3-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydroindazole hydrochloride, analgesic and antimicrobial agent

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely a new biologically active compound of indazole: 3-(3,4-dimethoxyphenyl)-4,5,6,7-tetahydroindazole hydrochloride (I) having formula presented above. The declared compound exhibit analgesic activity, twice less than Analgin and having higher action level. Furthermore, it exhibits high bacteriostatic activity on Staphylococcus aureus (3.8 mg/ml) and manifested bacteriostatic activity on Staphylococcus epidermidis (15.6-31.2 g/ml), Staphylococcus saprophyticus (250 mcg/ml) and the fungus Candida albicans (500-1000 mcg/ml) as well as bactericidal activity on these three species of staphylococci (62.5, 500 and 1000 mcg/ml respectively), having higher action level than phenyl salicylate. The compound (I) is referred to low-toxic (LD50=1500 mg/kg).

EFFECT: invention refers to analgesic and antimicrobial agents representing the compound (I).

3 cl, 2 tbl, 2 ex

 

The invention relates to the field of organic chemistry, namely, a new biologically active compound class indazole: 3-(3,4-acid)-4,5,6,7-tetrahydroindazole hydrochloride, problemem analgesic and antimicrobial activity, which enables it to offer its use in medicine as an analgesic and antibacterial agents.

In practical medicine known drug Metamizole (dipyrone), similar drugs (analgesic) effect [Mashkovsky PPM Medicines, 16th ed. - M, the New Wave: the publisher Merenkov, 2010, 164-165]. Antimicrobial action similar drug fenilsalitsilat [ibid, s-951].

Similar in structure to the expected compounds are 1,3-diarylalkylarsines (indazols), a cyclo-oxygenase inhibitors and anti-inflammatory agents (see Ferro M, Sui Z., M. Wachter Preparation of 1,3 and 2,3-diarylcycloalkano and cycloalkeno pyrazoles as selective inhibitors of cyclooxygenase-2 and antiflammatory agents, Pat. US 6083969; Chem. Abstracts, 2000, Vol.133, No. 7, 89521f). Nearest among them the analog has the following structure:

Information on analgesic and antimicrobial activity of analogues are missing.

More close structural analogues of the claimed compounds taken for the prototype, are the Foundation of the General formula

where R =n-tolyl, n-nitrophenyl (see Michael A.G., Aliyev SG, N. Bazin, Pantyukhin A.A., wahren M.I., 2-Aroylcyclopropane in the synthesis of azoles, CHC, 2010, No. 6, s-911). The main difference in structure from the claimed compounds in that they contain other radicals and are the reason, not hydrochloride. Data about analgesic and antimicrobial activity of these compounds in the literature is not available.

The task of creating the invention is the expansion of the means of influence on a living organism.

The problem is solved by the synthesis of 3-(3,4-acid)-4,5,6,7-tetrahydroindazole hydrochloride (I) of the formula:

The problem is solved analgesic agent, representing 3-(3,4-Acid)-4,5,6,7-tetrahydroindazole hydrochloride (I) of the formula:

The problem is solved antimicrobial agent representing 3-(3,4-Acid)-4,5,6,7-tetrahydroindazole hydrochloride (I) of the formula:

Compound I is produced by interaction of 2-(3,4-dimethoxybenzoyl)-cyclohexanone with hydrazinehydrate in the environment of isopropanol at the boiling for 30 minutes, followed by separation of the target products by the known methods. The reaction proceeds according to the scheme below.

The method of obtaining the source diketone similar described by us previously (see Michael A.G., Aliyev SG, N. Bazin, Pantyukhin A.A., wahren M.I. 2-Aroylcyclopropane in the synthesis of azoles, CHC, 2010, No. 6, s-911).

The technical result is obtained when the invention is in obtaining low-toxic compounds with high yield and high analgesic and antimicrobial activity. The synthesis technique is simple, the original connection readily available.

Example 1. Synthesis of 3-(3,4-acid)-4,5,6,7-tetrahydroindazole hydrochloride (I). To a solution of 2.62 g (0.01 mol) of 2-(3,4-dimethoxybenzoyl)-cyclohexanone in 10 ml of boiling 2-propanol was added 0.7 ml (15 mmol) (0.015 mol) of a 70% solution of hydrazine hydrate is added. The mixture was boiled for 30 minutes, cooled to 20°C., diluted with 100 ml ice water, the precipitated precipitate was filtered, dried, dissolved in 150 ml of ethyl acetate and passing dry gaseous HCl was received of hydrochlorid (I), which was filtered, dried and recrystallized from 2-propanol. Yield 67%. Tpl.238-240°C. Compound I: C15H18N2O2·HCl.

