Derived imidazo-[1,2-a]-benzimidazole - tool, providing cerebroprotective effect in radiation damage
The invention relates to the field of organic chemistry and medicine and relates to a derivative of imidazo-[1,2-a]-benzimidazole, specifically: 9-diethylaminoethyl-2-(3,4-dioksifenil)-imidazo-[1,2-a]-benzimidazole of dihydrobromide formula (I) providing cerebroprotective effect in radiation damage. The connection has a high activity. 8 table.
The invention relates to the pharmaceutical industry and for the expansion of the spectrum of pharmacological activity of synthetic derived imidazo-[1,2-a]-benzimidazole.
The closest pharmacological activity and mechanism of action is known concealer violations of cerebral circulation Cavinton (Vinpocetine).
Irradiation of animals was carried out on a standard therapeutic setting agate-With a dose of 2 Gy (gray) (power 0,0171 G/s, RIP 75 mm, box 2020, With60) [Goncharenko E. N., Kudryashov Y. B. Chemical protection against radiation injury. - M.: Publishing house of Moscow state University, 1985. - 248 S.].
The study cerebroprotective actions derived imidazo-[1,2-a]-benzimidazole was performed on the model of circulatory hypoxia of the brain, caused by occlusion of both common owls I. R. Oxygen starvation of the brain (experimental materials). - L.: Medgiz, 1949. - 48 S.].
The connection 1 and the comparison drug Cavinton was administered to irradiated rats for 14 days.
All animals were divided into 3 groups:
1-I series. 1 gr. control (irradiated); 2 gr. - product comparison Cavinton (5 mg/kg); 3 gr. connection 1 in a dose of 5 mg/kg
About the severity cerebroprotective activity was judged by the degree of survival of animals after 24, 48, 72 hours after playing hypoxia.
Control animals received an equivalent volume of isotonic sodium chloride intraperitoneally or orally.
The results of the experiments are presented in table. 1.
The research results show that compound 1 at a dose of 5 mg/kg in irradiated animals increases their survival rate three times compared with the control. This cerebroprotective effect of the studied compounds was more pronounced than the reverse (PL. 1).
The effect of compound 1 on cerebral blood flow (MK), the resistance vessels of the brain (SMS) and systemic blood pressure (SBP) was studied in anesthetized (teminal sodium, 40 mg/kg) irradiated rats polarographic method with registration direct manometric method, the resistance vessels of the brain was calculated mathematically [Study of cerebral blood flow in small laboratory animals. / Gayova M. D., Vereshchagin C. K., Abdul Wadoud Hazza Jasem, Miguel P. P. // Fiziol. Journe. Of the USSR. - 1985. - So 71, No. 9. - S. 1173-1175].
Autoregulatory response of cerebral vessels with a stepwise reduction of systemic arterial pressure was estimated by the change in flow rate of cerebral blood flow and the degree of resistance vessels of the brain. Calculation of the coefficient of autoregulation (CR) was performed according to a special formula [Moskalenko Yu E. Functional stability of the cerebral circulation system. // Fiziol. Journe. Of the USSR. - 1978. - So 64, No. 5, - S. 589-597, 654-659].
The experiments were carried out on 17 outbred rats male mass (165,0±5,0) grams contained in standard vivarium conditions. The test substance was administered orally at a dose of 5 mg/kg for 2 weeks.
Investigation of the effect of compounds 1 and Cavinton on cerebral blood flow and its autoregulation in irradiated animals was performed on the 14th day after radiation therapy with intraperitoneal injection of the investigated substances in a dose of 5 mg/kg
All animals were divided into 3 groups: 1 gr. control; 2 gr. - product comparison - reverse (5 mg is the Odile equivalent volume of isotonic solution of sodium chloride.
The experimental results showed that in rats 14 days after radiation exposure, a slight increase in MK, with significant increase in the GARDEN on average by 18.5% with indicators of non-irradiated animals (PL.2).
