Ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1'h-spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates and synthesis method thereof

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel derivatives of spiro{indeno[1,2-6]quinoline-6,3'-pyrroles} of formula where R=CH2Ph, Ph; X=H, Me, OMe. The invention also relates to a method for synthesis of the said compounds.

EFFECT: novel compounds, having analgesic activity, which can be used for synthesis of novel heterocyclic compounds, are obtained.

4 cl, 1 tbl

 

The invention relates to the field of organic chemistry, namely to new individual compounds of the class of Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole} and retrieval method that can be used as starting products for the synthesis of new heterocyclic systems.

Known structural analogues of the claimed compounds - ethyl 1'-benzyl-3,3-dimethyl-1,2'-dioxo-5'-phenyl-1',2,2',3,4,10-hexahydro-1H-Spiro[acridine-9,3'-pyrrole]-4'-carboxylates, which are products of the interaction of 5-phenyl-4-etoxycarbonyl-1H-pyrrole-2,3-diones with 3-(arylamino)-5,5-dimethylcyclohex-2-tonami formed according to the following scheme (Animalive, PSseries, L.p.lapteva, Rod // patent of the Russian Federation for the invention №2387651, IPC C07D 417/10, publ. 27.04.2010, bull. No. 12):

R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br

The disadvantages of this method include the inability to obtain ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates.

The objective of the invention is to develop a simple method for the synthesis of undescribed in the literature ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates and expand the Arsenal of means of influence on a living organism.

The task is carried out by reacting 5-phenyl-4-etoxycarbonyl-1H-pyrrole-2,3-diones with 3-aryl is Ino-1H-inden-1-areas in the ratio 1:1 in the environment of the solvent, followed by separation of the desired products, according to the following scheme:

I: R=CH2Ph (a)Ph (b);

II: X=H (a), Me (b), OMe ();

III: R-CH2Ph, X=H (a), Me (b), OMe (); R=Ph, X=H (g), Me (e), OMe (e).

The process is conducted at a temperature of 110-140°C, and the solvent used absolute toluene or other high-boiling inert aprotic solvents.

From the patent and technical literature were not identified ways to obtain ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates having similar characteristics with the claimed method, and it has not been used for the original products, solvents in which the reaction takes place, and the temperature, on what basis is it possible to make a conclusion on the compliance of the claimed technical solution the criterion of "novelty" and "inventive step".

The invention is illustrated by the following examples.

Example 1. Ethyl 1'-benzyl-4-methyl-3'7 dioxo-5'-phenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylate (IIIB).

To a solution of 1.0 mmol of 1-bezel-5-phenyl-4-etoxycarbonyl-1H-pyrrole-2,3-dione (Ia) in 20 ml of absolute toluene was added 1.0 mmol of 3-tolylamino-1H-inden-1-it (IIB), boiled for 5 h, cooled, the precipitate was filtered and recrystallized from ethyl acetate. Yield 62%, TPL 290-292°C. the Compound (IIIB), C36H28N2O4.

Found, %: C 78.17; H 5.1; N 4.93

Calculated, %: C 78.24; H, 5.11; N, 5.07.

The compound (IIIB) - orange crystalline substance, soluble in DMSO and DMF, insoluble in the usual organic solvents, insoluble in water and alkanes. Stable when stored under normal conditions.

In the IR spectrum of compound (IIIB), recorded in the form of paste in vaseline oil, are the bands of stretching vibrations of NH group in the form of a broad peak at 3200 cm-1, lactam carbonyl group C2'=O and ester carbonyl band at 1678 cm-1, ketonic carbonyl group C7=O at 1626 cm-1.

In the PMR spectrum of the compound (IIIB), recorded in solution in DMSO-d6besides the signals of the protons of aromatic rings present in the singlet protons of a methyl group at 2.24 ppm, two doublet protons of methylene group of the benzyl substituent at 4.57 and 4.61 ppm with a characteristic constant of the spin-spin interaction (J 16.7 Hz), a singlet proton of NH group at 10.96 ppm and a triplet, and multiplet, protons of methyl and methylene groups ethoxycarbonyl substituent at 0.61 and 3.58 ppm, respectively.