Found, %: C 60.93; H 6.37; N, 9.58; Cl 12.03;

Calculated, %: C 61.11; N, 6.50; N, 9.51; Cl 8.93;

Compound I is a colorless crystalline substance, easily soluble in DMSO, DMF, chloroform, it is difficult soluble in water and alcohol. Stable when stored in normal conditions is.

In the IR spectrum of the founding of the compounds I, made in the paste in vaseline oil, are the bands of stretching vibrations of NH groups indazol cycle (3250 cm-1). Getting the Foundation of substance I: aqueous suspension is treated with excess of aqueous ammonia, the resulting base is filtered off, thoroughly rinsing with water, and dried.

Range PMR hydrochloride I shot in CDCl3(300 MHz, internal standard - GMDS. The spectrum contains (δ, ppm): 1.79-1.81 multiplet, 4H, 5,6-(CH2)2; 2.63-2.69 multiplet, 4H, 4-CH2and 7-CH2; 3.85 s, 3H, (CH3About) and 3.89 s, 3H, (CH3Oh); 6.85-7.10, multiplet (3H, Ar); 12.63 singlet (2NH+).

Pharmacological studies suggested connections include determining acute toxicity, analgesic and antimicrobial activity.

Example 2. The primary stage of the research was to study the compound (I) on acute toxicity. Toxicity was studied on white mice (females) weighing 16-18 g. after a single oral administration. The observation was conducted for 6 days, daily behavior was noted and the death of animals (Belenky, M. elements of a quantitative evaluation of the pharmacological effect. - L.: Medgiz, 1963).

Evaluation of the analgesic properties studied in outbred mice weighing 18-22 grams method of thermal stimulation "hot plate" Eddie and Leimbach (N.B. Eddy, Leimbah D.J.-Pharmacol and.. Ther. 193, 385-393).

The study drugs were injected intraperitoneally as a suspension in 2% starch mucilage in the dose of 50 mg/kg In the intact animal the latent period of the defensive reflex does not exceed 10 seconds. Measure of pain sensitivity was the duration of stay of the animal on the hot plate until the licking of the hind paws, measured in seconds.

As a standard drug used Metamizole (dipyrone). The results of the experiment are presented in table 1.

Table 1
Evaluation of analgesic activity of compound (I).
№ p/pConnectionNumber of animals in the experiment (n)Dose and route of administration mg/kg(LD50), MG/KG orallyDefensive reflex 2.5 hours
1.In=101500 mg/kg orally1500.22,60±1,44
2.Control 2% krahm. mucusn=6 50 mg/kg b/W-of 10.75±1,63
3.Analginn=6*93 mg/kg (U50),/b*330016,33±3,02
*Values U50and LD50for dipyrone is taken from the book: Sigidin AA, Schwartz GY, Arzamastsev A.P., Lieberman S. Drug therapy of the inflammatory process: Experimental and clinical pharmacology of anti-inflammatory drugs. M.: Medicine, 1988. - 240 S.

As can be seen from the table, the claimed connection increases the defensive reflex to 22,60±1.44 minutes, which is higher than the comparison drug dipyrone (16,33±3,02 minutes). It should be noted that the tested dose of dipyrone (93 mg/kg) is almost 2 times higher than the dose of compound (I) (50 mg/ml). Thus, the test compound compared with dipyrone is more active in 2 times. As described in the literature, analgin compared with the proposed connection is less toxic (LD50=3300 mg/ml). The compound (I) for this value is set to 1500 mg/ml). At the same time, according to the classification Via it is low-toxic, which makes it promising in the quality drug.

Example. 3 Antimicrobial activity.

To determine the antimicrobial activity used conventional method twofold serial dilution (Pershin GN. Methods of experimental chemotherapy. - M.: Medicine, 1971, pp.109). Antimicrobial properties were determined on 4 Museum strains obtained from the collection of the fsri gisk named after. Lautareasca of Rospotrebnadzor (Moscow): Staphylococcus aureus (strain 906), Staphylococcus epidermidis (strain 52186), Staphylococcus saprophyticus (strain 15305) and Candida albicans No. ATCC 24433. The experiments were started with the preparation of initial dilution in nutrient broth Museum of microorganisms from daily agar culture optical standard sample turbidity (CCA) 10 ME. Microbial load corresponded to a 2.5×105microbial cells in 1 ml of Microbial suspension was made in the prepared cultivation of the drug in the medium (the compound was dissolved in 0.5 ml DMSO). The fact of inhibition (inhibition) the growth of bacteria and yeast-like fungi was observed after 20-hour incubation at 37°C.

