Bull. Soc. Chim. France 1987, 193; Olesen, P. H.; Hansen, J. C.; Engelstoft, M. J. Heterocyclic Chem. 1995, 32, 1641; Engqvist, R.; Javaid, A.; Bergman, J. Eur. J. Org. Chem. 2004; 2589.; Majumdar, K. C; Alam, S.J. Chem. Res. Synop. 2006, 289.]. Methods of the second group based on intramolecular cyclization of derivatives of 2-nitrophenyl-3-thiophene, leading to the construction of the pyrrole cycle between aromatic and thiophene nuclei [Smitrovich, J. N.; Davies, I. V. Org. Lett. 2004, 4, 533; Appukkuttan, P.; Van der Eycken, E.; Dehaen, W. Synlett 2005; 127.].

The disadvantages of the described methods is either a multi-stage process, or inaccessibility of raw materials.

The technical result is the synthesis of derivatives of 8H-thieno[2,3-b]indole (I, based on the electrophilic recyclization furan cycle 2-alkyl-5-(2-isothiocyanate)furan III, allowing you to extend the range of the pot is sciolino biologically active substances and represents a convenient starting compound for the synthesis of analogues of the natural alkaloid teodorin.

To achieve a technical result, in the method of obtaining derivatives 8H-thieno[2,3-b]indole of General formula I

Ia R1=H, R2=CH3b R1=H, R2=CH2CH3; R1=CI, R2=CH3d R1=CH3, R2=CH3; d R1=OCH3, R2=CH3.

2-alkyl-5-(2-isothiocyanate)furans III are stirred in 1,2-dichloroethane in the presence of aluminum chloride in a molar ratio of the initial substance and aluminum chloride 1:1÷1:2 at a temperature of from room temperature up to the boiling point of 1,2-dichloroethane from 30 minutes to 48 hours.

The proposed method for the synthesis of derivatives 8H-thieno[2,3-b]indole based on the reaction of electrophilic disclosure and subsequent recyclization furan ring 2-alkyl-5-(2-isothiocyanate)furans. However furan cycle during recyclization involved in the construction at the same time and pyrrole and thiophene rings.

The original 2-alkyl-5-(2-isothiocyanate)furans III can easily be obtained by known methods [Abaev, V..; Tsiunchik, F.A.; Gutnov, .V.; Butin, .V. Tetrahedron Lett. 2006, 47, 4029.] available amines II [Butin, .V. Tetrahedron Lett. 2006,47,4113.]:

II-III a R1=H, R2=N; b R1=H, R2=CH3; R1=CI, R2=H; R1=CH3, R2=CH3; d R1=OCH , R2=CH3.

The melting temperature, the data of elemental analysis and spectral characteristics of 2-alkyl-5-(2-isothiocyanate)furans IIIa-d are shown in table 1.

The technical result allows to expand the number of derivatives 8H-thieno[2,3-b]indole, and thus the range of potentially biologically active compounds.

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

Examples of the proposed method of obtaining 2-(8H-thieno[2,3-b]indolyl)ethane-2-he Ia:

Example 1.

A mixture of 1.29 g (6 mmol) of 2-methyl-5-(2-isothiocyanate)furan, 0.8 g (6 mmol) of aluminum chloride and 30 ml of 1,2-dichloroethane is stirred for 48 hours at room temperature. Then the reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (2×40 ml), the combined organic fractions are dried with sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of benzene/hexane. Exit 18% (0.23 g).

MP.=199-201°C.

Found for C12H9NOS, %: C, 67.07; N, 4.10; N, 6.64

Calculated: C, 66.95; N, 4.21; N, 6.51

Range1H NMR (DMSO-D6), (δ, M. D. and coupling constants,J, Hz): 2.55 (s, 3H, CH3), 7.16-7.20 (m, 1H, HAr), 7.26-7.30 (m, 1H, HAr), 7.50-7.53 (m, 1H, HAr), 7.86-7.89 (m, 1H, HAr), 8.37 (s, 1H, HTh), 12.03 (s,1H, NH).