Example 2. Ethyl 4-methyl-3',7-dioxo-1',5'-diphenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylate (G).

To a solution of 1.0 mmol of 1,5-diphenyl-4-etoxycarbonyl-1H-pyrrole-2,3-dione (IB) in 20 ml of absolute toluene was added 1.0 mmol of 3-tolyl the Mino-1H-inden-1-it (IIB) was boiled for 8 h, was cooled, the precipitate was filtered and recrystallized from ethyl acetate. Yield 60%, TPL 307-308°C. the Compound (G) C35H26N2O4.

Found, %: C 78.09; H 4.95; N, 5.33.

Calculated, %: C 78.05; H, 4.87; N, 5.20.

Connection (G) - orange crystalline substance, soluble in DMSO and DMF, insoluble in the usual organic solvents, insoluble in water and alkanes. Stable when stored under normal conditions.

In the IR spectrum of compound (G)recorded in the form of paste in vaseline oil, are the bands of stretching vibrations of NH group in the form of a broad peak at 3200 cm-1, lactam carbonyl group C2'=O and ester carbonyl band at 1694 cm-1, ketonic carbonyl group C7=O at 1630 cm-1.

In the PMR spectrum of the compound (G)recorded in solution in DMSO-d6besides the signals of the protons of aromatic rings present in the singlet protons of a methyl group at 2.32 ppm, a singlet proton of NH group at 11.02 ppm and a triplet, and multiplet, protons of methyl and methylene groups ethoxycarbonyl substituent at 0.66 and 3.63 ppm, respectively.

Example 3. Pharmacological study of ethyl 1'-benzyl-3',7-dioxo-5'-phenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylate (IIIA) and ethyl 1'-benzyl-4-methoxy-3',7-dioxo-5'-phenyl-1,6-digit is -1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylate (V) for analgesic activity.

Evaluation of the analgesic properties of the compounds (IIIA, b) studied in outbred mice weighing 18-22 grams method of thermal stimulation "hot plate" Eddie and Leimbach (N.B. Eddy, Leimbarh D.J. - Pharmacol and.. Gher., 1953, 385-393). As the comparison drug used analgin (Medmaravis, "Drugs", vol. 1, str, M, Medicine, 1978).

Studies have shown (see table)that the compounds (IIIA, b) possess analgesic activity. Data on pharmacological activity of analogues of the claimed compounds in the available literature no.

Analgesic activity of the compounds (IIIA, b).
No. of connectionsDose, mg/kgDefensive reflex through
2 hours2.5 hours
Control 2% krahm. mucus508.95±0.7810.75±1.63
Analgin93 (U50)17.56±1.11
IIIa50 21.60±0.93
W50Is the 23.60±0.93

The proposed method is simple, one-step and allows you to get undescribed in the literature ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1'H-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates (IIIA-e) in good yields, which will be used as starting products for the synthesis of heterocyclic systems, and pharmacology as potential medicines.

1. Ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1 N-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates of General formula

where R=CH2Ph, Ph; X=H, Me, OMe.

2. The way to obtain ethyl 3',7-dioxo-5'-phenyl-1,6-dihydro-1 N-Spiro{indeno[1,2-b]quinoline-6,3'-pyrrole}-4'-carboxylates of General formula

where R=CH2Ph, Ph; X=H, Me, OMe,
characterized in that 5-phenyl-4-etoxycarbonyl-1H-pyrrole-2,3-diones are subjected to interaction with 3-arylamino-1H-inden-1-areas in the ratio 1:1 in the environment of high-boiling inert aprotic solvent, followed by separation of the desired products.

3. The method according to claim 2, characterized in that the process is conducted at a temperature of 110-140°C.

4. The method according to claim 2 or 3, characterized in that the solvent used strictly the cosy toluene.



 

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20 cl, 505 ex, 4 tbl

FIELD: chemistry.

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15 cl, 257 ex

FIELD: chemistry.

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38 cl, 186 ex

FIELD: medicine, pharmaceutics.

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12 cl, 6 dwg, 16 ex

FIELD: chemistry.

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11 cl, 1 tbl, 69 ex

FIELD: medicine.

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22 cl, 42 ex

FIELD: medicine, pharmaceutics.