The results of the bactericidal effect was recorded after 7 days at 37°C, and finally after seeding on a solid beveled agar (RPA). The maximum tested concentration of compounds corresponded to 1 000,0 µg/ml Antimicrobial (inhibitory and bactericidal) activity was estimated by the minimum valid concentration.

P the results of the experiment are presented in table 2. As can be seen from the table, compound I inhibits the growth of Staphylococcus aureus at a concentration of 3.9 ág/ml, epidermal Staphylococcus - >15,6<31,2 µg/ml, saprophytic staphylococci - 250 µg/ml Corresponding to a bactericidal effect in respect of these crops is 62.5, 500 >1000 μg/ml Compound inhibits the growth of a culture of Candida Albicans in the range of >500<1000 μg/ml, the bactericidal effect was not found.

Table 2.
Research results of compound (I) on the Antimicrobial activity
№ p/pThe number of connectionsSt. aureusSt. epidermidisSt. saprophyticusCand. albicans
MICK*MBq**MICK*MBq**MICK*MBq**MICK*MBq**
1.E-7a 3.962,5>the 15.6<31,2 500,0250,0>1000,0>500,0<1000,0-
2.Fenilsalitsilat7502000>1000, 0>1000, 0>1000, 0>1000,0--
3.Control DMSOgrowthgrowthgrowthgrowth
Note: *MIC - minimum inhibitory concentration, μg/ml;
**MBC - minimum bactericidal concentration, µg/ml;
(-) - absence of antimicrobial action.
results for ACA on St. aureus obtained on the sample 22. 06. 2010(per. room 1480 YENI PSUNR)

Drug comparison fenilsalitsilat shows weak activity against Staphylococcus aureus (750 mg/ml)in respect of the OS the social species of Staphylococcus he practically inactive, in the inactive against Candida albicans.

Thus, the proposed connection shows analgesic activity, almost 2 times higher than dipyrone. In addition, it exhibits a high bacteriostatic activity against Staphylococcus aureus and expressed bakteriostaticescuu activity against Staphylococcus epidermidis, Staphylococcus saprophyticus, and the fungus Candida albicans, as well as bactericidal activity against three species of staphylococci, surpassing the level of action fenilsalitsilat. Connection refers to low-toxic. Considering the fact that the compound (I) exceeds the level of action of drugs used in medical practice, it may find application in medicine as an analgesic and antibacterial agents.

1. 3-(3,4-Acid)-4,5,6,7-tetrahydroindazole hydrochloride (I) of the formula:

2. Analgesic agent representing 3-(3,4-acid)-4,5,6,7-tetrahydroindazole hydrochloride (I) of the formula:

3. An antimicrobial agent representing 3-(3,4-acid)-4,5,6,7-tetrahydroindazole hydrochloride (I) of the formula:



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel biologically active indazole compounds: 3-(2-bromophenyl)-4,5,6,7-tetrahydroindazole hydrochloride (1a) and 3-benzyl-4,5,6,7-tetrahydroindazole hydrochloride (1b) of general formula: Ia, b (R=C6H4Br-2 (a), CH2C6H5 (b)). The invention also relates to an antimicrobial agent based on compounds of formula (1a) or (1b).

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2 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely a new biologically active indazole compound - 3-(1-naphthylmethyl)-4,5,6,7-tetrahydroindazole hydrochloride of formula 1. The compound 1 is produced by reaction of 2-(1-naphthylacetyl)-cyclohexane and hydrazine hydrate in the isopropanol medium in boiling followed by end product recovery by common techniques. The compound 1 represents a colourless crystalline substance, easily soluble in DMSO and DMFA, poorly soluble in water, alcohol, chloroform. The invention also refers to an agent exhibiting antimicrobial action.

EFFECT: compound 1 exhibits manifested S aureus strain inhibitory action and inhibits their growth in the concentration of 0,5 mcg/ml, shows bactericidal effect in the concentration of 2,0 mcg/ml, as well as inhibits the growth of Candida albicans in the concentration of 2 mcg/ml and kills the strain in the concentration of 62,5 mcg/ml oral LD50 makes more than 1000,0 mg/kg.

2 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

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16 cl, 318 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

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22 cl, 3 tbl, 29 ex

FIELD: chemistry.

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21 cl, 645 ex

FIELD: medicine, pharmaceutics.

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29 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

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12 cl, 13 ex

FIELD: chemistry.

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65 cl, 611 ex, 27 tbl

FIELD: chemistry.

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15 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

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7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: invention provides reduced spontaneous thrombocyte aggregation, inflammation inhibition by reducing histamine secretion, cell protection against neurotoxic actions of thrombin.

1 cl, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: higher anti-inflammatory activity.

13 cl, 10 dwg, 9 tbl

FIELD: medicine, pharmaceutics.

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4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as heparan sulphate-binding protein inhibitors. The invention also refers to a pharmaceutical or veterinary composition having heparan sulphate-binding protein inhibitory activity for preventing or treating a disorder in a mammal, and to the use of these compounds and compositions for antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic therapy in a mammal.

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10 cl, 31 ex, 11 tbl, 40 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an aminopropylidene derivative presented by formula wherein R1 and R2, which may be identical or different, represent hydrogen or a substitute specified in the following (a)-(c), provided the case of both representing hydrogen is excluded: (a) carbonyl substituted with hydroxy, alkoxy or hydroxy alkylamino, (b) carbonylalkyl substituted by hydroxy or alkoxy, and (c) acrylic acid including its alkyl ester, R3 and R4, which may be identical or different, represent hydrogen, alkyl which may be substituted by phenyl or cycloalkyl, or R3 and R4, which together form a heterocyclic ring with a nitrogen atom bound thereto, represent pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinyl substituted by alkyl or penyl, morpholino or thiomorpholino; A means oxo or is absento, B represents canbon or oxygen; one of X and Y represents carbon, while the other one represents sulphur, a part represented by a dash line represents a single bond or a double bond, and a wavy line represents a cys-form and/or a transform. Also, the invention refers to a pharmaceutical composition exhibiting histamine receptor antagonist activity on the basis of said compounds.

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10 cl, 12 tbl, 58 ex

FIELD: medicine, pharmaceutics.

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EFFECT: new pharmaceutical composition is characterised by a wide spectrum of pharmacological properties, stability, uniform distribution of the active ingredients.

9 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I) presented below wherein the radicals and symbols have the values presented in the patent claim, and/or to its racemate, enantiomer, diastereomers or its pharmaceutically acceptable salts and/or esters. The invention also refers to a method for preparing it, using it in preparing a drug preparation and to drug preparations containing the compound of formula (I).

EFFECT: compound of formula has analgesic action and may be used as an active compound for pain management.

20 cl, 3 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound having formula (I): wherein each of the groups R1, R2, R3 are independently H or C1-4 alkyl group or C2-4 acyl group; each of the groups R4 and R5 are independently H or the group of formula -SO3R6, wherein R6 is H or the C1-4 alkyl group or the C2-4 acyl group; provided at least one of the groups R4 and R5 is a group having formula -SO3R6, or a pharmaceutically acceptable salt thereof. The invention also refers to a method for preparing the specified compounds of formula (I) and a pharmaceutical composition possessing activity in the inhibition of IL-1 anti-inflammatory cytokines based on these compounds.

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for treating an inflammatory or autoimmune condition.

17 cl, 4 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology and immunology. Claimed is medication for treatment and prevention of TNF-dependent disorder, which contains molecule of TNF-binding nanobody, lyoprotector, surface-active substance and buffer, method of such medication obtaining, method of lyophilised preparation reduction and method of analysis of medication-manufacturing process, as well as method and set for treatment or prevention of TNF-dependent disorder.

EFFECT: invention ensures obtaining stable pharmaceutical preparations of TNF-binding nanobodies and can be applied in therapy of TNF-dependent diseases.

30 cl, 12 ex, 3 tbl, 32 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine and may be used to improve the adaptation possibilities and to correct the psychofunctional state in the patients with harmful working conditions. That is ensured by recommending a relaxed or partial load or motion state. Health food from Diet No.5, intake of low-mineralised (3.7 g/dm3) low-carbonate sulphate-hydrocarbonate sodium-calcium mineral water of 'Slavyanovskaya' source (Zheleznovodsk mineral water), 3.3 g/kg of body weight (200-250 ml) per one intake, 45 minutes before meals, 3 times a day. The patient takes baths with mineral water of the same composition at water temperature 36-37°C for 15 minutes, every second day, in the therapeutic course consisting of 10 procedures. The aromatherapy-assisted psychological autotraining sessions are prescribed for 14 days. Furthermore, Adaptol is prescribed for 14-day intake in a dose of 500 mg 3 times a day.

EFFECT: invention provides an improved adaptation, autonomic regulation, peroxide homeostasis, digestive functions, mental and emotional status of the patients exposed to the adverse effects of environmental factors due to the integrated treatment.

5 tbl, 3 ex

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