Range13With Yarm (DMSO-D6), (δ, M. D.): 25.7, 112.1, 119.4, 120.1, 122.0, 123.3, 124.7, 126.5, 136.1, 142.4, 147.5, 190.5

Example 2.

A mixture of 1.29 g (6 mmol) of 2-methyl-5-(2-isothiocyanate)furan, 0.8 g (6 mmol) of aluminum chloride and 30 ml of 1,2-dichloroethane is stirred for 30 hours at 50°C. Then the reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (2×40 ml), the combined organic fractions are dried with sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of benzene/hexane. Exit 17% (0.22 g).

Example 3.

A mixture of 1.29 g (6 mmol) of 2-methyl-5-(2-isothiocyanate)furan, 1.2 g (9 mmol) of aluminum chloride and 30 ml of 1,2-dichloroethane is stirred for 18 hours at 50°C. Then the reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (2×40 ml), the combined organic fractions are dried with sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of benzene/hexane. Exit 23% (0.3 g).

Example 4.

A mixture of 1.29 g (6 mmol) of 2-methyl-5-(2-isothiocyanate)furan, 1.6 g (12 mmol) of aluminum chloride and 30 ml of 1,2-dichloroethane is stirred for 3 hours 40 min at room temperature. Then the reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (2×40 ml), the combined organic fractions are dried with sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of benzene/hexane. Exit 42% (0.54 g).

Prima is 5.

A mixture of 1.29 g (6 mmol) of 2-methyl-5-(2-isothiocyanate)furan, 1.6 g (12 mmol) of aluminum chloride and 30 ml of 1,2-dichloroethane is stirred for 40 min at 50°C. Then the reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (2×40 ml), the combined organic fractions are dried with sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of benzene/hexane. Yield 58% (0.75 g).

Example 6.

A mixture of 1.29 g (6 mmol) of 2-methyl-5-(2-isothiocyanate)furan, 1.6 g (12 mmol) of aluminum chloride and 30 ml of 1,2-dichloroethane boil for 30 minutes Then the reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (2×40 ml), the combined organic fractions are dried with sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of benzene/hexane. Exit 40% (0.52 g).

Table 2 shows data on the effect of the number of aluminum chloride and the degree of heating of the reaction mixture to yield 2-(8H-thieno[2,3-b]indolyl)ethane-2-he Ia (examples 1-6).

Table 2

The influence of reaction conditions on the yield of 2(8H-thieno[2,3-b]indolyl)ethane-2-he Ia
ExampleRatio, molTemperature, °The reaction timeOutput %
Conn. IIIa-dAlC 3
111room48 hours18
2115030 PM17
311,55018 hours23
412room3 hours 40 min42
5125040 min58
612boiling30 min40

The use of aluminum chloride in the amount of < a twofold excess does not allow for the full conversion of the original isothiocyanate, resulting in the output of 8H-thieno[2,3-b]indoles of I does not exceed 23%. Boiling of the reaction mixture with a twofold excess of aluminum chloride leads to strong resinification of the reaction mixture.

Thus, the data of table 2 indicate that to obtain the derivatives of 8H-thieno[2,3-b]indole optimal I is carrying out the reaction in the processing isothioscyanates aluminium chloride in dichloromethane for 40 minutes.

The claimed method obtained a number of derivatives of 8H-thieno[2,3-b]indole Ia-d, the outputs of the melting temperature, the data cell battery (included) the private analysis and spectral parameters are given in table 3.

The method of obtaining derivatives of 8H-thieno[2,3-b]indole of General formula I

Ia) R1=N, R2=CH3b) R1=N, R2=CH2CH3in R1=Cl, R2=CH3, g) R1=CH3, R2=CH3d) R1=Co3, R2=CH3,

characterized by the fact that derivatives of 2-alkyl-5-(2-isothiocyanate)furans stirred in 1,2-dichloroethane in the presence of aluminum chloride in a molar ratio of the initial substance and aluminum chloride 1:1÷1:2 at a temperature of from room temperature up to the boiling point of 1,2-dichloroethane from 30 minutes to 48 hours



 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

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

6 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

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