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22 cl, 4 dwg, 16 ex

FIELD: chemistry.

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11 cl, 8 ex, 1 tbl

FIELD: chemistry.

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37 cl, 1 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: described are spirocyclic derivatives of cyclohexane of general formula . Values of radicals are given in the formula of invention. The compounds have affinity to the ORL1 receptor and can be used for treating abstinence syndrome (withdrawal syndrome) and pain. Also described is a medicinal agent and use of formula (I) compounds for preparing respective medicinal agents.

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13 cl, 17 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns application of 8-(trifluoromethyl)benzo[f] [1,2,3,4,5]pentathiepin-6-amine of formula 1 as an analgesic.

EFFECT: agent show high activity and low toxicity.

2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, obstetrics, gynecology and includes estimation of puerperas' state, depending on which treatment tactics is selected. Severity of state is estimated by two groups of criteria of table No 3, presented in the description, by 1 point: absence of factors of risk of purulent-septic complications (PSC), subfebrile condition with single rise to 38°C, arrested by antibacterial therapy (ABT), absence of easily arrested intestine paresis after Cesarean section, the cervix of uterus is formed, presence of uterus involution in hysteroscopy at the background of treatment with endometrectomy or vacuum-aspiration, USE-data - increase and extension of uterus cavity by 0.5-1.0 cm, absence of deformation in the area of scar or deformation up to 0.5 cm, on uterus walls - linear echo-positive structures up to 0.2-0.3 cm thick, local sections of reduced myometrium echogenicity in the region of scars not larger than 1.5x1.5 cm, absence of infiltration, hematoma in the region of scars, improvement of laboratory indices in dynamics. Criteria of group 2 are estimated in 2 points: presence of PSC risk factors, long-lasting fever with resumption after finishing ABT, intestine paresis with absence of effect from intensive or repeated treatment courses, absence of tendency to formation of uterus cervix, stable uterus subinvolution, by USE data: extension of uterus cavity ≥1 cm, deformation in scar ≥0.5 cm, echopositive structures ≥0.4 cm, reduces echogenicity in scar zone ≥2.5×1.5 cm, hematoma or infiltrate in retrovesical space, in area of scars, absence of positive dynamics or change of laboratory indices to the worse. If state of puerpera is characterised by criteria of the first group to 7 points, it is estimated as uncomplicated form of disease, if - more than 7 points or at least by one criterion from group 2, as complicated form.

EFFECT: method ensures reliable justification of adequate tactics of patient management, strict control of their state in dynamics, reduction of frequency of complicated generalised forms of PSC, terms of staying in hospital.

2 ex, 3 tbl

Analgesic // 2452510

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is using hyaluronidase immobilised by electron-beam synthesis nanotechnology as an analgesic.

EFFECT: high analgesic activity of the declared agent (pain response inhibition - 66,5 %) more manifested than that shown by indometacin is shown.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and veterinary science. A pharmaceutical or veterinary paste-like composition for treating a bacterial infection in a recipient's body in need thereof contains: a) an effective amount of a therapeutic agent which is 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulphonyl)phenyl)- 5H-furan-2-one or 3-(cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulphonyl)phenyl)-5H-furan-2-one, or pharmaceutically accepted salts or hydrates of these compounds; b) colloidal silicon dioxide; c) a viscosity modifier specified in PEG 200, PEG 300, PEG 400, PEG 600, monoethanol amine, triethanol amine, glycerine, propylene glycol, polyoxyethylene sorbitan monooleate or poloxamers; d) if required, an absorbent; e) if required, a colouring substance; and f) a carrier. Methods of treating inflammation, pain or fever, rheumatoid arthritis or osteoarthritis involve introducing an effective amount of the paste-like composition in a recipient in need thereof. The group of inventions also involves a method for preparing the paste-like composition.

EFFECT: group of inventions provides the paste-like composition which does not require heating or cooling in the process of preparation and shows low or no sensitivity to deviations in the process of preparation and shows low or no sensitivity to temperature that enables long storage with minimum physical or chemical changes of the paste-like composition.

16 cl, 12 tbl, 9 ex, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula I where: R1 represents a group selected from among -CH2OH, -NH(CO)H while R2 represents a hydrogen atom or R1, together with R2, forms group -NH-C(O)-CH=CH- where the nitrogen atom is bonded to the carbon atom in the phenyl ring whereto R1 is bonded, the carbon atom bonded to the carbon atom in the phenyl ring whereto R2 is bonded; R3a and R3b are independently selected from the group consisting of hydrogen atoms and C1-4alkyl groups; X and Y are independently selected from the group consisting of an ordinary bond and an oxygen atom; n, m and q (each) independently have a value selected from among 0, 1, 2 and 3; p has a value selected from among 1, 2 and 3; R4 and R5 are independently selected from the group consisting of hydrogen atoms, a halogen atoms, C1-4alcoxy, -CONH2, -NHCONH2, -SR7, -SO2R7 where R7 represents C3-4cycloalkyl; R6 is selected from the group consisting of hydrogen atoms, a halogen atoms, C1-4 alkyl and C1-4alcoxy or its pharmaceutically acceptable salt or a stereoisomer thereof. Additionally, the invention relates to a pharmaceutical composition based on the compound with formula I and to a method for β2-adrenergic receptor activity modulation.

EFFECT: produced are new 4-(2-amino-1-hydroxiethyl) phenol derivatives possessing the activity of β2-adrenergic receptor antagonists.

22 cl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, in which: one of A, B, C and D denotes N, and the rest independently denote CH and C(R1); m equals a whole number from 1 to 4; n equals a whole number from 0 to 4; R1 denotes halogen; R2 and R3 denote hydrogen; R4 is selected from H, C1-6alkyl; Ar denotes aryl, optionally substituted with one or more halogen atoms; X denotes -C(Ra)(Rb)-, where Ra and Rb denote H; Y denotes -S(O)2-. The invention also relates to a pharmaceutical composition having CRTH2 receptor antagonist properties and containing a compound of formula I, to use of a compound of formula I when producing a drug for treating or preventing CRTH2 mediated diseases and a method for antagonistic action on CRTH2 receptor in mammals.

EFFECT: novel compound, which can be useful as a CRTH2 receptor antagonist, is obtained and described.

16 cl, 6 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

(where values of radicals are given in the claim), as well as salts of such compounds and pharmaceutical compositions based on such compounds. The described compounds exhibit type 1 channel antagonists with transient receptor potential (TRPV1).

EFFECT: compounds can be used to treat diseases and conditions causing pain.

30 cl, 255 ex, 40 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a pharmaceutical gel of ketoprofen with analgesic and anti-inflammatory action. The presented gel contains ketoprofen (1.0-6.0 wt %) and target additives: ethanol - 10.0-20.0 wt %, propyleneglycol - 10.0-20.0 wt %, UV filter Escalol 567 - 1.0-40.0 wt %, cyclomethicone DC 345 - 5.0-20.0 wt %, organosilicone emulsifier DC 5329 - 1.0-4.0 wt %, acrylate emulsion of copolymer Salcare SC80 - 1.0-3.5 wt %, trometamol - 1.0-2.5 wt %, fragrance - 0.2-0.4 wt %, preservative SHAROMIX MCI - 0.1-0.5 wt %, purified water - to 100.0 wt %.

EFFECT: due to said composition of target additives, the invention provides stabilisation of photosensitive ketoprofen and its improved penetration in derma, ethanol reduction in the gel, improved gel protection against microorganisms.

1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention describes 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-7H-pyrroles) and 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole) of the formula (I) (a, b, c) wherein Ar means C6H5 (a); p-C6H4OMe (b); p-C6H4Br (c) eliciting analgesic activity and related to substituted 13-aza-analogs of steroids, and to a method for their synthesis. Invention provides the development of a simple method of synthesis of 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrroles) related to 13-azagonanes - heterocyclic analogs of steroid comprising a spiro-heterocyclic substitute at position 16 of tetracyclic system among them compound 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole) elicits analgesic activity and these compounds have not been described. The proposed reaction represents a novel approach to synthesis of heterocyclic analogs of steroids.

EFFECT: improved method of synthesis, valuable medicinal property of compound.

2 tbl, 3 ex

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