The analyzed connection statistically significantly increased MK on average (41,96,8)% compared to baseline levels. This SMS was decreased by (33,0±2,9)%, and the GARDEN was slightly down (7,51,6)% (table.3).
In these same conditions, the reverse was significantly increased MK (46,0±3,9)%, reducing the SMS to (30,7±1,4)%, while there was a slight decrease in the GARDEN (6,7±0,9)% (table.4).
Autoregulatory response of the cerebral vessels was detected in irradiated (14 days after radiation exposure) animals.
On the 14th day after radiation exposure at lower GARDEN to 60 mm RT.article observed preservation of autoregulatory responses of cerebral vessels. CR was equal (0,76±0,07). Further reduction of the GARDEN up to 40 mm RT.article reduced MK and SMS on(42,9±1,4)%, (55,3±4,3)% respectively. This CR was equal to (0,84±0,04). The lower GARDEN to 30 mm RT.article led to the death of the animal (PL.5).
Introduction the compounds contributed to the preservation autoregulatory reacts is on (45,3±3,4)% and (46,3±6,5)%, this CR was equal to (0,74±0,08) (table. 6), indicating that the preservation of autoregulation MK.
In these conditions, the introduction of Cavinton also contributed to the normalization of the autoregulatory reactions MK. The lower GARDEN to 40 mm RT.article significantly reduced MK and SMS on average (31,2±5,8)% and (64,1±3,7)%, respectively. CR was equal (0,87±0,06) (table. 7), indicating that preservation of autoregulation MK.
The study of the influence of the compounds on the structure of brain irradiated animals was performed by the method of optical microscopy, on the basis of the histopathology laboratory of the Pyatigorsk branch of the Bureau of forensic medical examination of the Stavropol territory. Mortification animals was carried out in diethyl ether at 3 and 14 days after radiation exposure. AutoUpdate brain were fixed in 10% neutral formalin and 70% ethanol. Prepared microtome sections were stained with hematoxylin-eosin and Nissly for differential diagnostics of protein synthetic function in neurotitan [Merkulov N. In. The rate of histological techniques. - M.: Medicine, 1962, 362].
The experiments were carried out on 28 white rats male Wistar mass (162,5±2,5) grams contained in the standard conditions vivari> the rats at 3 and 14 days after radiation exposure are found in violation of cerebral hemodynamics as manifested in morphotectonics intracerebral-subarachnoid shunting of blood, expressed arteriole-venular-capillary hyperemia, spongiosa, Ochakovo hemorrhage, the spasms of PIAL arterioles, legirovanii and separation of blood, RBC aggregation. Appear foci of necrosis, the breaker of nerve fibers. Draws attention to the lack of microglial cells around individual foci of necrosis, performing in the Central nervous system function system faguoqitirute of mononuclear cells.
The introduction of these compounds after exposure to radiation leads to the dominance of compensatory processes in cytopathogenic the relationship between brain structures over alterative. Compensatory-adaptive reactions was active functioning of subarachnoid-intracapillary collectors, motobreath sphincter around their mouths, regulating blood flow; forming pericardectomy spaces, communicating with the subarachnoid. There are signs paleometeorology: wall collectors for structuring resemble the structure of painovich granularized, according to morphological data, and blood rheology: no slackerdom, separation and stasis of blood. As a result of stabilization of the vascular wall is sharply reduced edema neuropile. Among neurons is dominated by cells with a clearly verifiable nuclear chromatin and conservation of the protein synthetic function. Around a single dark neurocytol visible foci of satellization. Tinctorially properties of nerve fibers is practically not changed. Near the myelin conductors witnessed consolidation of oligodendrocytes are involved in the synthesis of myelin. Alterative changes of brain structures is minimal.
According to the degree of morphological and pharmacological activity can be build in the following order: RU-185 > reverse.
Antioxidant effects of compounds 1 and Cavinton studied on the degree of accumulation of products of lipid peroxidation (in particular, malondialdehyde), which form colored products with thiobarbituric acid. The effect of compound 1 on the content of TBA-active products in arterial and venous blood of irradiated animals was assessed spectrophotometrically.
All animals were divided into 4 groups: 1 gr. - non-irradiated animals; 2 gr. - irradiated animals; CLASS="ptx2">To determine the antioxidant activity of tested compounds was administered within 2 weeks after radiation exposure. The indicators were determined at 14 days after radiation exposure.
The results of the experiments showed that in the control rats at 14 days after radiation exposure there was a reliable increase in the content of TBA-active products in arterial and venous blood in an average of 30.5 and 27.9%, respectively, compared to the group of non-irradiated animals (PL. 8).
The analyzed compound 1 significantly reduces the concentration of TBA-active products in arterial blood in an average of 47.5 and 49.8% compared to the control. In the venous blood concentration of TBA-active products decreased by 32.0 and 39.2%, respectively (table.8).
Similar to the introduction of Cavinton caused a significant decrease in the concentration of TBA-active products on average 22.4-22,2% (table.8).
Thus, the connection ROUX-185 and to a lesser extent, reverse oral introduction had a marked reduction in the concentration of TBA-active products in the blood of irradiated animals.
The research results show that the studied compound enhances functional stability of the system cerebral blood which indicates a stronger cerebroprotective and antioxidant action than the reverse.
Derivative 9-diethylaminoethyl-2-(3,4-dioksifenil)-imidazo-[1,2-a]-benzimidazole dihydrobromide
providing cerebroprotective effect in radiation damage.
< / BR>where In= N, CH3R= alkyl, IN1=N, CH3, Cl, co3m=0-8, n=0-2, X=residue of formula
< / BR>where Y= NH, O, B=H, H, CL, which may find application as antivalent-stabilizer for silver halide photographic emulsions sensitized carbocyanine dyes, as well as to methods of sensitizing silver halide emulsions and their use
< / BR>in which: R1is hydrogen, CI/C1-C4/ alkylamino,
C1-C12the alkyl may be substituted by one to three substituents: C1-C4alkoxy, C1-C4alkylthio, halogen, hydroxy, C1-C4cycloalkyl, benzoyloxy, fullam, phenyl, possibly substituted by nitro, one to three halogen, C1-C4alkyl groups or C1-C4alkoxy groups, carboxy, C1-C4alkoxycarbonyl, cyano or three/C1-C4/ alkylammonium a halide;
C3-C12alkenyl may be substituted by one to three substituents: C1-C4alkoxy, phenyl, halogen or C1-C4alkoxycarbonyl;
C3-C6cycloalkyl, can be substituted one to three C1-C4alkyl groups;
C3-C16the quinil may be substituted by one to three halogen or a cation;
R2is C1-C4by alkyl;
R3is C1-C4the alkyl or C3-C6cyclo is the best C1-C4cycloalkyl possibly replaced by stands;
B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;
R4is C1-C11the alkyl, chlorochilon or phenyl, possibly substituted with halogen, nitro or C1-C4by alkyl;
R5is C1-C4the alkyl or phenyl, possibly substituted C1-C4by alkyl;
X, Y and Z each independently is CR6, CR7R8, N or NR9with the proviso that at least one of X, Y and Z must be N or NR9;
configuration is either a simple bond or double bond with the proviso that when any of X, Y or Z is CR7R8or NR9then === configuration, attached to it, is a simple connection, with one proviso that at least one of the === configuration represents a simple bond;
R6, R7and R8are independently hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl may be substituted one is;
R9is hydrogen or C1-C4the alkyl possibly substituted by hydroxy or one to three halogen, C1-C4alkoxy groups, or C1-C4alkylthio groups;
Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;
their optical isomers, when R2and R3not the same or when R7and R8unequal;
their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation